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  • KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease.

KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease.

Cell metabolism (2021-05-06)
Yutaro Mori, Amrendra K Ajay, Jae-Hyung Chang, Shan Mou, Huiping Zhao, Seiji Kishi, Jiahua Li, Craig R Brooks, Sheng Xiao, Heung-Myong Woo, Venkata S Sabbisetti, Suetonia C Palmer, Pierre Galichon, Li Li, Joel M Henderson, Vijay K Kuchroo, Julie Hawkins, Takaharu Ichimura, Joseph V Bonventre
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cytochalasin D, from Zygosporium mansonii, ≥98% (TLC and HPLC), powder
Sigma-Aldrich
Bovine Serum Albumin, heat shock fraction, pH 7, ≥98%
Sigma-Aldrich
Anti-Actin, α-Smooth Muscle - Cy3 antibody, Mouse monoclonal, clone 1A4, purified from hybridoma cell culture
Millipore
Anti-CD36 Antibody, clone SM-phi, clone SM-phi, Chemicon®, from mouse
Sigma-Aldrich
Anti-Actin, α-Smooth Muscle - FITC antibody, Mouse monoclonal, clone 1A4, purified from hybridoma cell culture
Sigma-Aldrich
Anti-CD3, T Cell antibody produced in rabbit, whole antiserum