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The Physiological and Pathophysiological Roles for Dietary Vitamin A and the Endogenous Retinoid System in the Kidney

The regulation of gene expression by vitamin A’s main endogenously bioactive form, retinoic acid, is a key process in diverse biological processes. The important role of RA signalling during embryonic development of the kidneys via its receptors is well documented, however the data regarding its role in the postnatal kidney is relatively lacking. Postnatal vitamin A deficiency is associated with complications in renal control of the acid-base balance state and is linked to urolithiasis, renal inflammation and scarring. Murine studies show that endogenous RA activity appears to be localised in the principal and intercalated cells of the collecting duct and continues to be active into adulthood. RA is also involved in acute kidney injury, whereby its interaction with renal macrophages and proximal tubular epithelial cells is thought to regulate post injury damage control and repair. In addition, RA is implicated in pathogenesis of chronic kidney disease, whereby a newly discovered connection between peroxisome proliferator activated proteins (PPARs) and RA receptor (RAR) is linked to a feature of chronic kidney disease, renal intestinal fibrosis, regardless of the primary cause. Alterations in metabolism of vitamin A is also linked to the pathogenesis of diabetic nephropathy. Furthermore, RA activity is deemed important in podocytopathies, whereby its activity is thought to ameliorate podocyte damage. Ultimately, due to the involvement of Vitamin A in various renal pathologies, there is increasing interest in utilising this vitamin for therapeutic purposes.

 


1. Introduction


 

More than a century has passed since the debut of investigations into the functional role of vitamin A (retinol) in human physiology (Semba 2012; Wolf 2001). The lack of endogenous vitamin A synthesising machinery in mammals, makes diet the critical source of this essential vitamin. The importance of vitamin A in kidney development, cellular differentiation and proliferation as well as regulation of inflammation is long established and investigated. Retinoic acid (RA), a key metabolite of vitamin A is linked to many important physiological functions, and as such it is also implicated in much pathology, ranging from cancer biology to skin and kidney disease (Das et al. 2014).

The retinoid system, which contains chemical compounds that are chemically related to vitamin A, plays an indispensible role during kidney development, namely nephrogenesis, however there remains much to be discovered regarding the role of endogenous RA activity in the postnatal kidney. Cases of post-natal vitamin A deficiency and subsequent profiling of gene expression in said cases have been beneficial in delineating possible associations between various kidney pathologies and the endogenous RA activity in the kidney.

During mid 1920s and later through today studies into the functional deficits of the kidneys in vitamin A deficiency have reported of increased renal tubular susceptibility towards certain renal pathologies such as polyuria, urolithiasis, calculogenesis, infections and renal scarring secondary to pyelonephritis (Woelfel et al. 1965; Van Leersum 1928; Dalirani et al. 2011; Dzhagalov et al. 2007), thus highlighting the significant of vitamin A in the renal system.

Here, we will look at the biochemistry of the retinoid system and attempt to highlight recent advances in understanding the role of endogenous retinoid activity in the post-natal kidney, with special focus on the role of RA signalling after and during acute kidney injury and on renal conditions that can lead to chronic kidney disease (CKD) such as diabetic nephropathy and podocytopathies.

 


2. Vitamin A & the Retinoid System


 

2.1 Retinoid Syntheses and Chemistry

RA signalling is an evolutionary conserved pathway that plays an indispensible role in diverse developmental and cellular functions in most metazoans. Dietary consumption of vitamin A (retinol) in forms of retinol, retinil esters or β-carotenes is the primary source of this compound, as mammals lack a natural mechanism for de novo retinoid biosynthesis. Vitamin A related compounds including its natural and synthetic analogues are referred to as retinoids, with each containing four isoprenoid units (Semba 2012).

The biochemical conversion of retinoids or carotenoids into RA takes place in a sequential manner, beginning in the intestine, then the liver and ultimately in the target cells; Currently, there are 6 active isoforms of retinol including all-trans (ATRA), 11-cis, 13-cis, 9,13-di-cis, 9-cis and 11, and 13-di-cis retinol, with ATRA being the most abundant form found in organisms (Napoli 1996). Retinoid transport is dependent on various binding proteins in serum and body fluids. Retinoid transport from liver to its target tissues is primarily mediated by retinol binding protein (RBP). These target-tissues contain tissue-specific proteins known as the cellular retinol binding proteins (CRBPs), which aid the incorporation of retinoids into the cells (Kawaguchi et al. 2007). Once retinoids are inside the cell in either form of RA or retinol molecules, it binds to another family of retinol-specific binding proteins that are involved in metabolism and nuclear import of RA, these are known as cellular acid retinoid binding proteins (CRABPs) (Zanotti & Berni 2004). RA catabolism is promoted by CRABP-I and its nuclear translocation is facilitated by CRABP-II for interaction with retinoid nuclear receptors (Fig.1) (Delva et al. 1999).

Animal derived retinyl esters can be hydrolysed to yield retinol. Retinyl esters are formed from the action of lecithin-retinol acyltransferase (LRAT) enzyme on the retinol-CRBPII complex, which acts as the substrate for said reaction (MacDonald & Ong 1988; Schweigert & Raila 2002). The hydrolysis of retinyl ester gives rise to retinol, which binds with RBP and is secreted into the serum, wherein by binding transthyretin (TTR) prevents its elimination by the kidney (Noy et al. 1992).

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Figure 1 | A. The conversion of retinol (vitamin A) into various forms of retinoic acid (RA) in presence of three main groups of enzymes. B. Retinoid action in the target cell. After being taken up from blood, retinol binds CRBP (cellular retinol binding protein) in the cytoplasm. The conversion of retinol to retinal is carried out by the retinol dehydrogenase, subsequently retinal is metabolised to RA by retinaldehyde dehydrogenases (RALDHs). CRABP (cellular RA-binding proteins) binds RA in the cytoplasm. RA entry in to the nucleus is followed by its binding to RA receptors (RARs) and retinoid X receptors (RXRs), which undergo hetero-dimerisation and bind the RARE (RA response-element) sequence of DNA to activate transcription of target gene (Adapted from Maden 2002).

