Division of Nephrology, Mount Sinai School of Medicine, New York, New York, USA.
RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Kidney Int. 2011 Mar;79(6):624-634. doi: 10.1038/ki.2010.470. Epub 2010 Dec 8.
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.
全反式视黄酸可预防 HIV-1 转基因小鼠（Tg26）中 HIV 相关肾病（HIVAN）的发生。体外研究表明，全反式视黄酸通过激活其受体-α（RARα）抑制 HIV 诱导的足细胞增殖并恢复足细胞分化标志物。在此，我们报告水溶性 RARα 特异性激动剂 Am580 可减轻蛋白尿、肾小球硬化和足细胞增殖，并恢复 Tg26 小鼠肾脏中的足细胞分化标志物。此外，与 RARα+/-Tg26 小鼠相比，RARα-/-Tg26 小鼠的肾脏和足细胞损伤更为严重。Am580 未能改善 RARα-/-Tg26 小鼠的肾脏损伤，证实了我们的假设，即 Am580 通过 RARα 发挥作用。虽然 RARα 靶基因的表达在 Tg26 小鼠和 HIVAN 患者的肾脏中受到抑制，但 HIVAN 患者与微小病变性肾病患者肾脏中 RARα 的表达并无差异。然而，在 Tg26 小鼠的肾脏皮质和分离的肾小球中，视黄酸的组织水平降低。与此一致的是，视黄酸合成途径中的两个关键酶，视黄醇脱氢酶 1 和 9，以及视黄酸合成的整体酶活性，在 Tg26 小鼠的肾小球中显著降低。因此，内源性视黄酸合成的缺陷导致视黄酸在 HIVAN 中失去保护作用。因此，RARα 激动剂可能是治疗 HIVAN 的潜在药物。
