Transforming Growth Factor-β–Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy
Open Access
- 15 August 2013
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 62 (9), 3151-3162
- https://doi.org/10.2337/db13-0305
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.Keywords
This publication has 50 references indexed in Scilit:
- MicroRNAs and the glomerulusExperimental Cell Research, 2012
- MicroRNAs in Stress Signaling and Human DiseaseCell, 2012
- A microRNA circuit mediates transforming growth factor-β1 autoregulation in renal glomerular mesangial cellsKidney International, 2011
- Low‐dose paclitaxel ameliorates fibrosis in the remnant kidney model by down‐regulating miR‐192The Journal of Pathology, 2011
- TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosisCell and tissue research, 2011
- MicroRNA-29c Is a Signature MicroRNA under High Glucose Conditions That Targets Sprouty Homolog 1, and Its in Vivo Knockdown Prevents Progression of Diabetic NephropathyPublished by Elsevier BV ,2011
- RETRACTED: Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma DevelopmentCancer Cell, 2010
- TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTENNature, 2009
- MicroRNAs: Target Recognition and Regulatory FunctionsCell, 2009
- MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressorsProceedings of the National Academy of Sciences of the United States of America, 2007