Journal
CELL METABOLISM
Volume 33, Issue 5, Pages 1042-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2021.04.004
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Funding
- National Institute of Health/NIDDK [2R01DK072381, R37DK039773, DK072381, DK099473-01]
- Boehringer Ingelheim Pharmaceuticals
- Uehara Memorial Foundation
- Japan Society for the Promotion of Science (JSPS)
- JSPS
- Chuo Clinic
- American Heart Association
- Juvenile Diabetes Research Foundation International [3-PDF-2014-110-A-N]
- Royal Australasian College of Physicians
- Ben J. Lipps Research Fellowship of the American Society of Nephrology
- Monahan Foundation
- Fondation pour la Recherche Medicale
- Groupe Pasteur Mutualite
- Societe Francophone de Transplantation
- Arthur Sachs fellowship
- Philippe Foundation
- Fulbright Scholarship
- ATIP Avenir program
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Tubulointerstitial abnormalities can predict the progression of diabetic kidney disease, with KIM-1 playing a crucial role in this process. Targeting KIM-1 could be a potential therapeutic approach to alleviate renal damage.
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.
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