title: 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.
authors: Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors: Supriya D
authors: SD
authors: Deshpande
authors: Sumanth
authors: S
authors: Putta
authors: Mei
authors: M
authors: Wang
authors: Jennifer Y
authors: JY
authors: Lai
authors: Markus
authors: M
authors: Bitzer
authors: Robert G
authors: RG
authors: Nelson
authors: Linda L
authors: LL
authors: Lanting
authors: Mitsuo
authors: M
authors: Kato
authors: Rama
authors: R
authors: Natarajan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C539618:Mirn192 microRNA, mouse; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53
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