Truncated suPAR simultaneously causes kidney disease and autoimmune diabetes mellitus

Soluble urokinase-type plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. Here we report the presence of C-terminal suPAR fragment, D2D3, in patients with diabetic nephropathy. D2D3-positive human sera inhibited glucose-stimulated insulin release in human islets and were associated with patients requiring insulin therapy. D2D3 transgenic mice presented kidney disease and diabetes marked by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic β-cell mass, and high fasting glucose. D2D3 fragment dysregulated glucose-induced cytoskeletal dynamics, impaired maturation and trafficking of insulin granules, and inhibited bioenergetics of β-cells in culture. An anti-uPAR antibody restored β-cell function in D2D3 transgenic mice. We show that the D2D3 fragment injures the kidney and pancreas, offering a unique dual therapeutic approach for kidney diseases and insulin-dependent diabetes. Summary Proteolytic suPAR fragment, D2D3, simultaneously injures two organs, the kidney and pancreas, thus causing a dual organ disease. ### Competing Interest Statement S. S. and J.R. are co-founders and shareholders of Walden Biosciences, a biotechnology company that develops novel kidney-protective therapies. S.S, J.R. and C.W. are inventors on a pending patent application pertaining to the role of D2D3 fragment in diabetes and diabetic nephropathy. The remaining authors declare no competing interests.