Transforming Growth Factor-β–Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy

Abstract

Elevated p53 expression is associated with several kidney diseases including diabetic nephropathy (DN). However, the mechanisms are unclear. We report that expression levels of transforming growth factor-β1 (TGF-β), p53, and microRNA-192 (miR-192) are increased in the renal cortex of diabetic mice, and this is associated with enhanced glomerular expansion and fibrosis relative to nondiabetic mice. Targeting miR-192 with locked nucleic acid–modified inhibitors in vivo decreases expression of p53 in the renal cortex of control and streptozotocin-injected diabetic mice. Furthermore, mice with genetic deletion of miR-192 in vivo display attenuated renal cortical TGF-β and p53 expression when made diabetic, and have reduced renal fibrosis, hypertrophy, proteinuria, and albuminuria relative to diabetic wild-type mice. In vitro promoter regulation studies show that TGF-β induces reciprocal activation of miR-192 and p53, via the miR-192 target Zeb2, leading to augmentation of downstream events related to DN. Inverse correlation between miR-192 and Zeb2 was observed in glomeruli of human subjects with early DN, consistent with the mechanism seen in mice. Our results demonstrate for the first time a TGF-β–induced feedback amplification circuit between p53 and miR-192 related to the pathogenesis of DN, and that miR-192–knockout mice are protected from key features of DN.

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

“…61 The antibodies used were nephrin (Abcam, Inc., Cambridge, MA), caspase 1 (Abcam, Inc.), and glyceraldehyde-3-phosphate dehydrogenase (SigmaAldrich, St. Louis, MO). Densitometric analysis was performed using ImageJ software (National Institutes of Health, Bethesda, MD).…”

“…Analysis of histologic changes in the kidney by PAS and Masson trichrome staining was done according to previously reported studies. 36,61 Image-Pro 6.1 software (Media Cybernetics, Inc., Bethesda, MD) was used to process the images for quantification of glomerular area and mesangial expansion index.…”

microRNAs in Diabetic Kidney Disease

“…Results from miR-192 KO type I diabetic mice confirm this positive relationship between miR-192 and renal expression of TGF-and p53 [58]. All these results suggest that the TGF-/Smad3 signaling plays an essential role of regulating microRNA expression during DN.…”

“…In addition, a recent study demonstrates that TGFstimulates a crosstalk circuit between p53 and miR-192 related to the pathogenesis of DN [58]. It is known that expression levels of TGF-1, p53, and miR-192 are increased in expanded glomeruli of diabetic mice [58,101,102].…”

“…It is known that expression levels of TGF-1, p53, and miR-192 are increased in expanded glomeruli of diabetic mice [58,101,102]. Suppression of miR-192 function in vivo inhibits p53 expression in the renal cortex of control and streptozotocin injected diabetic mice [58].…”