  

2.2 Retinoid Metabolism

The conversion of retinols into retinyl ester occurs in presence of LRAT and is subsequently packaged into cytoplasmic lipid droplets (Blaner et al. 2009). The RBP receptor (also known as ‘stimulate by retinoic acid 6’ [STRA6]) mediates the uptake of the retinol-RBP-TTR complex in the plasma (Berry et al. 2012). Once in the target cell, free retinol is either bound to CRBP or is oxidised by retinol dehydrogenase (RDH) to give retinal. Consequently, retinaldehyde dehydrogenase (RALDH) coverts retinal to RA, whereby its successive binding to cellular RA binding protein (CRABP) facilitates its nuclear entry, allowing it to bind and act as a ligand for nuclear receptors such as RAR and RXR (Duester 2000).

 

2.3 Retinoid Receptors and Their Genomic Actions

Retinoid receptors are divided into two main families, with each containing three different receptor subtypes and distinct isoforms. These are the RA receptors (RARα, RARβ and RARγ) and the retinoid X receptors (RXRα, RXRβ and RXRγ). The availability of numerous subtypes and isoforms permits the assembly of large group of distinct receptor dimers. ATRA and 9-cis retinoic acid are both able to activate RARs, however, 9-cis retinoic acid is the only activator for RXR (Heyman et al. 1992). Nuclear retinoid receptors are ligand-activated transcription factors that exert their transcriptional function by binding DNA at RA response elements (RAREs) located in the promoters and enhancers of their target genes with high affinity. In addition to being self-sufficient homodimers, RXRs are able to form functional heterodimers with other type II nuclear receptors including RARs and proliferation peroxisome activated receptor (PPAR), FXR (farnesoid X receptor) and VDR (vitamin D receptor) receptors respectively (Evans & Mangelsdorf 2014).

Interactions of the ligand binding domains on each receptor are key in the process of receptor dimerization. The heterodimeric receptor is responsible for binding to the DNA at the RARE. However, if there is no ligand binding, the un-liganded RAR-RXR heterodimers recruit corepressors such as nuclear co-repressor 1 (NCOR1) and NCOR2, which go on to recruit histone deacetylase (HDAC) and Polycomb repressive complex 2 (PRC2), resulting in histone H3 lysine 27 trimethylation (H3K27me3), thus collectively causing chromatin condensation and silencing of gene transcription (Das et al. 2014).

Alternatively, the conformational change in the RAR-RXR heterodimer after ligand (RA) binding promotes the exchange of repressive factors for co-activators including nuclear receptor co-activator 1 (NCOA1), NCOA2 and NCOA3. The recruitment of these co-activators initiates the recruitment of histone acetylase (HAT) and Trithorax proteins, ultimately resulting in acetylation of histone proteins and aiding the decompression of the chromatin, thus kick-starting the transcription machinery (R. Blomhoff & H. K. Blomhoff 2006).

 


3. Endogenous Retinoid Activity in the Kidneys


 

For a long time, studies particularly in the field of developmental biology, have investigated the role and function of RA signalling in living organisms, analysing its various components including its receptors, target genes as well as it synthesising and metabolising enzymes (Duester 2008). Early studies in to RA activity in kidney development showed that maternal vitamin A deficiency results in rat foetuses with extreme kidney malformation (Wilson & Warkany 1948). Towards the end of the nineteenth century, researchers observed that compound mutants of RAR and RXR isotypes have impaired kidney development (Mendelsohn et al. 1994). This was followed by studies showing that omission of the key RA synthesising enzyme RALDH2 severely disrupts nephrogenesis (Niederreither et al. 1999). Therefore, there remains little doubt as to the importance of RA, this primary bioactive vitamin A derivative, in nephrogenesis and the devastating effects that its absence can have on renal development by disrupting the RA-RXR/RAR-RARE pathway (Niederreither et al. 2002).

On the other hand, despite the plethora of evidence for RA’s critical role in nephrogenesis, its post-embryonic activity and function in the kidney is less investigated. Although there are emerging data supporting the notion that endogenous RA activity continues to function long after nephrogenesis has completed; acting as an important housekeeping mechanism for the health of the postnatal kidney. High performance liquid chromatography (HPLC) has revealed the presence of endogenous RA activity in murine kidneys after birth (Xu et al. 2010; Maureen A Kane et al. 2008) & (Starkey et al. 2010), which is synthesised by RALDH1-4 locally (Bhat et al. 1998),(Lin et al. 2003).

The Nuclear Receptor Signalling Atlas (NURSA), which contains data on tissue specific expression level of nuclear receptors, shows that the two most commonly used strains of adult mice (C57BL/6J and 129X1/SvJ) express all six isotypes of RA receptors in their kidneys. In these two strains, the kidneys have exceptionally high levels of RARα expression followed by RARβ, albeit to a slightly lesser extent (Wong et al. 2011). The contemporary presence of endogenous RA and its apparatus has set precedence for studies seeking to prove the presence of transcriptionally active endogenous RA signalling in the kidneys after birth.

From an evolutionary perspective, if the role of RA activity was only limited to that of developmental phase, it would be logical for its transcriptional activity to cease after birth. However, current literature and existing evidence is a clear testament to the continuing activity of RA in the body, supported by the presence of it’s synthesising hormones as well as the retinoid nuclear receptors in various organs especially the kidneys (Wong et al. 2011).

RA activity is detected to be present in the cortical and medullary collecting ducts which are derived from the ureteric bud, starting from the neonatal stage and continuing into adulthood. Interestingly, both major cell types present in the collectingdducts, the principal and intercalated cells, both contain RA activity demonstrated by using specific markers for these tissues (Wong et al. 2011). The detection of expression of RARβ2, which is a direct target gene for RA in murine tubules, adds to the evidence for endogenous RA activity in the adult kidneys (Rosselot et al. 2010).

