| Autor: |
Zhu, Ke, Mukherjee, Kamalika, Wei, Changli, Hayek, Salim S., Collins, Agnieszka, Gu, Changkyu, Corapi, Kristin, Altintas, Mehmet M., Wang, Yong, Waikar, Sushrut S., Bianco, Antonio C., Koch, Alexander, Tacke, Frank, Reiser, Jochen, Sever, Sanja |
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| Zdroj: |
Science Translational Medicine; 9/20/2023, Vol. 15 Issue 714, p1-13, 13p |
| Abstrakt: |
Soluble urokinase plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. In addition to suPAR, proteolysis of membrane-bound uPAR results in circulating D1 and D2D3 proteins. We showed that when exposed to a high-fat diet, transgenic mice expressing D2D3 protein developed progressive kidney disease marked by microalbuminuria, elevated serum creatinine, and glomerular hypertrophy. D2D3 transgenic mice also exhibited insulin-dependent diabetes mellitus evidenced by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic β cell mass, and high fasting blood glucose. Injection of anti-uPAR antibody restored β cell mass and function in D2D3 transgenic mice. At the cellular level, the D2D3 protein impaired β cell proliferation and inhibited the bioenergetics of β cells, leading to dysregulated cytoskeletal dynamics and subsequent impairment in the maturation and trafficking of insulin granules. D2D3 protein was predominantly detected in the sera of patients with nephropathy and insulin-dependent diabetes mellitus. These sera inhibited glucose-stimulated insulin release from human islets in a D2D3-dependent manner. Our study showed that D2D3 injures the kidney and pancreas and suggests that targeting this protein could provide a therapy for kidney diseases and insulin-dependent diabetes mellitus. Editor's summary: Soluble urokinase plasminogen activator receptor (suPAR) is a risk factor for chronic kidney disease (CKD) progression. However, proteolysis of uPAR can also lead to generation of D2D3 protein. Here, Zhu and colleagues found that in serum samples from patients with diabetic nephropathy, D2D3 protein was predominantly associated with type 1 diabetes. They then generated D2D3 transgenic mice that developed kidney injury, insulin insufficiency, and diabetes associated with β cell injury on a high-fat diet, which could be improved by treatment with an anti-suPAR antibody. These findings highlight a role for D2D3 protein in the development of both kidney disease and diabetes and suggest that interventions targeting this protein could potentially improve both conditions. —Melissa Norton [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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