Principal Investigator: Joseph V. Bonventre
Diabetic kidney disease (DKD) is the most prevalent cause of kidney failure. Our lab previously discovered Kidney Injury Molecule-1 (KIM-1), which is produced by cells that are damaged. We found that KIM-1 expression on cells takes up palmitic acid (PA)-bound albumin, which then results in kidney inflammation and fibrosis. KIM-1 is expressed in human patient kidneys. Both in cells and in mice, KIM-1-mediated PA-albumin uptake into kidney cells caused inflammation and fibrosis which are major causes of progression of kidney diseases. We discovered a new drug, TW-37, which reduced progression of DKD. In conclusion, KIM-1 makes DKD worse and TW-37 protects against progression of DKD.
Background: Kidney tubulointerstitial damage is predictive of progression of diabetic kidney disease (DKD). Blood and urinary Kidney Injury Molecule-1 (KIM-1) levels are increased in human diabetes and predict progression of DKD. We hypothesized that KIM-1-mediated uptake of palmitic acid (PA)- albumin contributes to tubulointerstitial damage in DKD.
Method: Human DKD renal biopsy samples were analyzed. PA-albumin uptake was evaluated in renal epithelial cells expressing KIM-1 as was cell death and pro-inflammatory and pro-fibrotic effects in vitro. In vivo, an aristolochic acid-induced new DKD-associated model was created both in wild-type and KIM-1 functional knockout (KIM-1Δmucin) mice. An inhibitor for KIM-1-mediated endocytosis was screened for and then tested.
Results: KIM-1 was expressed in DKD kidneys, correlating with tubulointerstitial inflammation and fibrosis. PA-albumin was taken up by KIM-1-positive cells, inducing IL-1β and TGF-β1 production through inflammasomes and cell death, or G2/M cell cycle arrest. In vivo, wild-type mice showed more macrophage infiltration and myofibroblast activation than KIM-1Δmucin mice did. A KIM-1 inhibitor, TW-37, was identified which prevented PA-albumin uptake and subsequent injury both in vitro and in vivo.
Conclusions: KIM-1 mediates the PT uptake of PA-albumin, leading to pro-inflammatory and pro- fibrotic responses. Our findings establish KIM-1 as a therapeutic target for DKD.