Aldose reductase regulates miR-200a-3p/141-3p to coordinate Keap1–Nrf2, Tgfβ1/2, and Zeb1/2 signaling in renal mesangial cells and the renal cortex of diabetic mice

Abstract

Aberrant regulation in oxidative stress, fibrogenesis, and the epithelial-mesenchymal transition (EMT) in renal cells under hyperglycemic conditions contributes significantly to the onset and progression of diabetic nephropathy. The mechanisms underlying these hyperglycemia-induced dysregulations, however, have not been clearly elucidated. Herein, we report that aldose reductase is capable of regulating the expression of miR-200a-3p/141-3p negatively in renal mesangial cells. MiR-200a-3p/141-3p, in turn, act to target Keap1, Tgfβ2, fibronectin, and Zeb2 directly and regulate Tgfβ1 and Nrf2 indirectly under high-glucose conditions, resulting in profound dysregulations in Keap1-Nrf2, Tgfβ1/2, and Zeb1/2 signaling. In vivo in streptozotocin-induced diabetic mice, we found that aldose reductase deficiency caused significant elevations in miR-200a-3p/141-3p in the renal cortex, which were accompanied by a significant downregulation of Keap1, Tgfβ1/2, and fibronectin but significant upregulation of Nrf2. Moreover, in vivo administration of inhibitors of miR-200a-3p in diabetic animals significantly exacerbated cortical and glomerular fibrogenesis and increased urinary albumin excretion, tightly linking dysregulated miR-200a-3p with the development of diabetic nephropathy. Collectively, our results reveal a novel mechanism whereby hyperglycemia induces aldose reductase to regulate renal expression of miR-200a-3p/141-3p to coordinately control hyperglycemia-induced renal oxidative stress, fibrogenesis, and the EMT. Our novel findings also suggest that inhibition of aldose reductase and in vivo renal cortical restoration of miR-200a-3p/141-3p or their combination are very promising avenues for the development of therapeutic strategies or drugs against diabetic nephropathy.

LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway

“…Therefore, we hypothesized that HULC might promote angiogenesis as related to changes in ZEB1 and miR-200a-3p. It has been reported that ZEB1 is a target of miR-200a-3p via a luciferase reporter [42]. Notably, the EMT activators transforming growth factor beta2 and ZEB1 are the predominant targets downregulated by miR-200c.…”

New insights on microRNAs in diabetic nephropathy: potential biomarkers for diagnosis and therapeutic targets

“…В эксперименте у мышей с СД было убедительно показано, что альдозоредуктаза (фермент сорбитолового пути утилизации глюкозы, содержа-ние которого увеличено при СД) снижает экспрессию miR-200а-3р и miR-141-3р и регулирует оксидативный стресс, воздействуя на ряд сигнальных путей (TGF-β1/ TGF-β2 и Zeb1/Zeb2 и др.) в мезангиальных клетках [49].…”

The Role of MicroRNAs in Diabetic Nephropathy

“…The study established a reciprocal inhibiting effect between miR-200a/miR-141 and TGF- β 2. More recently, aldose reductase was found to elevate miR-200a-3p and miR-141 so as to coordinate kelch-like ECH-associated protein 1/NFE2-related factor 2, attenuating TGF- β 1/2 signaling in both renal cortex of STZ-induced mice and MMCs [55]. …”

“…Isoflavone and 3,3′-diindolylmethane (DIM) restored the expression of let7-b and led to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells [104]. Because of the renal-protective role of miR-200a [54, 105] and let7-b [68], CDF, isoflavone, and DIM might prevent DN through regulating these two miRNAs.…”