Role of the retinoic acid receptor-α in HIV-associated nephropathy

Abstract

All-trans retinoic acid protects against the development of HIV-associated nephropathy (HIVAN) in HIV-1 transgenic mice (Tg26). In vitro, all-trans retinoic acid inhibits HIV-induced podocyte proliferation and restores podocyte differentiation markers by activating its receptor-α (RARα). Here, we report that Am580, a water-soluble RARα-specific agonist, attenuated proteinuria, glomerosclerosis, and podocyte proliferation, and restored podocyte differentiation markers in kidneys of Tg26 mice. Furthermore, RARα−/− Tg26 mice developed more severe kidney and podocyte injury than did RARα+/− Tg26 mice. Am580 failed to ameliorate kidney injury in RARα−/− Tg26 mice, confirming our hypothesis that Am580 acts through RARα. Although the expression of RARα-target genes was suppressed in the kidneys of Tg26 mice and of patients with HIVAN, the expression of RARα in the kidney was not different between patients with HIVAN and minimal change disease. However, the tissue levels of retinoic acid were reduced in the kidney cortex and isolated glomeruli of Tg26 mice. Consistent with this, the expression of two key enzymes in the retinoic acid synthetic pathway, retinol dehydrogenase type 1 and 9, and the overall enzymatic activity for retinoic acid synthesis were significantly reduced in the glomeruli of Tg26 mice. Thus, a defect in the endogenous synthesis of retinoic acid contributes to loss of the protection by retinoic acid in HIVAN. Hence, RARα agonists may be potential agents for the treatment of HIVAN.

Proteinuria Impairs Podocyte Regeneration by Sequestering Retinoic Acid

“…20 Interestingly, RA was previously found to provide protection in multiple experimental models of kidney disease, including mesangioproliferative GN, 21 puromycin-induced nephrosis, 22 lupus nephritis, 23 diabetic nephropathy, 24 and HIV nephropathy. 25 A recent study suggested that RA upregulates podocyte protein expression on parietal epithelial cells. 26 In addition, treatment with RA reduced proteinuria in two patients with lupus nephritis.…”

Induction of Retinol Dehydrogenase 9 Expression in Podocytes Attenuates Kidney Injury

“…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.…”

A New Mechanism for Albuminuria-Induced Podocyte Injury

“…In contrast, key observations from previous studies reveal alteration of key RA synthesis enzymes in other kidney diseases. 16,17 In the final set of experiments, the authors validated a recent study by Zhang et al 18 by showing that RA-induced podocyte differentiation results from restoration of novel podocytes from the transdifferentiation of renal progenitor cells into podocytes. ADR treatment of RARE-lacz transgenic mice showed an increase in endogenous RARE activity exclusively in the renal progenitor cells, and not in podocytes.…”

“…Because many groups have shown that podocytes express receptors for RA, some endogenous RARE activity in podocytes would have been expected in the RARE-lacz mice. 14,17,19 Moreover, Vaughn et al showed that RA induces podocyte differentiation and increases nephrin and podocin expression in the setting of podocyte injury. 20 In addition to activation of transcription factors involved in podocyte differentiation, KLF15, by RA, 21 we have previously shown that RA can attenuate podocyte dedifferentiation by activation of a cAMP-dependent pathway via retinoic acid receptor-a in the podocytes.…”

“…Novel derivatives of RA receptor agonists, such as Am580 and BD4, induce the expression of podocyte differentiation markers in the setting of podocyte injury. 17,19 Future studies will need to be conducted to determine whether these new derivatives provide similar efficacy of podocyte regeneration with lower toxicity.…”