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Yanling Zhang1, Kerri Thai1, David M Kepecs1
1Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.
Abstract:
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.
Insights
Diabetic kidney disease involves excessive kidney fibrosis. This study shows that a deficiency in the chemokine CXCL10 contributes to this fibrosis, and restoring CXCL10 levels prevents its development in mice.
Area of Science:
- Nephrology
- Immunology
- Endocrinology
Background:
- Diabetic kidney disease (DKD) is characterized by excessive extracellular matrix accumulation in the kidney, correlating with functional decline.
- While profibrotic factors are well-studied, the role of diminished endogenous antifibrotic factors in DKD is less understood.
- ELR-negative CXC chemokines, including CXCL10, act as antifibrotic signals.
Purpose of the Study:
- To investigate the role of the chemokine CXCL10 as an endogenous antifibrotic factor in diabetic kidney disease.
- To determine if CXCL10 deficiency contributes to kidney fibrosis in experimental diabetes.
- To evaluate the therapeutic potential of restoring CXCL10 levels in preventing DKD progression.
Main Methods:
- Compared plasma and bone marrow chemokine levels in diabetic (db/db) and control (db/m) mice.
- Assessed the effect of CXCL10 on kidney fibroblast collagen production in high glucose and TGF-β conditions in vitro.
- Administered recombinant murine CXCL10 to db/db mice to evaluate its effects on kidney pathology, albuminuria, and glomerular hypertrophy in vivo.
- Investigated the role of CXCR3, the receptor for CXCL10, by gene silencing.
Main Results:
- Diabetic mice exhibited significantly lower plasma and bone marrow concentrations of CXCL10 compared to controls.
- CXCL10 inhibited collagen production by kidney fibroblasts in response to high glucose and TGF-β.
- In vivo administration of CXCL10 reduced kidney fibrosis, albuminuria, and glomerular hypertrophy in diabetic mice.
- Silencing of CXCR3 abolished the antifibrotic effects of bone marrow secretions.
Conclusions:
- Experimental diabetes is characterized by a deficiency in the antifibrotic chemokine CXCL10.
- Restoration of CXCL10 levels effectively prevents kidney fibrosis and the development of diabetic kidney disease in a mouse model.
- CXCL10 and its receptor CXCR3 play a critical role in regulating kidney fibrosis in diabetes.
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