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Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy.
Dis Model Mech. 2015 Oct 01; 8(10):1311-21.DM

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+Show Affiliations

Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan Institute of Clinical Medicine, National Cheng Kung University, Tainan 701, Taiwan.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.Department of Physiology, National Cheng Kung University, Tainan 701, Taiwan.Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan.Department of Physiology, National Cheng Kung University, Tainan 701, Taiwan.Department of Pathology, National Cheng Kung University Hospital, Tainan 704, Taiwan.National Laboratory Animal Center, National Applied Research Laboratories, Taipei 115, Taiwan.Division of Nephrology, Department of Internal Medicine, E-DA Hospital/I-Shou University, Kaohsiung 824, Taiwan.Department of Physiology, National Cheng Kung University, Tainan 701, Taiwan.R&D Center, NovoTaiwan Biotech, Taipei 238, Taiwan.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26398934

Citation

Jheng, Huei-Fen, et al. "Albumin Stimulates Renal Tubular Inflammation Through an HSP70-TLR4 Axis in Mice With Early Diabetic Nephropathy." Disease Models & Mechanisms, vol. 8, no. 10, 2015, pp. 1311-21.
Jheng HF, Tsai PJ, Chuang YL, et al. Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy. Dis Model Mech. 2015;8(10):1311-21.
Jheng, H. F., Tsai, P. J., Chuang, Y. L., Shen, Y. T., Tai, T. A., Chen, W. C., Chou, C. K., Ho, L. C., Tang, M. J., Lai, K. T., Sung, J. M., & Tsai, Y. S. (2015). Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy. Disease Models & Mechanisms, 8(10), 1311-21. https://doi.org/10.1242/dmm.019398
Jheng HF, et al. Albumin Stimulates Renal Tubular Inflammation Through an HSP70-TLR4 Axis in Mice With Early Diabetic Nephropathy. Dis Model Mech. 2015 Oct 1;8(10):1311-21. PubMed PMID: 26398934.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy. AU - Jheng,Huei-Fen, AU - Tsai,Pei-Jane, AU - Chuang,Yi-Lun, AU - Shen,Yi-Ting, AU - Tai,Ting-An, AU - Chen,Wen-Chung, AU - Chou,Chuan-Kai, AU - Ho,Li-Chun, AU - Tang,Ming-Jer, AU - Lai,Kuei-Tai A, AU - Sung,Junne-Ming, AU - Tsai,Yau-Sheng, Y1 - 2015/08/06/ PY - 2014/12/01/received PY - 2015/07/29/accepted PY - 2015/9/24/entrez PY - 2015/9/24/pubmed PY - 2016/7/20/medline KW - Albuminuria KW - Damage-associated molecular pattern (DAMP) KW - Diabetic nephropathy KW - Toll-like receptor KW - Tubular injury SP - 1311 EP - 21 JF - Disease models & mechanisms JO - Dis Model Mech VL - 8 IS - 10 N2 - 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. SN - 1754-8411 UR - https://www.unboundmedicine.com/medline/citation/26398934/Albumin_stimulates_renal_tubular_inflammation_through_an_HSP70_TLR4_axis_in_mice_with_early_diabetic_nephropathy_ L2 - http://dmm.biologists.org/lookup/pmidlookup?view=long&pmid=26398934 DB - PRIME DP - Unbound Medicine ER -