Discover Brigham
Poster Session

Wednesday, November 3rd, 2021 | 1pm - 3:45pm et

Virtual Event

Yutaro Mori, MD, PhD

Research Fellow
Engineering in Medicine, Renal Medicine
KIM-1-mediated Proximal Tubular Uptake of Palmitic Acid-Albumin Leads to Progressive Diabetic Kidney Disease

Principal Investigator: Joseph V. Bonventre

Authors: Yutaro Mori, Amrendra K. Ajay, Takaharu Ichimura, Joseph V. Bonventre
Lay Abstract

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.

Scientific Abstract

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.

Clinical Implications
We have found a mechanism of progressive diabetic kidney disease (DKD) which was previously unknown. We have also discovered a potential new therapeutic approach to explore to reduce progression of DKD.

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