The regulation of acid-base balance and water transport is an important function of the collecting duct system, dependent on thepprincipal cells and the intercalated cells, respectively. Genetic investigations have shown that both cell types have the necessary machinery to support transcriptional activity of RA. In addition, the encoding gene for the water channel aquaporin 2 appears to contain a RAR/RXR, RXR/RXR, and PPAR/RXR recruiting element (Yu et al. 2009).

Disturbances of urinary pH and metabolites in experimental murine models which have post natal vitamin A deficiency is associated with increased risk of developing urolithiasis (Zile et al. 1972); (Grases et al. 1998) & (HIGGINS 1935). In addition the same models display glomerular and tubular basement membrane changes in their composition and structure, as well as altered cytokeratin expression in renal pelvic epithelium (Marín et al. 2005; Gijbels et al. 1992).

RA’s ability in stimulating kidney formation, has led many to postulate possible beneficial roles for this signalling molecule in postnatally acquire kidney injury by re-instigating the developmental platform (Kavukcu et al. 2001; Wagner 2001). Fin regeneration in zebrafish is dependent on endogenous RA activity (de Groh et al. 2010), if this regenerative power of endogenous RA activity is also applicable in murine kidneys, considering the fact the RA is detected in abundance in the collecting duct system which spans the whole kidney covering the cortex and inner medulla, makes it an exciting and plausible candidate as an instigator of a repair mechanism to deal with kidney injury in the collecting ducts and possibly other areas of the kidney.

Various studies have reported of altered endogenous retinoid system in various models of kidney disease including, glomerulonephritis (Liebler et al. 2004) and diabetic nephropathy (Starkey et al. 2010), whereby a reduced level of renal endogenous RA is observed in a number of said cases. These will be discussed in more depth during the course of this review.

It can be assumed that replacement of depleted endogenous RA activity in the kidney by exogenous RA can help in stopping disease progress. However there are contrasting data regarding the therapeutic value of exogenous RA in murine models of fibrotic kidney disease, whereby administration of high dose exogenous RA not only does not ameliorate, but also worsens kidney fibrosis (Xu et al. 2010). Careful analysis of the extent to which exogenous RA imitates the activity of endogenous RA can help in delineating the route and retinoid systems that exogenous RA activates in the body and whether the activation of this retinoid system elsewhere in the body apart from the kidneys leads to the destructive effects of exogenous RA. Current data is highly indicative of the presence of an intact and functioning retinoid system after birth, thus warranting further studies to further unravel the role of endogenous RA signalling and its target gene in kidney, especially in the collecting ducts.

 


4. Retinoic Acid in Kidney Disease


 

4.1 Acute Kidney Injury

There has been an increasing interest in the role of RA signalling during and after acute kidney injury. Using a mouse model of ischemia reperfusion induced acute kidney injury (IR-AKI) researchers have focused on delineating the possible roles of RA signalling in such situation. It is believed that after AKI, there is an activation of a signalling cascade that triggers and regulates macrophage dependent injury and repair (Chiba et al. 2016). Data from loss and gain of function studies suggests that reactivation of RA signalling serves to reduce the severity of tubular injury and the ensuing fibrosis after AKI, rather than re-enacting its embryological functions in form of proliferative repair (Chiba et al. 2015).

Furthermore, RA signalling inhibition is shown to increase fibrosis post-injury, but has negligible effect on tubular injury and no consequence on renal function post IR-AKI (Chiba et al. 2016). On the other hand, there is significant data supporting ATRA’s ability in reducing post injury fibrosis as well as limiting tubular injury and enhancing recovery after IR-AKI (Rankin et al. 2013). One explanation for this contrast between endogenous RA signalling and ATRA can be that there is an alternative mechanism through which exogenous RA acts, which is different to that of the intrinsic RA pathway in the post AKI kidney. Another reason can be related to the variations in the doses of ATRA used post IR-AKI, such that it may have a more profound effect than the reactivated intrinsic RA signalling pathway due to its higher bioavailability.

RA-dependent effects on renal injury are understood to be mediated by renal macrophages. There is ample controversy surrounding the role of resident renal mononuclear phagocytes in AKI, with data indicating both protective and detrimental functions. However, using transgenic mice a recent study by Ferenbach et al. 2012, has helped to resolve this argument by depleting either or both monocyte/mononuclear phagocytes before IR-AKI and observing the outcome. It was shown that when using liposomal clondronate which spares CD206-positive renal macrophages leaving CD11c-positive cells unscathed, resulted in marked reduction in renal failure and ischemia. This protective effect of clondronate may have manifested from a cyto-protective intrarenal population of mononuclear phagocytes that may be under the influence of RA signalling (Ferenbach et al. 2012).

Thus, with reference to these findings we can delineate the possible reason, and suggest a model, as to why inhibition of RA signalling in IR-AKI increases inflammatory macrophage dependent injury. It is possible that RA synthesis acts as a repressor of inflammatory macrophages, and can also act, post AKI, as an activator of M2 macrophages (involved in tissue repair and wound healing) in the proximal tubular epithelial cells. The transition of macrophage phenotypes after IR-AKI falls in line with the kinetics of RA signalling (Lee et al. 2011; M.-Z. Zhang et al. 2012).

The activation of macrophages post AKI, appears to be an RA and proximal tubule epithelial cell dependent mechanism, whereby inhibition of the former within the latter inhibits expression of M2 spectrum macrophage markers (Chiba et al. 2016). However, in mice with a double negative variant of RAR, a reduction in levels of inflammatory macrophage markers is also observed; this could be due to a compensatory increase in RA synthesis, whereby it dampens activity of M1 spectrum macrophages (pro inflammatory) in this animal model, a phenomenon that is observed in zebrafish embryos that are depleted of RARα variant (Chiba et al. 2016); thus implying the presence of a positive feedback mechanism when inhibiting RAR signalling.

