KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease.
Animals
Benzamides
/ pharmacology
Cell Cycle Checkpoints
/ drug effects
DNA Damage
/ drug effects
Diabetes Mellitus, Experimental
/ chemically induced
Diabetic Nephropathies
/ metabolism
Endocytosis
Fatty Acids
/ metabolism
Fibrosis
Hepatitis A Virus Cellular Receptor 1
/ antagonists & inhibitors
Humans
Kidney Tubules, Proximal
/ cytology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Palmitic Acid
/ chemistry
RNA Interference
RNA, Small Interfering
/ metabolism
Serum Albumin, Bovine
/ chemistry
Sulfones
/ pharmacology
DNA damage response
HAVCR1
TIM-1
albuminuria
chronic kidney disease
diabetic nephropathy
proximal tubule
renal fibrosis
senescence
tubulointerstitial disease
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
04 05 2021
04 05 2021
Historique:
received:
08
06
2020
revised:
03
01
2021
accepted:
08
04
2021
entrez:
5
5
2021
pubmed:
6
5
2021
medline:
23
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33951465
pii: S1550-4131(21)00170-4
doi: 10.1016/j.cmet.2021.04.004
pmc: PMC8132466
mid: NIHMS1697831
pii:
doi:
Substances chimiques
Benzamides
0
Fatty Acids
0
HAVCR1 protein, human
0
Hepatitis A Virus Cellular Receptor 1
0
RNA, Small Interfering
0
Sulfones
0
TW-37 compound
0
Serum Albumin, Bovine
27432CM55Q
Palmitic Acid
2V16EO95H1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1042-1061.e7Subventions
Organisme : NIDDK NIH HHS
ID : K01 DK099473
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK072381
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK121101
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK039773
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests J.V.B. and T.I. are co-inventors on KIM-1 patents assigned to Mass General Brigham. J.V.B. and A.K.A. have filed a patent for the discovery of TW-37 as inhibitor of KIM-1 to alleviate chronic kidney disease. J.V.B. is a consultant to Cadent, Praxis, Seattle Genetics, Aldeyra, Sarepta, Praxis, and Angion and owns equity in Goldfinch, Innoviva, MediBeacon, DxNow, Verinano, Autonomous Medical Devices, Renalytix, Pacific Biosciences, and Sentien. V.K.K. has an ownership interest in Tizona Therapeutics, Celsius Therapeutics, and Bicara Therapeutics. V.K.K. has financial interests in Biocon Biologic, BioLegend, Elpiscience Biopharmaceutical Ltd., Equilium Inc., and Syngene Intl. V.K.K. is a member of SABs for Elpiscience Biopharmaceutical Ltd., GSK, Rubius Therapeutics, and Tizona Therapeutics. J.V.B.’s and V.K.K.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. S.X. is an employee and shareholder of Celsius Therapeutics. J.H. is a full-time employee of Boehringer Ingelheim Pharmaceuticals, Inc. TW-37 was identified as a KIM-1 inhibitor in a screen supported by Boehringer Ingelheim Pharmaceuticals, Inc.
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