title: Inhibition of c-Src/p38 MAPK pathway ameliorates renal tubular epithelial cells apoptosis in db/db mice.
abstract: Renal tubular epithelial cells (RTEC) apoptosis, which plays a key role in the pathogenesis and progression of diabetic nephropathy (DN), is believed to be contributive to the hyperglycemia-induced kidney failure, though the exact mechanisms remain elusive. In this study, we investigated how inhibition of c-Src/p38 MAPK pathway would affect RTEC apoptosis. The c-Src inhibitor PP2 i.p. administered every other day for 8 weeks to diabetic db/db mice significantly reduced their kidney weights, daily urinary volumes, blood glucose, blood urea nitrogen, serum creatinine, triglyceride and urine albumin excretion, whereas deactivation of c-Src and p38 MAPK were also observed, along with decreases in both Bax/Bcl-2 ratio and cleaved caspase-3 level in the kidneys. In vitro, exposure of HK-2 cells (a human RTEC line), to high glucose (HG) promoted phosphorylation of c-Src and p38 MAPK, and subsequently, as revealed by western blotting, TUNEL assay and flow cytometry, increased cell death, which can be inhibited by PP2. Especially, a specific p38 MAPK inhibitor, SB203580, that both attenuated HG-induced c-Src activation and abrogated the expression of PPARγ and CHOP, also reduced apoptosis. Taken together, PP2 inhibits c-Src and therefore reduces apoptosis in RTEC, which at least in part, is due to suppressed p38 MAPK activation in diabetic kidney.
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhufang, China.
authors.forename: Haijiang
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhufang, China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Oncology & Immunotherapy, Hebei General Hospital, Shijiazhuang, China.
authors.forename: Xinna
authors.initials: X
authors.lastname: Deng
authors.affiliation: Mathew Mailing Centre for Translational Transplantation Studies, Lawson Health Research Institute, London Health Sciences Centre, Department of Medicine, and Pathology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Ye
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhufang, China.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Du
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhufang, China.
authors.forename: Jinying
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhufang, China.
authors.forename: Yunzhuo
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhufang, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhufang, China.
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhufang, China. Electronic address: duanhuijun999@163.com.
authors.forename: Huijun
authors.initials: H
authors.lastname: Duan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004847:Epithelial Cells; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: C412373:AG 1879; D011743:Pyrimidines
keywords: Apoptosis; Diabetic nephropathy; c-Src; db/db mice; p38 MAPK