Considering these points, it can be suggested that inhibition of RA signalling in proximal tubular epithelial cells reduces markers of M2 spectrum macrophage, however a simultaneous increase in local RA synthesis results in repression of inflammatory renal macrophages after IR AKI albeit through a different mechanism. Various in vitro studies have documented RA’s direct suppressive effects on inflammatory macrophage markers expression (Aggarwal 1996; Dzhagalov et al. 2007), thus increasing the likelihood of RA acting directly on renal macrophages (Fig. 2).

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Figure 2 |  Regulation of renal macrophage phenotypes by RA signalling after ischemia reperfusion acute kidney injury (IR-AKI) in mice. PTEC (proximal tubular epithelial cells). (Adapted from Chiba et al. 2016)

In conclusion, RA signalling appears to be an important player in limiting the extent of injury in the kidneys after AKI in both mouse and zebrafish, this most likely occurs by RA mediated coordination of the equilibrium of macrophage activation, which includes suppression of macrophage mediated injury and promoting M2 macrophage activity, thus enhancing kidney repair and restoration after an episode of AKI.

The expression of Raldh2, an enzyme essential for RA synthesis, is also seen in interstitial macrophages resident in the adult kidneys post IR-AKI (Chiba et al. 2015). Furthermore, the expression of Raldh3 post IR-AKI is not only limited to the epithelium as is during embryonic development, as it is also expressed in infiltrating macrophages, and in contrast to embryonic kidneys its expression precedes Raldh2. In addition, a more restricted lineage of cells go on to harbour Raldh2 expression, namely the macrophages. RA signalling is also believed to be active in reparative proximal tubular epithelial cells. RA signalling is shown to help in amelioration of injury post IR-AKI in both mouse and zebrafish. However, RA signalling does not lead to proliferation in proximal tubular epithelial cells in mice as it does in zebrafish. These finding indicate the preservation of RA signalling in the vertebrate phyla as a signalling system that is involved in post AKI repair; but also shows that this RA mediated repair mechanism may be of different nature in various organisms (Chiba et al. 2015).

In the research carried out by Chiba et al. despite the focus of the author on supporting a role for exogenous RA and the endogenous RA/RAR in AKI, the effect from chemical RAR antagonist and exogenous RA seen in the experiments were not solely specific to proximal tubules and inflammatory cells, whereby the collecting ducts may have also been involved in the response. Furthermore, it would be interesting to also focus on Raldh expression in the renal tubules. Since Raldh expression is not necessarily a marker of RA activity, the significant RARE-LacZ activity observed by Chiba et al. in CD cells may have stemmed from other CD molecules (e.g. CD45+) or from renal tubular cells. In addition, due to the significant differences in anatomy and physiology of mice and zebrafish, the extent to which findings within these animal models can be applied to human physiology remains debatable.

 

4.2 Chronic Kidney Disease (CKD)

A fraction of CKD cases exhibit renal interstitial fibrosis (RIF); this feature is often present regardless of the nature of the instigating primary renal syndrome (Zhou et al. 2013). RIF is characterised by excess accumulation of extracellular matrix and proliferation of renal interstitial fibroblasts (Yang et al. 2012; Zhu et al. 2011). To study this condition further, researchers have been carrying out experiments on mice models with unilateral ureteral obstruction (UUO) resulting in obstruction nephropathy and ultimately RIF (Correa-Costa et al. 2010).

 

4.2.1 Renal Interstitial Fibrosis

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors comprising three subtypes (PPARα, PPARγ and PPARβ/δ) with each distributed in various tissues. The kidneys, adipose tissue, the liver, vascular endothelial cells and macrophages harbour one of the most important subtypes of PPARs, PPARγ. This subtype is a key player in basic regulatory and homeostatic processes including cell proliferation, differentiation and apoptosis (Okunuki et al. 2013). Some types of disease respond positively to PPARγ agonists, whereby its believed that such agonist activity assists in regulating the balance of blood glucose, reduction in proteinuria, declining fibrosis etc. (Kusunoki et al. 2013). Although the definitive effect of PPAR agonists in patients with end stage renal failure (ESRF) is yet inconclusive.

There is a growing body of evidence that emphasises the importance of RARs in development of renal disease and their possible involvement in the pathogenesis of RIF (Zhou & Qin 2013). Studies have shown that a decline in expression of RARα/RARβ is concomitant with ECM accumulation in rats with progressing RIF, thus suggestive of a potentially manipulative target for hindrance of RIF progression (Long et al. 2012).

The formation of a heterodimeric complex between PPARγ and RXR is thought to affect many fundamental biological processes including cellular proliferation, differentiation and apoptosis as well as the regulation of lipid and glucose metabolism. In a study by Lin et al. (2005), it was shown that macrophage infiltration in the renal interstitium of UUO rats in linked to expression of PPARγ; such that elevated levels of expression significantly hindered macrophage infiltration, thus alleviating the RIF index an lowering TGF- β1 expression.

A few recent studies have started to further explore the relationship between PPARγ and RARα in the progression of RIF by using UUO rats. Since PPARγ is believed to play an important role in the process of cell apoptosis, and its agonists can potentially have protective effects in interstitial fibrosis (Okunuki et al. 2013). It has been shown that there is a negative correlation between RIF index and PPARγ expression and also to the expression of TGF-β1, Collagen type four and fibronectin (FN) proteins. Fibroblasts that are induced via the activity of TGF-β1 are suppressed by PPARγ expression, whereby in vitro studies on renal interstitial fibroblasts show a marked reduction in mRNA expression of Collagen type three (W. Wang et al. 2007). The observation of altered inflammation and fibrosis in renal tissue of rats with varying levels of PPARγ expression is indicative of a role for this protein in response to inflammation and fibrosis observed in CKD.

