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Thrombospondin 1 Deficiency Ameliorates the Development of Adriamycin-Induced Proteinuric Kidney Disease
Hasiyeti Maimaitiyiming1,2, Qi Zhou1,2, Shuxia Wang1,2
1Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, United States of America.
Abstract:
Accumulating evidence suggests that thrombospondin 1 (TSP1) is an important player in diabetic nephropathy. However, the role of TSP1 in podocyte injury and the development of non-diabetic proteinuric kidney disease is largely unknown. In the current study, by using a well-established podocyte injury model (adriamycin-induced nephropathy mouse model), we examined the contribution of TSP1 to the development of proteinuric kidney disease. We found that TSP1 was up-regulated in the glomeruli, notably in podocytes, in adriamycin injected mice before the onset of proteinuria. ADR treatment also stimulated TSP1 expression in cultured human podocytes in vitro. Moreover, increased TSP1 mediated ADR-induced podocyte apoptosis and actin cytoskeleton disorganization. This TSP1's effect was through a CD36-dependent mechanism and involved in the stimulation of p38MAPK pathway. Importantly, in vivo data demonstrated that TSP1 deficiency protected mice from ADR induced podocyte loss and foot process effacement. ADR induced proteinuria, glomerulosclerosis, renal macrophage infiltration and inflammation was also attenuated in TSP1 deficient mice. Taken together, these studies provide new evidence that TSP1 contributes to the development of non-diabetic proteinuric kidney disease by stimulating podocyte injury and the progression of renal inflammation.
Insights
Thrombospondin 1 (TSP1) drives non-diabetic kidney disease by harming podocytes. TSP1 deficiency protects against adriamycin-induced kidney injury, reducing proteinuria and inflammation.
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Thrombospondin 1 (TSP1) is implicated in diabetic nephropathy.
- The role of TSP1 in non-diabetic proteinuric kidney disease and podocyte injury remains unclear.
Purpose of the Study:
- To investigate the contribution of TSP1 to podocyte injury and non-diabetic proteinuric kidney disease development.
- To elucidate the mechanisms underlying TSP1-mediated podocyte damage.
Main Methods:
- Utilized the adriamycin-induced nephropathy mouse model for podocyte injury.
- Examined TSP1 expression in vivo and in cultured human podocytes.
- Investigated TSP1's role in podocyte apoptosis, cytoskeleton, and inflammatory pathways (CD36, p38MAPK).
- Assessed the effects of TSP1 deficiency on kidney injury markers.
Main Results:
- TSP1 was upregulated in glomeruli and podocytes following adriamycin (ADR) treatment, preceding proteinuria.
- ADR stimulated TSP1 expression in cultured podocytes.
- TSP1 promoted ADR-induced podocyte apoptosis and actin disorganization via CD36 and p38MAPK.
- TSP1-deficient mice showed protection against ADR-induced podocyte loss, proteinuria, glomerulosclerosis, and inflammation.
Conclusions:
- TSP1 significantly contributes to the pathogenesis of non-diabetic proteinuric kidney disease.
- TSP1 exacerbates kidney injury by inducing podocyte damage and promoting renal inflammation.
- Targeting TSP1 may offer a therapeutic strategy for proteinuric kidney diseases.
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