Thrombospondin 1 mediates renal dysfunction in a mouse model of high-fat diet-induced obesity
Wenpeng Cui1, Hasiyeti Maimaitiyiming, Xinyu Qi
1Graduate Center for Nutritional Sciences, Univ. of Kentucky, Wethington Bldg. Rm. 583, 900 S. Limestone St., Lexington, KY 40536. swang7@uky.edu.
Abstract:
Obesity is prevalent worldwide and is a major risk factor for many diseases including renal complications. Thrombospondin 1 (TSP1), a multifunctional extracellular matrix protein, plays an important role in diabetic kidney diseases. However, whether TSP1 plays a role in obesity-related kidney disease is unknown. In the present studies, the role of TSP1 in obesity-induced renal dysfunction was determined by using a diet-induced obese mouse model. The results demonstrated that TSP1 was significantly upregulated in the kidney from obese mice. The increased TSP1 was localized in the glomerular mesangium as well as in the tubular system from obese wild-type mice. Obese wild-type mice developed renal hypertrophy and albuminuria, which was associated with increased kidney macrophage infiltration, augmented kidney inflammation, and activated transforming growth factor (TGF)-β signaling and renal fibrosis. In contrast, obese TSP1-deficient mice did not develop these kidney damages. Furthermore, in vitro studies demonstrated that leptin treatment stimulated the expression of TSP1, TGF-β1, fibronectin, and collagen type IV in mesangial cells isolated from wild-type mice. These leptin-stimulated effects were abolished in TSP1-deficient mesangial cells. Taken together, these data suggest that TSP1 is an important mediator for obesity- or hyperleptinemia-induced kidney dysfunction.
Insights
Thrombospondin 1 (TSP1) is upregulated in obesity-induced kidney disease, contributing to renal dysfunction. TSP1 deficiency prevents obesity-related kidney damage, highlighting its role in hyperleptinemia-induced kidney dysfunction.
Area of Science:
- Nephrology
- Metabolic disease research
- Extracellular matrix biology
Background:
- Obesity is a global health issue linked to numerous diseases, including kidney complications.
- Thrombospondin 1 (TSP1), an extracellular matrix protein, is implicated in diabetic kidney disease.
- The role of TSP1 in obesity-related kidney disease remains largely unexplored.
Purpose of the Study:
- To investigate the role of TSP1 in the development of obesity-induced kidney dysfunction.
- To determine if TSP1 mediates renal damage in a diet-induced obese mouse model.
Main Methods:
- Utilized a diet-induced obese mouse model to study obesity-related kidney disease.
- Assessed TSP1 expression and localization in kidney tissues of obese wild-type and TSP1-deficient mice.
- Evaluated renal hypertrophy, albuminuria, kidney inflammation, TGF-β signaling, and fibrosis.
- Conducted in vitro studies using isolated mesangial cells treated with leptin.
Main Results:
- TSP1 was significantly upregulated in the kidneys of obese mice, localized in glomeruli and tubules.
- Obese wild-type mice exhibited renal hypertrophy, albuminuria, inflammation, and fibrosis, which were absent in obese TSP1-deficient mice.
- Leptin treatment stimulated TSP1, TGF-β1, fibronectin, and collagen type IV expression in wild-type mesangial cells, but not in TSP1-deficient cells.
Conclusions:
- TSP1 is a key mediator in obesity- and hyperleptinemia-induced kidney dysfunction.
- Targeting TSP1 may offer a therapeutic strategy for obesity-related kidney diseases.