| First Author | Zhu K | Year | 2023 |
| Journal | Sci Transl Med | Volume | 15 |
| Issue | 714 | Pages | eabq6492 |
| PubMed ID | 37729431 | Mgi Jnum | J:343513 |
| Mgi Id | MGI:7567745 | Doi | 10.1126/scitranslmed.abq6492 |
| Citation | Zhu K, et al. (2023) The D2D3 form of uPAR acts as an immunotoxin and may cause diabetes and kidney disease. Sci Transl Med 15(714):eabq6492 |
| abstractText | 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 beta cell mass, and high fasting blood glucose. Injection of anti-uPAR antibody restored beta cell mass and function in D2D3 transgenic mice. At the cellular level, the D2D3 protein impaired beta cell proliferation and inhibited the bioenergetics of beta 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. |