There exists a positive correlation between protein expression of PPARγ and RARα. There are various speculations as to the means by which the cooperation between PPARγ and RARα affects RIF disease in UUO rats. One such mechanism is related to reduction in expression of TGF-β1 and consequently collagen type four and FN, which can be achieved by up-regulating the expression of PPARγ and RARα by PPARγ agonist rosiglitazone sodium (Jiang et al. 2014). This finding highlights the possibility for the existence of a signalling pathway between PPARγ and RARα involved in RIF progression in UUO rats (Kusunoki et al. 2013).

Determining the relationship between PPARγ and RARα can be beneficial as a therapeutic target for the regulation of cell apoptosis and slowing down of cellular and tissue injury. To investigate this, studies need to be conducted wherein examination of gene interference in UUO rats is investigated in vivo. Also in vitro studies utilising renal tubular epithelial cells can be of great help in this pursuit. Although, vitamin A has the potential to instigate production of RXR activating 9-cis retinoic acid as well as RAR agonists ATRA, there is yet no substantial evidence regarding the presence of 9-cis RA in the kidneys.

 

4.2.2 Podocyte and RA/RAR activation

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Figure 3 |  Podocyte injury and retinoids. Podocyte injury is responsive to retinoic acid activity (RA). The mechanism by which retinoic acid attenuates podocyte injury is dependent on the type of initial podocyte injury. Murine models of podocyte injury (Adriamycin induced nephropathy, focal segmental glomerular sclerosis (FSGS) and HIV associated nephropathy (HIVAN)) show marked improvements in podocyte apoptosis and dedifferentiation upon RA treatment respectively. Murine models of nephrotoxic serum (NTS) induced crescenteric glomerulonephritis respond positively to RA, with reduced proliferation of parietal epithelial cell and podocyte restoration by PEC trans-differentiation (Adapted from Sandeep K Mallipattu 2015).

Injury and damage to the kidney’s main filtration system, the glomerulus, accounts for the primary aetiology of CKD. The task of maintaining the renal filtration barrier in the glomerulus is dependent on podocytes, which are terminally differentiated epithelial cells. The pathology of many glomerular diseases such as focal segmental glomerular sclerosis (FSGS) and HIV associated nephropathy (HIVAN) involves podocyte injury (Fig. 3) (Sandeep K Mallipattu 2015). As a result of such conditions, podocytes react by dedifferentiating, proliferating, detaching or undergoing apoptosis; which can ultimately lead to loss of function in maintaining the glomerular filtration barrier. The progression of kidney disease is dependent on the extent of podocyte injury and loss of its function to maintain the renal filtration barrier.

RA plays an important role in podocyte differentiation. The activity of RA in both in vitro and in vivo models of HIVAN results in sequestration of proliferative markers and maintenance of podocyte specific differentiation markers (Vaughan et al. 2005). Thus reducing podocyte dedifferentiation, which is thought to involve the cyclic adenosine monophosphate (cAMP) pathway (Lehrke et al. 2002). Proliferation of epithelial cells in Bowman’s space is often observed with podocyte injury in FSGS, a feature termed pseudo-crescent (Albaqumi & BARISONI 2008). It is believed that RA activity, be it endogenous or exogenous, is key to this proliferative process (Sandeep K Mallipattu 2015). It has been demonstrated in rat models of membranous nephropathy that RA activity results in podocyte restoration by augmenting the number of epithelial cells that express podocyte differentiation markers in the glomerulus (J. Zhang et al. 2012). 

Hindrance of RA activity by albumin in nephrotic range albuminuria slows down podocyte regeneration in animal models of podocyte injury (Peired et al. 2013). Studies have shown that differentiation of progenitor cells towards a podocyte lineage is inversely proportional to increasing levels of albuminuria (Peired et al. 2013). This is in part believed to be due to prevention of RARE mediated regulation of podocyte differentiation, which can be rescued with RA (Peired et al. 2013). RALDH2 levels are also upregulated as a consequence of podocyte injury (Suzuki et al. 2003). RALDH2 level is also detected to rise after podocyte injury in a rat model of podocytopathy (Suzuki et al. 2003). Thus it seems that both the substrate and enzyme for RA signalling are necessary for repair of injured podocytes. In addition, recent studies have shown that specific molecules in the RA synthesis pathways, such as retinol dehydrogenases (RDHs), which are important for downstream conversion of retinol to retinal can have potential therapeutic effects for treatment of glomerular disease. For example, RDH9 expression in mice models of podocyte injury rescues podocytes from irreversible damage, perhaps by triggering the expression of podocyte specific differentiation markers (Li et al. 2014).

 

4.2.3 Diabetic Nephropathy and Altered Vitamin A Metabolism

The pathogenesis of diabetic nephropathy is entangled to hyperglycaemia, oxidative stress, advanced glycation products, increased polyol pathway as well as activation of TGF-β1, which can ultimately lead to CKD. The current scope of literature regarding the role of RA metabolism in diabetic nephropathy is relatively limited. Recently, studies have been using a systems biology approach to assimilate the numerous proteins involved in said pathology into higher order vessels that may be functional in diabetic cells and tissues (González Díaz et al. 2008; Strange 2005). This unbiased and global approach can be beneficial in understanding the interconnectivity of various proteins deemed involved in diabetic nephropathy.

Utilising such an approach, it has been shown that mice models of type 2 diabetes exhibit alterations in vitamin A metabolism in the renal cortex. A recent study has reported that ATRA can bind PAPRβ/δ and activate transcription; this suggests that changes in RA metabolism can potentially be linked to insulin resistance and fatty acid metabolism (Shaw et al. 2003; Berry & Noy 2009). However, there are studies that show a failure in ATRA’s ability to induce transcriptional activity of PAPRβ/δ, thus this notion remains controversial (Rieck et al. 2008).

