| Literature DB >> 33951465 |
Yutaro Mori1, Amrendra K Ajay2, Jae-Hyung Chang2, Shan Mou3, Huiping Zhao4, Seiji Kishi5, Jiahua Li2, Craig R Brooks2, Sheng Xiao6, Heung-Myong Woo7, Venkata S Sabbisetti2, Suetonia C Palmer2, Pierre Galichon2, Li Li2, Joel M Henderson8, Vijay K Kuchroo9, Julie Hawkins10, Takaharu Ichimura2, Joseph V Bonventre11.
Abstract
Tubulointerstitial abnormalities are predictive of the progression of diabetic kidney disease (DKD), and their targeting may be an effective means for prevention. Proximal tubular (PT) expression of kidney injury molecule (KIM)-1, as well as blood and urinary levels, are increased early in human diabetes and can predict the rate of disease progression. Here, we report that KIM-1 mediates PT uptake of palmitic acid (PA)-bound albumin, leading to enhanced tubule injury with DNA damage, PT cell-cycle arrest, interstitial inflammation and fibrosis, and secondary glomerulosclerosis. Such injury can be ameliorated by genetic ablation of the KIM-1 mucin domain in a high-fat-fed streptozotocin mouse model of DKD. We also identified TW-37 as a small molecule inhibitor of KIM-1-mediated PA-albumin uptake and showed in vivo in a kidney injury model in mice that it ameliorates renal inflammation and fibrosis. Together, our findings support KIM-1 as a new therapeutic target for DKD.Entities:
Keywords: DNA damage response; HAVCR1; TIM-1; albuminuria; chronic kidney disease; diabetic nephropathy; proximal tubule; renal fibrosis; senescence; tubulointerstitial disease
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Year: 2021 PMID： 33951465 PMCID： PMC8132466 DOI： 10.1016/j.cmet.2021.04.004
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287