PMID- 31949126 OWN - NLM STAT- MEDLINE DCOM- 20210114 LR - 20210115 IS - 2041-4889 (Electronic) VI - 11 IP - 1 DP - 2020 Jan 16 TI - Drp1-mediated mitochondrial fission promotes renal fibroblast activation and fibrogenesis. PG - 29 LID - 10.1038/s41419-019-2218-5 [doi] LID - 29 AB - Excessive mitochondrial fission acts as a pro-proliferative marker in some cancers and organ fibrosis; its potential role in renal fibroblast activation and fibrogenesis has never been investigated. Here, we showed more pronounced fragmented mitochondria in fibrotic than in non-fibrotic renal fibroblast in humans and mice. In a mouse model of obstructive nephropathy, phosphorylation of Drp1 at serine 616 (p-Drp1S616) and acetylation of H3K27(H3K27ac) was increased in fibrotic kidneys; pharmacological inhibition of mitochondrial fission by mdivi-1 substantially reduced H3K27ac levels, fibroblasts accumulation, and interstitial fibrosis. Moreover, mdivi-1 treatment was able to attenuate the established renal fibrosis. In cultured renal interstitial fibroblasts, targeting Drp1 using pharmacological inhibitor or siRNA suppressed TGF-beta1-elicited cell activation and proliferation, as evidenced by inhibiting expression of alpha-smooth muscle actin (alpha-SMA) and collagen I, as well as by reducing DNA synthesis. In contrast, Drp1 deletion enhanced cell apoptosis, along with decreased mitochondrial fragmentation, mtROS elevation, and glycolytic shift upon TGF-beta1 stimulation. In Drp1 deletion fibroblasts, re-expression of wild-type Drp1 rather than Drp1S616A mutant restores the reduction of TGF-beta-induced-Drp1 phosphorylation, H3K27ac, and cell activation. Moreover, TGF-beta1 treatment increased the enrichment of H3K27ac at the promoters of alpha-SMA and PCNA, which was reversed in Drp1-knockdown fibroblasts co-transfected with empty vector or Drp1S616A, but not wild-type Drp1. Collectively, our results imply that inhibiting p-Drp1S616-mediated mitochondrial fission attenuates fibroblast activation and proliferation in renal fibrosis through epigenetic regulation of fibrosis-related genes transcription and may serve as a therapeutic target for retarding progression of chronic kidney disease. FAU - Wang, Yating AU - Wang Y AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. FAU - Lu, Miaoqing AU - Lu M AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. AD - Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. FAU - Xiong, Liping AU - Xiong L AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. FAU - Fan, Jinjin AU - Fan J AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. FAU - Zhou, Yi AU - Zhou Y AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. FAU - Li, Huiyan AU - Li H AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. FAU - Peng, Xuan AU - Peng X AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. FAU - Zhong, Zhong AU - Zhong Z AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. FAU - Wang, Yihan AU - Wang Y AD - Laboratory for Kidney Pathology, Inc., Nashville, TN, USA. FAU - Huang, Fengxian AU - Huang F AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. FAU - Chen, Wei AU - Chen W AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. FAU - Yu, Xueqing AU - Yu X AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. FAU - Mao, Haiping AU - Mao H AD - Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. maohp@mail.sysu.edu.cn. AD - NHC Key Laboratory of Nephrology, Guangzhou, China. maohp@mail.sysu.edu.cn. AD - Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. maohp@mail.sysu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200116 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Histones) RN - 0 (Proliferating Cell Nuclear Antigen) RN - 0 (Reactive Oxygen Species) RN - 0 (Transforming Growth Factor beta1) RN - 17885-08-4 (Phosphoserine) RN - EC 3.6.5.5 (Dnm1l protein, mouse) RN - EC 3.6.5.5 (Dnm1l protein, rat) RN - EC 3.6.5.5 (Dynamins) RN - K3Z4F929H6 (Lysine) SB - IM MH - Animals MH - Apoptosis MH - Cell Proliferation MH - Dynamins/antagonists & inhibitors/*metabolism MH - Fibroblasts/metabolism/*pathology/ultrastructure MH - Fibrosis MH - Gene Knockdown Techniques MH - Histones/metabolism MH - Humans MH - Kidney/*pathology MH - Lysine/metabolism MH - Male MH - Mice, Inbred C57BL MH - Mitochondria/metabolism/ultrastructure MH - *Mitochondrial Dynamics MH - Phosphorylation MH - Phosphoserine/metabolism MH - Proliferating Cell Nuclear Antigen/metabolism MH - Promoter Regions, Genetic/genetics MH - Protein Binding MH - Rats MH - Reactive Oxygen Species/metabolism MH - Transforming Growth Factor beta1/metabolism PMC - PMC6965618 COIS- The authors declare that they have no conflict of interest. EDAT- 2020/01/18 06:00 MHDA- 2021/01/15 06:00 PMCR- 2020/01/16 CRDT- 2020/01/18 06:00 PHST- 2019/08/31 00:00 [received] PHST- 2019/12/17 00:00 [accepted] PHST- 2019/12/15 00:00 [revised] PHST- 2020/01/18 06:00 [entrez] PHST- 2020/01/18 06:00 [pubmed] PHST- 2021/01/15 06:00 [medline] PHST- 2020/01/16 00:00 [pmc-release] AID - 10.1038/s41419-019-2218-5 [pii] AID - 2218 [pii] AID - 10.1038/s41419-019-2218-5 [doi] PST - epublish SO - Cell Death Dis. 2020 Jan 16;11(1):29. doi: 10.1038/s41419-019-2218-5.