The Beneficial Role of Retinoids in Glomerular Disease

Abstract

The primary etiology of CKD is a direct consequence of initial dysfunction and injury of the glomerulus, the main filtration system. Podocytes are terminally differentiated epithelial cells in the glomerulus, whose major function is the maintenance of this renal filtration barrier. Podocyte injury is implicated in many glomerular diseases including focal segmental glomerular sclerosis and HIV-associated nephropathy. In many of these diseased conditions, the podocyte can either undergo dedifferentiation and proliferation, apoptosis, or cell detachment. Regardless of the initial type of injury, the podocyte ultimately loses its functional capacity to maintain the glomerular filtration barrier. Significant injury resulting in a loss of the podocytes and failure to maintain the renal filtration barrier contributes to progressive kidney disease. Consequently, therapies that prevent podocyte injury and promote their regeneration will have a major clinical impact on glomerular disease. Retinoic acid (RA), which is a derivative of vitamin A, has many cellular functions including induction of cell differentiation, regulation of apoptosis, and inhibition of inflammation and proliferation. RA is required for kidney development and is essential for cellular differentiation in the setting of podocyte injury. The mechanism by which RA directs its beneficial effects is multifactorial, ranging from its anti-inflammatory and anti-fibrotic effects to a direct effect of upregulating podocyte differentiation markers in the podocyte. The focus of this review is to provide an overview of RA in kidney development and glomerular disease. We also highlight the key mechanism(s) by which RA restores podocyte differentiation markers and ameliorates glomerular disease.

Amelioration of Diabetic Nephropathy Using a Retinoic Acid Receptorβ2 Agonist

“…In our HFD-DN study, we did not detect changes to renal transcript levels of RARα across all experimental groups, but we did measure significant reductions in RARβ2, RARγ, and CRBP1 renal mRNA levels in HFD-fed mice. The trends of these findings are in agreement with a study by Ratnam et al (Ratnam et al, 2011) which demonstrated that renal levels of RARβ, but not RARα, are reduced in the CKD HIV-associated nephropathy (HIVAN) (Ratnam et al, 2011), despite evidence that RARα and RARα agonists are relevant to both the pathogenesis and treatment of HIVAN (Ratnam et al, 2011;Dai et al, 2017) and other CKDs (Ratnam et al, 2011;Zhong et al, 2011;Mallipattu and He, 2015). Our data, coupled to the Ratnam et al (Ratnam et al, 2011) demonstrating that the anti-CKD and podocyte-preserving effect of highly selective RARα agonists correlates with an increase in podocyte expression of RARβ only (Zhong et al, 2011).…”

“…In the larger context of retinoid-CKD research, our findings highlight for the first time a potential role for RARβ2 in CKD, while the vast of majority of retinoid-CKD research has focused on a role for RARα, and the renal protective properties of RARα agonists (Lehrke et al, 2002;Ratnam et al, 2011;Zhong et al, 2011;Mallipattu and He, 2015;Dai et al, 2017). In our HFD-DN study, we did not detect changes to renal transcript levels of RARα across all experimental groups, but we did measure significant reductions in RARβ2, RARγ, and CRBP1 renal mRNA levels in HFD-fed mice.…”

“…However, a convincing body of data demonstrates that VA, acting through RA, shows protective properties in several renal diseases (Lazzeri et al, 2014;Mallipattu and He, 2015), such as experimental glomerulonephritis (Wagner et al, 2000;Schaier et al, 2001;Lehrke et al, 2002;Perez et al, 2004;Chiba et al, 2016), HIV-associated nephropathy (Lu et al, 2008;Ratnam et al, 2011), and DN (Han et al, 2004;Kim et al, 2015).…”

Retinoic acid improves nephrotoxic serum–induced glomerulonephritis through activation of podocyte retinoic acid receptor α

“…Furthermore, RA has also been shown to attenuate inflammation and apoptosis in models of podocyte injury 39 . In this current study we sought to address whether RA can improve renal function and ameliorate kidney injury in the context of NTS-GN and whether this would be mediated directly through the inhibition of podocyte injury.…”

Fundamental role of Warburg effect in various pathophysiological processes

“…Rowe 577 et al showed that glycolysis has been increased in PKD and showed the treatment option by 578 inhibition of glycolysis which decreased the proliferation in PKD (171). Podocytes dedifferentiation 579 leading to glomerular dysfunction and ending in chronic kidney disease (CKD) has been shown 580 already, interestingly retinoids were used as a treatment option to reduce the glomerular dysfunction 581 and it was used as a differentiation therapy in this condition (172). Ascorbic acid as a differentiation 582 therapy may work in renal dysfunctions.…”