Reversing CXCL10 Deficiency Ameliorates Kidney Disease in Diabetic Mice
| Autor: | Richard E. Gilbert, Kerri Thai, Daniel A. Winer, David M. Kepecs, Yanling Zhang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty medicine.medical_treatment CXCR3 Diabetes Mellitus Experimental Pathology and Forensic Medicine Mice 03 medical and health sciences 0302 clinical medicine immune system diseases Fibrosis Diabetes mellitus Internal medicine Animals Medicine Diabetic Nephropathies Kidney business.industry Growth factor medicine.disease Chemokine CXCL10 Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure 030220 oncology & carcinogenesis Albuminuria CXCL9 medicine.symptom business Kidney disease |
| Zdroj: | The American Journal of Pathology. 188:2763-2773 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2018.08.017 |
| Popis: | The excessive accumulation of extracellular matrix material in the kidney is a histopathologic hallmark of diabetic kidney disease that correlates closely with declining function. Although considerable research has focused on the role of profibrotic factors, comparatively little attention has been paid to the possibility that a diminution in endogenous antifibrotic factors may also contribute. Among the latter, the ELR− CXC chemokines, CXCL9, CXCL10, and CXCL11, have been shown to provide a stop signal to prevent excessive fibrosis. Although the plasma concentrations of CXCL9 and CXCL11 were similar, those of CXCL10 were markedly lower in diabetic db/db mice compared with control db/m mice. In cell culture, CXCL10 inhibited kidney fibroblast collagen production in response to high glucose and the prosclerotic growth factor, transforming growth factor-β. In vivo, recombinant murine CXCL10 reduced mesangial and peritubular matrix expansion, albuminuria, and glomerular hypertrophy in db/db mice. In bone marrow, a major source of circulating chemokines, the concentration of CXCL10 was lower in cells derived from diabetic mice than from their nondiabetic counterparts. Silencing of CXCR3, the cognate receptor for CXCL10, abrogated the antifibrotic effects of bone marrow–derived secretions. In conclusion, experimental diabetes is a state of CXCL10 deficiency and that restoration of CXCL10 abundance prevented fibrosis and the development of diabetic kidney disease in mice. |
| Databáze: | OpenAIRE |
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