In addition, RALDH1 is detected to be deregulated in the renal cortex of the well-established mice model of type 2 diabetes (db/db mice) (Starkey et al. 2010). Such alterations in RALDH1 are linked to significant reduction in renal cortical levels of ATRA and PAPRβ/δ despite increased plasma levels of retinol and ATRA (Starkey et al. 2010). A suggested mechanism for this observation involves increased renal cortical levels of CYP2E1, an ethanol inducible P450 enzyme involved in metabolism of fatty acids, ketone bodies, lipid hydroperoxides and ATRA (Raza et al. 2004; Z. Wang et al. 2003). This enzyme is also linked to generation of reactive oxygen species in the mitochondria (Bai & Cederbaum 2006). There are significant yet limited changes in CYP2E1 activity in animal models of diabetes (Sandeep K Mallipattu 2015). Nevertheless, the pathophysiological mechanism that result in reduced levels of ATRA on a cellular and molecular level remains an area of interest in need of further research.

 


Conclusion


 

Retinoids have repeatedly proven essential as a vital group of vitamins that regulate a variety of important biological functions, playing an indispensable role during development and day-to-day tissue homeostasis. Retinoids exert their genomic function via their nuclear DNA binding receptors, which go on to recruit corepressors and coactivator to regulate gene transcription. The essential role of retinoids in the kidney have been highlighted in recent years, with a huge amount of focus on their therapeutic effects in kidney disease, albeit with mixed and often disappointing clinical results. Although the synthesis of newer generation retinoids with higher therapeutic efficiency can be beneficial, but understanding the endogenous RA mechanism during normal and diseased kidney function can be extremely insightful for further developments.

The studies covered in this review, unanimously support the presence of a dynamically activated RA signalling in the murine adult kidney. More specifically, the activation of RA signalling after acute kidney injury is linked to regulation of macrophage dependent injury and repair, which is necessary for preventing further damage and possibly repair of the affected tissue. Although the exact mechanism between macrophage activity and RA signalling is yet to be elucidated, but it is suggested that RA can directly exert its effect on macrophages in an attempt to curb inflammation or that the interaction between proximal tubular epithelial cells and macrophages involved in the process of post IR-AKI is directed by RA signalling. These suggestions can further explore the role of RA signalling during and after acute kidney injury.

Furthermore, RA appears to be involved in renal interstitial fibrosis, a hallmark of chronic kidney disease, such that there is an upregulation of PPARγ and RARα in RIF rats and that the PPARγ expression positively correlates with RARα expression in the same tissues, however future studies can be more illuminating as to the exact mechanism of the cooperation between the two systems. Future studies will undoubtedly pave the way for new discoveries in the role of endogenous RA signalling and help in emergence of novel and effective methods of therapy.

Cite this article as: Milad Golsharifi, "The Physiological and Pathophysiological Roles for Dietary Vitamin A and the Endogenous Retinoid System in the Kidney," in Projmed, May 14, 2016, https://www.projmed.com/2016/05/the-physiological-and-pathophysiological-roles-for-dietary-vitamin-a-and-the-endogenous-retinoid-system-in-the-kidney/.


