title: Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy.
abstract: Increased urinary albumin excretion is not simply an aftermath of glomerular injury, but is also involved in the progression of diabetic nephropathy (DN). Whereas Toll-like receptors (TLRs) are incriminated in the renal inflammation of DN, whether and how albumin is involved in the TLR-related renal inflammatory response remains to be clarified. Here, we showed that both TLR2 and TLR4, one of their putative endogenous ligands [heat shock protein 70 (HSP70)] and nuclear factor-κB promoter activity were markedly elevated in the kidneys of diabetic mice. A deficiency of TLR4 but not of TLR2 alleviated albuminuria, tubulointerstitial fibrosis and inflammation induced by diabetes. The protection against renal injury in diabetic Tlr4(-/-) mice was associated with reduced tubular injuries and preserved cubilin levels, rather than amelioration of glomerular lesions. In vitro studies revealed that albumin, a stronger inducer than high glucose (HG), induced the release of HSP70 from proximal tubular cells. HSP70 blockade ameliorated albumin-induced inflammatory mediators. HSP70 triggered the production of inflammatory mediators in a TLR4-dependent manner. Moreover, HSP70 inhibition in vivo ameliorated diabetes-induced albuminuria, inflammatory response and tubular injury. Finally, we found that individuals with DN had higher levels of TLR4 and HSP70 in the dilated tubules than non-diabetic controls. Thus, activation of the HSP70-TLR4 axis, stimulated at least in part by albumin, in the tubular cell is a newly identified mechanism associated with induction of tubulointerstitial inflammation and aggravation of pre-existing microalbuminuria in the progression of DN.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan Institute of Clinical Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Huei-Fen
authors.initials: HF
authors.lastname: Jheng
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Pei-Jane
authors.initials: PJ
authors.lastname: Tsai
authors.affiliation: Department of Physiology, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Yi-Lun
authors.initials: YL
authors.lastname: Chuang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Shen
authors.affiliation: Department of Physiology, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Ting-An
authors.initials: TA
authors.lastname: Tai
authors.affiliation: Department of Pathology, National Cheng Kung University Hospital, Tainan 704, Taiwan.
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Chen
authors.affiliation: National Laboratory Animal Center, National Applied Research Laboratories, Taipei 115, Taiwan.
authors.forename: Chuan-Kai
authors.initials: CK
authors.lastname: Chou
authors.affiliation: Division of Nephrology, Department of Internal Medicine, E-DA Hospital/I-Shou University, Kaohsiung 824, Taiwan.
authors.forename: Li-Chun
authors.initials: LC
authors.lastname: Ho
authors.affiliation: Department of Physiology, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tang
authors.affiliation: R&D Center, NovoTaiwan Biotech, Taipei 238, Taiwan.
authors.forename: Kuei-Tai A
authors.initials: KT
authors.lastname: Lai
authors.affiliation: Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan jmsung@mail.ncku.edu.tw yaustsai@mail.ncku.edu.tw.
authors.forename: Junne-Ming
authors.initials: JM
authors.lastname: Sung
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan Institute of Clinical Medicine, National Cheng Kung University, Tainan 701, Taiwan Research Center of Clinical Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan, Republic of China jmsung@mail.ncku.edu.tw yaustsai@mail.ncku.edu.tw.
authors.forename: Yau-Sheng
authors.initials: YS
authors.lastname: Tsai
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000419:Albuminuria / Q000150:complications; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001706:Biopsy; D003928:Diabetic Nephropathies / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D057809:HEK293 Cells; D024243:HMGB1 Protein / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology*; D018374:LLC-PK1 Cells; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000418:Albumins; D024243:HMGB1 Protein; D018840:HSP70 Heat-Shock Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D005947:Glucose
keywords: Albuminuria; Damage-associated molecular pattern (DAMP); Diabetic nephropathy; Toll-like receptor; Tubular injury