RT Journal Article
SR Electronic
T1 Truncated suPAR simultaneously causes kidney disease and autoimmune diabetes mellitus
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.26.489589
DO 10.1101/2022.04.26.489589
A1 Ke Zhu
A1 Kamalika Mukherjee
A1 Changli Wei
A1 Salim S. Hayek
A1 Agnieszka Collins
A1 Changkyu Gu
A1 Kristin Corapi
A1 Mehmet M. Altintas
A1 Yong Wang
A1 Sushrut S. Waikar
A1 Antonio C. Bianco
A1 Jochen Reiser
A1 Sanja Sever
YR 2022
UL http://biorxiv.org/content/early/2022/04/28/2022.04.26.489589.abstract
AB 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 StatementS. 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.