title: p53 induces miR199a-3p to suppress SOCS7 for STAT3 activation and renal fibrosis in UUO.
abstract: The role of p53 in renal fibrosis has recently been suggested, however, its function remains controversial and the underlying mechanism is unclear. Here, we show that pharmacological and genetic blockade of p53 attenuated renal interstitial fibrosis, apoptosis, and inflammation in mice with unilateral urethral obstruction (UUO). Interestingly, p53 blockade was associated with the suppression of miR-215-5p, miR-199a-5p&3p, and STAT3. In cultured human kidney tubular epithelial cells (HK-2), TGF-β1 treatment induced fibrotic changes, including collagen I and vimentin expression, being associated with p53 accumulation, p53 Ser15 phosphorylation, and miR-199a-3p expression. Inhibition of p53 by pifithrin-α blocked STAT3 activation and the expression of miR-199a-3p, collagen I, and vimentin during TGF-β1 treatment. Over-expression of miR-199a-3p increased TGFβ1-induced collagen I and vimentin expression and restored SOCS7 expression. Furthermore, SOCS7 was identified as a target gene of miR-199a-3p, and silencing of SOCS7 promoted STAT3 activation. ChIp analyses indicated the binding of p53 to the promoter region of miR-199a-3p. Consistently, kidney biopsies from patients with IgA nephropathy and diabetic nephropathy exhibited substantial activation of p53 and STAT3, decreased expression of SOCS7, and increase in profibrotic proteins and miR-199a-3p. Together, these results demonstrate the novel p53/miR-199a-3p/SOCS7/STAT3 pathway in renal interstitial fibrosis.
authors.affiliation: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.|Department of Emergency Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Ruhao
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Jinwen
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Xiang
authors.affiliation: Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.|Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Dongshan
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation; D005922:Glomerulonephritis, IGA / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014521:Urethra / Q000378:metabolism / Q000473:pathology; D014524:Urethral Obstruction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; C577160:MIRN215 microRNA, mouse; D035683:MicroRNAs; D009687:Nuclear Proteins; C108775:SOCS7 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D014746:Vimentin; C531408:mirn199 microRNA, human