Truncated suPAR simultaneously causes kidney disease and autoimmune diabetes mellitus

Zhu, K.; Mukherjee, K.; Wei, C.; Hayek, S. S.; Collins, A.; Gu, C.; Corapi, K.; Altintas, M. M.; Wang, Y.; Sushrut, W. S.; Bianco, A. C.; Reiser, J.; Sever, S.

doi:10.1101/2022.04.26.489589

bioRxiv · 10.1101/2022.04.26.489589

Truncated suPAR simultaneously causes kidney disease and autoimmune diabetes mellitus

Zhu, K.·Mukherjee, K.·Wei, C.·Hayek, S. S.·Collins, A.·Gu, C.·Corapi, K.·Altintas, M. M.·Wang, Y.·Sushrut, W. S.·Bianco, A. C.·Reiser, J.·Sever, S.

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Abstract

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 {beta}-cell mass, and high fasting glucose. D2D3 fragment dysregulated glucose-induced cytoskeletal dynamics, impaired maturation and trafficking of insulin granules, and inhibited bioenergetics of {beta}-cells in culture. An anti-uPAR antibody restored {beta}-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. SummaryProteolytic suPAR fragment, D2D3, simultaneously injures two organs, the kidney and pancreas, thus causing a dual organ disease.

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Zhu, K., Mukherjee, K., Wei, C., Hayek, S. S., Collins, A., Gu, C., Corapi, K., Altintas, M. M., Wang, Y., Sushrut, W. S., Bianco, A. C., Reiser, J., Sever, S.. 2022-04-28. Truncated suPAR simultaneously causes kidney disease and autoimmune diabetes mellitus. https://doi.org/10.1101/2022.04.26.489589

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