title: Intrarenal renin-angiotensin system mediates fatty acid-induced ER stress in the kidney.
abstract: Obesity-related kidney disease is related to caloric excess promoting deleterious cellular responses. Accumulation of saturated free fatty acids in tubular cells produces lipotoxicity involving significant cellular dysfunction and injury. The objectives of this study were to elucidate the role of renin-angiotensin system (RAS) activation in saturated fatty acid-induced endoplasmic reticulum (ER) stress in cultured human proximal tubule epithelial cells (HK2) and in mice fed with a high-fat diet. Treatment with saturated fatty acid palmitic acid (PA; 0.8 mM) for 24 h induced ER stress in HK2, leading to an unfolded protein response as reflected by increased expressions of the ER chaperone binding immunoglobulin protein (BiP) and proapoptotic transcription factor C/EBP homologous protein (CHOP) protein as evaluated by immunoblotting. PA treatment also induced increased protein expression of inositol requiring protein 1α (IRE1α), phosphorylated eukaryotic initiation factor-α (eIF2α), and activating transcription factor 4 (ATF4) as well as activation of caspase-3. PA treatment was associated with increased angiotensin II levels in cultured medium. The angiotensin II type 1 receptor (AT1R) blocker valsartan or renin inhibitor aliskiren dramatically suppressed PA-induced upregulation of BiP, CHOP, IRE1α, p-eIF2α, and ATF4 in HK2 cells. In contrast, valsartan or aliskiren did not prevent ER stress induced by tunicamycin. C57BL/6 mice fed with a high-fat diet for 14 wk exhibited increased protein expressions of BiP and CHOP compared with control mice, which were significantly attenuated by the valsartan treatment. Increased angiotensin II levels in serum and urine were observed in mice fed with a high-fat diet when compared with controls. It is suggested that the intrarenal RAS activation may play an important role in diabetic kidney injury via mediating ER stress induced by saturated fatty acid.
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
authors.forename: Chunling
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
authors.forename: Renfei
authors.initials: R
authors.lastname: Luo
authors.affiliation: Department of Orthopedics, The 5th Affiliated Hospital, Sun Yat-sen University, Zhuhai, China;
authors.forename: Shaoming
authors.initials: S
authors.lastname: Chen
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; wangwd6@mail.sysu.edu.cn.
authors.forename: Feifei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
authors.forename: Peili
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Division of Hypertension and Renal Diseases, University of Colorado Denver, Aurora, Colorado; and.
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Medicine, Division of Renal Diseases and Hypertension, University of Utah, Salt Lake City, Utah.
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
mesh_terms: D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood / Q000652:urine; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005650:Fumarates / Q000494:pharmacology; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D019308:Palmitic Acid / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D000068756:Valsartan / Q000494:pharmacology
chemical_list: D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D005650:Fumarates; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; D014415:Tunicamycin; D000804:Angiotensin II; D051742:Transcription Factor CHOP; D019308:Palmitic Acid; C446481:aliskiren; D000068756:Valsartan
keywords: angiotensin II; kidney; saturated fatty acid; valsartan