References



  1. Aggarwal, B.B., 1996. Determination and regulation of nitric oxide production from macrophages by lipopolysaccharides, cytokines and retinoids. Methods Enzymol, 269, pp.166–171.
  2. Albaqumi, M. & BARISONI, L., 2008. Current views on collapsing glomerulopathy. Journal of the American Society of Nephrology : JASN, 19(7), pp.1276–1281.
  3. Bai, J. & Cederbaum, A.I., 2006. Overexpression of CYP2E1 in mitochondria sensitizes HepG2 cells to the toxicity caused by depletion of glutathione. Journal of Biological Chemistry, 281(8), pp.5128–5136.
  4. Berry, D.C. & Noy, N., 2009. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. Molecular and Cellular Biology, 29(12), pp.3286–3296.
  5. Berry, D.C. et al., 2012. Cross talk between signaling and vitamin A transport by the retinol-binding protein receptor STRA6. Molecular and Cellular Biology, 32(15), pp.3164–3175.
  6. Bhat, P.V. et al., 1998. Changing patterns of renal retinal dehydrogenase expression parallel nephron development in the rat. Journal of Histochemistry & Cytochemistry, 46(9), pp.1025–1032.
  7. Blaner, W.S. et al., 2009. Hepatic stellate cell lipid droplets: A specialized lipid droplet for retinoid storage. Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids, 1791(6), pp.467–473.
  8. Blomhoff, R. & Blomhoff, H.K., 2006. Overview of retinoid metabolism and function. Journal of neurobiology, 66(7), pp.606–630.
  9. Chiba, T. et al., 2016. Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI. Journal of the American Society of Nephrology : JASN, 27(2), pp.495–508.
  10. Chiba, T., Skrypnyk, N.I. & Skvarca, L.B., 2015. Retinoic acid signaling coordinates macrophage-dependent injury and repair after AKI. J Am Soc Nephrol [ ….
  11. Correa-Costa, M. et al., 2010. Induction of Heme Oxygenase-1 Can Halt and Even Reverse Renal Tubule-Interstitial Fibrosis C. Chatziantoniou, ed. PLOS ONE, 5(12), p.e14298.
  12. Dalirani, R. et al., 2011. Role of vitamin A in preventing renal scarring after acute pyelonephritis. Iranian journal of kidney diseases, 5(5), pp.320–323.
  13. Das, B.C. et al., 2014. Retinoic acid signaling pathways in development and diseases. Bioorganic & Medicinal Chemistry, 22(2), pp.673–683.
  14. de Groh, E.D. et al., 2010. Inhibition of histone deacetylase expands the renal progenitor cell population. Journal of the American Society of Nephrology : JASN, 21(5), pp.794–802.
  15. Delva, L. et al., 1999. Physical and functional interactions between cellular retinoic acid binding protein II and the retinoic acid-dependent nuclear complex. Molecular and Cellular Biology, 19(10), pp.7158–7167.
  16. Duester, G., 2000. Families of retinoid dehydrogenases regulating vitamin A function. European Journal of Biochemistry, 267(14), pp.4315–4324.
  17. Duester, G., 2008. Retinoic Acid Synthesis and Signaling during Early Organogenesis. Cell, 134(6), pp.921–931.
  18. Dzhagalov, I., Chambon, P. & He, Y.-W., 2007. Regulation of CD8+ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor gamma. The Journal of Immunology, 178(4), pp.2113–2121.
  19. Evans, R.M. & Mangelsdorf, D.J., 2014. Nuclear Receptors, RXR, and the Big Bang. Cell, 157(1), pp.255–266.
  20. Ferenbach, D.A. et al., 2012. Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice. Kidney International, 82(8), pp.928–933.
  21. Gijbels, M.J.J. et al., 1992. Alterations in cytokeratin expression precede histological changes in epithelia of vitamin A-deficient rats. Cell and Tissue Research, 268(1), pp.197–203.
  22. González Díaz, H. et al., 2008. Proteomics, networks and connectivity indices. PROTEOMICS, 8(4), pp.750–778.
  23. Grases, F. et al., 1998. Vitamin A and urolithiasis. Clinica chimica acta, 269(2), pp.147–157.
  24. Heyman, R.A. et al., 1992. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell, 68(2), pp.397–406.
  25. HIGGINS, C.C., 1935. PRODUCTION AND SOLUTION OF URINARY CALCULI: EXPERIMENTAL AND CLINICAL STUDIES. JAMA, 104(15), pp.1296–1299.
  26. Jiang, L. et al., 2014. The potential signaling pathway between peroxisome proliferator-activated receptor gamma and retinoic acid receptor alpha in renal interstitial fibrosis disease. Journal of Receptors and Signal Transduction, 35(4), pp.258–268.
  27. Kavukcu, S., Turkmen, M.A. & Soylu, A., 2001. Could the effective mechanisms of retinoids on nephrogenesis be also operative on the amelioration of injury in acquired renal lesions? Pediatric Nephrology, 16(8), pp.689–690.
  28. Kawaguchi, R. et al., 2007. A Membrane Receptor for Retinol Binding Protein Mediates Cellular Uptake of Vitamin A. Science, 315(5813), pp.820–825.
  29. Kusunoki, H. et al., 2013. Cardiac and Renal Protective Effects of Irbesartan via Peroxisome Proliferator-Activated Receptorγ–Hepatocyte Growth Factor Pathway Independent of Angiotensin II Type 1a Receptor Blockade in Mouse Model of Salt-Sensitive Hypertension. Journal of the American Heart Association, 2(2), pp.e000103–e000103.
  30. Lee, S. et al., 2011. Distinct macrophage phenotypes contribute to kidney injury and repair. Journal of the American Society of Nephrology : JASN, 22(2), pp.317–326.
  31. Lehrke, I. et al., 2002. Retinoid receptor-specific agonists alleviate experimental glomerulonephritis. American Journal of Physiology – Renal Physiology, 282(4), pp.F741–51.
  32. Li, X. et al., 2014. Induction of Retinol Dehydrogenase 9 Expression in Podocytes Attenuates Kidney Injury. Journal of the American Society of Nephrology, 25(9), pp.ASN.2013111150–1941.
  33. Liebler, S. et al., 2004. The renal retinoid system: time-dependent activation in experimental glomerulonephritis. American Journal of Physiology – Renal Physiology, 286(3), pp.F458–F465.
  34. Lin, M. et al., 2003. Mouse retinal dehydrogenase 4 (RALDH4), molecular cloning, cellular expression, and activity in 9-cis-retinoic acid biosynthesis in intact cells. Journal of Biological Chemistry, 278(11), pp.9856–9861.
  35. Long, Y.-B. et al., 2012. Association of Retinoic Acid Receptors with Extracellular Matrix Accumulation in Rats with Renal Interstitial Fibrosis Disease. International Journal of Molecular Sciences, 13(11), pp.14073–14085.
  36. MacDonald, P.N. & Ong, D.E., 1988. Evidence for a lecithin-retinol acyltransferase activity in the rat small intestine. Journal of Biological Chemistry, 263(25), pp.12478–12482.
  37. Maden, M., 2002. Retinoid signalling in the development of the central nervous system. Nature Reviews Neuroscience, 3(11), pp.843–853.
  38. Marín, M.P. et al., 2005. Vitamin A deficiency alters the structure and collagen IV composition of rat renal basement membranes. The Journal of Nutrition, 135(4), pp.695–701.
