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

Tubulointerstitial abnormalities are predictive of diabetic kidney disease (DKD) progression, and targeting these abnormalities may offer a promising approach for prevention. Proximal tubular (PT) expression of kidney injury molecule (KIM)-1, along with elevated blood and urinary levels, is increased early in human diabetes and can predict the rate of disease progression. In this study, we demonstrate that KIM-1 mediates the PT uptake of palmitic acid (PA)-bound albumin, which exacerbates tubule injury, leading to DNA damage, PT cell-cycle arrest, interstitial inflammation, fibrosis, and secondary glomerulosclerosis. This injury can be mitigated by the genetic deletion of the KIM-1 mucin domain in a high-fat-fed streptozotocin mouse model of DKD. Additionally, we identified TW-37 as a small molecule inhibitor of KIM-1-mediated PA-albumin uptake and showed that in vivo administration of TW-37 in a kidney injury mouse model reduces renal inflammation and fibrosis. Together, these findings highlight KIM-1 as a novel therapeutic target for DKD.