title: Atgl gene deletion predisposes to proximal tubule damage by impairing the fatty acid metabolism.
abstract: Fibrosis is the final common pathway of chronic kidney disease (CKD). Normal lipid metabolism is integral to renal physiology, and disturbances of renal lipid metabolism are increasingly being linked with CKD, including the fibrosis. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme of lipolysis. In the present study, we used Atgl-/-mice to investigate whether ATGL played a role in the regulation of proximal convoluted tubule (PCT) lipid metabolism and renal fibrosis development. ATGL deficiency led to lipid vacuolation of PCT and tubulointerstitial fibrosis, accompanied by massive albuminuria and decreased creatinine clearance rate (Ccr). In vitro experiments indicated that inhibition of ATGL in proximal tubular cell line HK-2 promoted intracellular lipid deposition, reactive oxygen species (ROS) accumulation and cell apoptosis. Both in vitro and in vivo experiments showed that ATGL inhibition decreased the renal peroxisome proliferator-activated receptorα(PPARα) expression, which implied the suppressed lipid metabolism. The antioxidant N-acetylcysteine (NAC) could partially reverse the effect of ROS accumulation and cell apoptosis, but could not restore the PPARαdecrease. These data raise the possibility that ATGL deficiency could impair the renal fatty acid metabolism though inhibiting PPARαexpression, which may lead to lipid deposition and cell apoptosis of PCT, and finally contribute to the renal fibrosis and dysfunction.
authors.affiliation: Department of Endocrinology, The 303th Hospital of PLA, Nanning, Guangxi Province 530000, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.affiliation: Institute of Burn Research, Southwest Hospital, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Diseases Proteomics, Chongqing 400038, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, The 303th Hospital of PLA, Nanning, Guangxi Province 530000, China.
authors.forename: Shiwu
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Department of Obstetrics and Gynecology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Diao
authors.affiliation: Department of Obstetrics and Gynecology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400038, China. Electronic address: hj.obgyn@outlook.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Han
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D017353:Gene Deletion; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D000217:Acyltransferases
chemical_list: D005227:Fatty Acids; D008049:Lipase; D047493:PPAR alpha; D017382:Reactive Oxygen Species; C494794:PNPLA2 protein, human; D000217:Acyltransferases; C494445:PNPLA2 protein, mouse
keywords: ATGL; Apoptosis; Lipometabolism; PPARα; Proximal tubule; ROS