Induction of Retinol Dehydrogenase 9 Expression in Podocytes Attenuates Kidney Injury

The intracellular concentration of retinoic acid is determined by two sequential oxidation reactions that convert retinol to retinoic acid. We recently demonstrated that retinoic acid synthesis is significantly impaired in glomeruli of HIV-1 transgenic mice (Tg26), a murine model of HIV-associated nephropathy. This impaired retinoic acid synthesis correlates with reduced renal expression of retinol dehydrogenase 9, which catalyzes the rate-limiting step of retinoic acid synthesis by converting retinol to retinal. Because retinoic acid has renal protective effects and can induce podocyte differentiation, we hypothesized that restoration of retinoic acid synthesis could slow the progression of renal disease. Herein, we demonstrate that overexpression of retinol dehydrogenase 9 in cultured podocytes induces the expression of podocyte differentiation markers. Furthermore, we confirm that podocyte-specific overexpression of retinol dehydrogenase 9 in mice with established kidney disease due to either HIV-associated nephropathy or adriamycin-induced nephropathy decreases proteinuria, attenuates kidney injury, and restores podocyte differentiation markers. Our data suggest that restoration of retinoic acid synthesis could be a new approach to treat kidney disease.Retinoic acids (RAs) are derivatives of vitamin A and have multiple cellular functions, including inhibition of proliferation, induction of cell differentiation, and inhibition of inflammation.¹ In addition to their established benefits in the treatment of a variety of cancers, RA has also been shown to protect against renal injury in multiple experimental models of kidney disease,² including HIV-associated nephropathy (HIVAN).³ Both in vitro and in vivo studies suggest that RA restores the expression of podocyte differentiation markers, including nephrin, podocin, and synaptopodin.^3,4 These studies provide strong evidence supporting the therapeutic benefit of RA in kidney diseases with podocyte injury. In fact, a phase II clinical trial examining the efficacy of RA for treatment of podocyte diseases, including minimal change disease, FSGS, or collapsing glomerulopathy, is ongoing (ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00098020","term_id":"NCT00098020"}}NCT00098020). However, clinical use of RA is challenging because of its side effects.⁵After cellular uptake, retinol is converted to RA by two sequential oxidation reactions. Retinol dehydrogenases (RHDs) oxidize retinol to retinal,⁶ which is further metabolized to retinoic acid by retinaldehyde dehydrogenases (ALDHs).⁷ The expression of these enzymes varies greatly among different cell types and at different stages of cell differentiation.⁷ Both the synthesis and metabolism of the bioactive metabolites of retinol are impaired in cancer cells.⁸ The kidney is a major organ for retinoid metabolism. However, not much is known regarding how retinoid metabolism is altered in renal disease.Our previous work showed that although the expression of retinoic acid receptor-α–target genes is suppressed in kidneys of a murine model of HIVAN (Tg26) and of patients with HIVAN, the expression of retinoic acid receptor-α is not different between normal and diseased kidneys.⁹ The concentration of RA, however, is significantly reduced in the kidney cortex and isolated glomeruli of Tg26. We also found that the glomerular concentration of RA is >10-fold higher than the concentration in the kidney cortex.⁹ Examination of enzymes involved in RA metabolism reveal that two key enzymes in the RA synthetic pathway, retinol dehydrogenase type 1 and type 9 (RDH1 and RDH9), were significantly downregulated in Tg26 glomeruli.⁹ RDH9 is a rate-limiting enzyme in RA synthesis. Because it is known that RA has renal protective effects and is able to induce podocyte differentiation, we hypothesize that overexpression of RDH9 to restore endogenous RA synthesis could slow the progression of renal disease.Consistent with our findings, recent studies also showed that endogenous RA synthesis is impaired in kidneys of diabetic db/db mice¹⁰ and TGF-β transgenic mice.¹¹ These data together with ours suggest that endogenous RA synthesis is impaired in diseased kidneys. Thus, a better understanding of RA metabolism in kidney disease could help us to identify potential new therapy for kidney diseases.