Increased urinary albumin excretion is not simply an aftermath of glomerular injury, and also involves in the progression of diabetic nephropathy (DN). While toll-like receptors (TLRs) are incriminated in renal inflammation of DN, whether and how albumin is involved in TLR-related renal inflammatory response remains to be clarified. Here we showed that both TLR2 and TLR4, one of their putative endogenous ligands HSP70, and NF-κB promoter activity were markedly elevated in the kidney of diabetic mice. A deficiency of TLR4, but not 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, 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 ameliorates diabetes-induced albuminuria, inflammatory response, and tubular injury. Finally, we found that DN patients 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 novel mechanism associated with inducing tubulointerstitial inflammation and aggravating pre-existing microalbuminuria in the progression of DN.
Albumin stimulates renal tubular inflammation through a HSP70-TLR4 axis in early diabetic nephropathy
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Huei-Fen Jheng, Pei-Jane Tsai, Yi-Lun Chuang, Yi-Ting Sheng, Ting-An Tai, Wen-Chung Chen, Chuan-Kai Chou, Li-Chun Ho, Ming-Jer Tang, Kuei-Tai A. Lai, Junne-Ming Sung, Yau-Sheng Tsai; Albumin stimulates renal tubular inflammation through a HSP70-TLR4 axis in early diabetic nephropathy. Dis Model Mech 2015; dmm.019398. doi: https://doi.org/10.1242/dmm.019398
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