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Lookup NU author(s): Dr Kathryn White, Suzanne Advani, Dr Andrew Advani
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Discovery of common pathways that mediate both pancreatic -cell function and end-organ function offers the opportunity to develop therapies that modulate glucose homeostasis and separately slow the development of diabetes complications. Here, we investigated the in vitro and in vivo effects of pharmacological agonism of the prostaglandin I-2 (IP) receptor in pancreatic -cells and in glomerular podocytes. The IP receptor agonist MRE-269 increased intracellular 3,5-cyclic adenosine monophosphate (cAMP), augmented glucose-stimulated insulin secretion (GSIS), and increased viability in MIN6 -cells. Its prodrug form, selexipag, augmented GSIS and preserved islet -cell mass in diabetic mice. Determining that this preservation of -cell function is mediated through cAMP/protein kinase A (PKA)/nephrin-dependent pathways, we found that PKA inhibition, nephrin knockdown, or targeted mutation of phosphorylated nephrin tyrosine residues 1176 and 1193 abrogated the actions of MRE-269 in MIN6 cells. Because nephrin is important to glomerular permselectivity, we next set out to determine whether IP receptor agonism similarly affects nephrin phosphorylation in podocytes. Expression of the IP receptor in podocytes was confirmed in cultured cells by immunoblotting and quantitative real-time PCR and in mouse kidneys by immunogold electron microscopy, and its agonism 1) increased cAMP, 2) activated PKA, 3) phosphorylated nephrin, and 4) attenuated albumin transcytosis. Finally, treatment of diabetic endothelial nitric oxide synthase knockout mice with selexipag augmented renal nephrin phosphorylation and attenuated albuminuria development independently of glucose change. Collectively, these observations describe a pharmacological strategy that posttranslationally modifies nephrin and the effects of this strategy in the pancreas and in the kidney.
Author(s): Batchu SN, Majumder S, Bowskill BB, White KE, Advani SL, Brijmohan AS, Liu YA, Thai K, Azizi PM, Lee WL, Advani A
Publication type: Article
Publication status: Published
Journal: Diabetes
Year: 2016
Volume: 65
Issue: 5
Pages: 1398-1409
Print publication date: 01/05/2016
Online publication date: 11/02/2016
Acceptance date: 01/02/2016
ISSN (print): 0012-1797
ISSN (electronic): 1939-327X
Publisher: American Diabetes Association
URL: http://dx.doi.org.10.2337/db15-0783
DOI: 10.2337/db15-0783
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