Role of mitochondrial dysfunction in renal fibrosis promoted by hypochlorite-modified albumin in a remnant kidney model and protective effects of antioxidant peptide SS-31.
Oxidative stress aggravates renal fibrosis, a pathway involved in almost all forms of chronic kidney disease (CKD). However, the underlying mechanism involved in the pathogenesis of renal oxidative stress has not been completely elucidated. In this study, we explored the role and mechanism of hypochlorite-modified albumin (HOCl-alb) in mediating oxidative stress and fibrotic response in a remnant-kidney rat model. Five-sixths nephrectomy (5/6 NX) was performed on the rats and then the animals were randomly assigned to intravenous treatment with either vehicle alone, or HOCl-rat serum albumin (RSA) in the presence or absence of SS-31 (administered intraperitoneally). A sham-operation control group was set up concurrently. Compared with the control group, 5/6 NX animals displayed marked mitochondrial (mt) dysfunction, as evidenced by decrease of mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and manganese superoxide dismutase (MnSOD) activity, release of cytochrome C (Cyto C) from mitochondria to the cytoplasm, and increase of mitochondrial reactive oxygen species in renal tissues. They also displayed increased levels of HOCl-alb in both plasma and renal tissues. These changes were accompanied by accumulation of extracellular matrix, worsened proteinuria, deteriorated renal function, and a marked increase of macrophage infiltration along with up-regulation of monocyte chemoattractant protein (MCP)-1 and transforming growth factor (TGF)-β1 expression. HOCl-alb challenge further exacerbated the above biological effects in 5/6 NX animals, but these adverse effects were prevented by administration of SS-31, a mitochondrial targeted antioxidant peptide. These data suggest that accumulation of HOCl-alb may promote renal inflammation and fibrosis, probably related to mitochondrial oxidative stress and dysfunction and that the mitochondrial targeted peptide SS-31 might be a novel therapy for renal fibrosis and chronic renal failure (CRF).
Division of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
Hao
H
Zhao
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515,China.
Yan-Jun
YJ
Liu
Division of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Division of Nephrology, Taian City Central Hospital, Taian 271000, China.
Zong-Rui
ZR
Liu
Division of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Division of Nephrology, Huadu District people's Hospital, Southern Medical University, Guangzhou 510800, China.
Dong-Dong
DD
Tang
Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Xiao-Wen
XW
Chen
Division of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
Yi-Hua
YH
Chen
Southern Medical University, Guangzhou 510515, China.
Ru-Ning
RN
Zhou
Division of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
Si-Qi
SQ
Chen
Division of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China. Electronic address: nhongxin@126.com.
Hong-Xin
HX
Niu
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006997:Hypochlorous Acid / Q000737:chemistry*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D000975:Antioxidants; D015415:Biomarkers; D009842:Oligopeptides; D012709:Serum Albumin; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D006997:Hypochlorous Acid
Antioxidant peptide; Chronic renal failure; Formaldehyde (PubChem CID: 712); H2DCFDA (PubChem CID: 77718); Hypochlorite-modified albumin; Hypochlorous acid (PubChem CID: 24341); JC-1 (PubChem CID: 5492929); Mitochondrial dysfunction; Oxidative stress; Renal fibrosis; Tween-20 (PubChem CID: 443314); WST-8 (PubChem CID: 101049151)