  39. Maureen A Kane et al., 2008. Quantitative Profiling of Endogenous Retinoic Acid in Vivo and in Vitro by Tandem Mass Spectrometry. Analytical Chemistry, 80(5), pp.1702–1708.
  40. Mendelsohn, C. et al., 1994. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development, 120(10), pp.2749–2771.
  41. Napoli, J.L., 1996. Biochemical Pathways of Retinoid Transport, Metabolism, and Signal Transduction. Clinical immunology and immunopathology, 80(3), pp.S52–S62.
  42. Niederreither, K. et al., 2002. Differential expression of retinoic acid-synthesizing (RALDH) enzymes during fetal development and organ differentiation in the mouse. Mechanisms of Development, 110(1-2), pp.165–171.
  43. Niederreither, K. et al., 1999. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nature Genetics, 21(4), pp.444–448.
  44. Noy, N., Slosberg, E. & Scarlata, S., 1992. Interactions of retinol with binding proteins: Studies with retinol-binding protein and with transthyretin. Biochemistry, 31(45), pp.11118–11124.
  45. Okunuki, Y. et al., 2013. Peroxisome proliferator-activated receptor-γ agonist pioglitazone suppresses experimental autoimmune uveitis. Experimental Eye Research, 116, pp.291–297.
  46. Peired, A. et al., 2013. Proteinuria impairs podocyte regeneration by sequestering retinoic acid. Journal of the American Society of Nephrology : JASN, 24(11), pp.1756–1768.
  47. Rankin, A.C. et al., 2013. An in vitro model for the pro‐fibrotic effects of retinoids: mechanisms of action. British Journal of Pharmacology, 170(6), pp.1177–1189.
  48. Raza, H. et al., 2004. Elevated mitochondrial cytochrome P450 2E1 and glutathione S-transferase A4-4 in streptozotocin-induced diabetic rats: tissue-specific variations and roles in oxidative stress. Diabetes, 53(1), pp.185–194.
  49. Rieck, M. et al., 2008. Ligand-mediated regulation of peroxisome proliferator-activated receptor (PPAR) beta/delta: a comparative analysis of PPAR-selective agonists and all-trans retinoic acid. Molecular Pharmacology, 74(5), pp.1269–1277.
  50. Rosselot, C. et al., 2010. Non-cell-autonomous retinoid signaling is crucial for renal development. Development, 137(2), pp.283–292.
  51. Sandeep K Mallipattu, J.C.H., 2015. The Beneficial Role of Retinoids in Glomerular Disease. Frontiers in medicine, 2(4), p.459.
  52. Schweigert, F.J. & Raila, J., 2002. Mechanisms Involved in the Intestinal Digestion and Absorption of Dietary Vitamin A. The Journal of Nutrition, 132(2), pp.324–324.
  53. Semba, R.D., 2012. On the “Discovery” of Vitamin A. Annals of Nutrition and Metabolism, 61(3), pp.192–198.
  54. Shaw, N., Elholm, M. & Noy, N., 2003. Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor beta/delta. Journal of Biological Chemistry, 278(43), pp.41589–41592.
  55. Starkey, J.M. et al., 2010. Altered Retinoic Acid Metabolism in Diabetic Mouse Kidney Identified by 18 O Isotopic Labeling and 2D Mass Spectrometry A. T. Y. Lau, ed. PLOS ONE, 5(6), p.e11095.
  56. Strange, K., 2005. The end of “naïve reductionism”: rise of systems biology or renaissance of physiology? American Journal of Physiology-Cell Physiology, 288(5), pp.C968–C974.
  57. Suzuki, A. et al., 2003. Retinoids regulate the repairing process of the podocytes in puromycin aminonucleoside-induced nephrotic rats. Journal of the American Society of Nephrology, 14(4), pp.981–991.
  58. Van Leersum, E.C., 1928. Vitamin A Deficiency and Urolithiasis. Journal of Biological Chemistry, 76, pp.137–42.
  59. Vaughan, M.R. et al., 2005. ATRA induces podocyte differentiation and alters nephrin and podocin expression in vitro and in vivo. Kidney International, 68(1), pp.133–144.
  60. Wagner, J., 2001. Potential role of retinoids in the therapy of renal disease. Nephrology Dialysis Transplantation, 16(3), pp.441–444.
  61. Wang, W., Liu, F. & Chen, N., 2007. Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) Agonists Attenuate the Profibrotic Response Induced by TGF-β1 in Renal Interstitial Fibroblasts. Mediators of inflammation, 2007(6), pp.1–7.
  62. Wang, Z. et al., 2003. Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans. British Journal of Clinical Pharmacology, 55(1), pp.77–85.
  63. Wilson, J.G. & Warkany, J., 1948. Malformations in the genito‐urinary tract induced by maternal vitamin a deficiency in the rat. American Journal of Anatomy, 83(3), pp.357–407.
  64. Woelfel, C.G. et al., 1965. Volume and Osmolality of Urine of Hypovitaminotic A Holstein Heifers. Journal of Dairy Science, 48(10), pp.1346–1352.
  65. Wolf, G., 2001. Discovery of Vitamin A, Chichester, UK: John Wiley & Sons, Ltd.
  66. Wong, Y.F. et al., 2011. Endogenous Retinoic Acid Activity in Principal Cells and Intercalated Cells of Mouse Collecting Duct System J.-C. Dussaule, ed. PLOS ONE, 6(2), p.e16770.
  67. Xu, Q. et al., 2010. Kidneys of Alb/TGF-beta1 transgenic mice are deficient in retinoic acid and exogenous retinoic acid shows dose-dependent toxicity. Nephron Experimental Nephrology, 114(4), pp.e127–32.
  68. Yang, J., Zhou, Y. & Guan, Y., 2012. PPARγ as a therapeutic target in diabetic nephropathy and other renal diseases. Current Opinion in Nephrology and Hypertension, 21(1), pp.97–105.
  69. Yu, M.-J. et al., 2009. Systems-level analysis of cell-specific AQP2 gene expression in renal collecting duct. Proceedings of the National Academy of Sciences of the United States of America, 106(7), pp.2441–2446.
  70. Zanotti, G. & Berni, R., 2004. Plasma Retinol-Binding Protein: Structure and Interactions with Retinol, Retinoids, and Transthyretin. In Vitamins & Hormones. Elsevier, pp. 271–295.
  71. Zhang, J. et al., 2012. Retinoids augment the expression of podocyte proteins by glomerular parietal epithelial cells in experimental glomerular disease. Nephron Experimental Nephrology, 121(1-2), pp.e23–37.
  72. Zhang, M.-Z. et al., 2012. CSF-1 signaling mediates recovery from acute kidney injury. The Journal of Clinical Investigation, 122(12), pp.4519–4532.
  73. Zhou, T.-B. & Qin, Y.-H., 2013. Signaling pathways of prohibitin and its role in diseases. Journal of Receptors and Signal Transduction, 33(1), pp.28–36.
  74. Zhou, T.-B. et al., 2013. Prohibitin Attenuates Oxidative Stress and Extracellular Matrix Accumulation in Renal Interstitial Fibrosis Disease C. Chatziantoniou, ed. PLOS ONE, 8(10), p.e77187.
  75. Zhu, C. et al., 2011. Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage. The American Journal of Pathology, 178(5), pp.2020–2031.
  76. Zile, M., DeLuca, H.F. & Ahrens, H., 1972. Vitamin A deficiency and urinary calcium excretion in rats, The Journal of nutrition.

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