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

Cell Metab. 2021 May 4;33(5):1042-1061.e7. doi: 10.1016/j.cmet.2021.04.004.

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.

Keywords: DNA damage response; HAVCR1; TIM-1; albuminuria; chronic kidney disease; diabetic nephropathy; proximal tubule; renal fibrosis; senescence; tubulointerstitial disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cell Cycle Checkpoints / drug effects
  • DNA Damage / drug effects
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology*
  • Endocytosis
  • Fatty Acids / metabolism*
  • Fibrosis
  • Hepatitis A Virus Cellular Receptor 1 / antagonists & inhibitors
  • Hepatitis A Virus Cellular Receptor 1 / genetics
  • Hepatitis A Virus Cellular Receptor 1 / metabolism*
  • Humans
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Palmitic Acid / chemistry
  • Palmitic Acid / metabolism
  • Palmitic Acid / pharmacology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Serum Albumin, Bovine / chemistry
  • Serum Albumin, Bovine / pharmacology
  • Sulfones / pharmacology

Substances

  • Benzamides
  • Fatty Acids
  • HAVCR1 protein, human
  • Hepatitis A Virus Cellular Receptor 1
  • RNA, Small Interfering
  • Sulfones
  • TW-37 compound
  • Serum Albumin, Bovine
  • Palmitic Acid