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Prostaglandin I2 Receptor Agonism Preserves β-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms

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.

Publication metadata

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


DOI: 10.2337/db15-0783


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Funder referenceFunder name
Heart and Stroke/Richard Lewar Centre of Excellence
Keenan Family Foundation KRESCENT
Queen Elizabeth II/Dr. Arnie Aberman Graduate Scholarship in Science and Technology
Banting & Best Diabetes Centre Hugh Sellers
Canadian Diabetes Association
Yow Kam-Yuen Graduate Scholarship in Diabetes Research from the Banting & Best Diabetes Centre
MOP-133631Diabetes Innovation Award from Novo Nordisk and a Canadian Institutes of Health Research Operating Grant
RGPIN-2015-05802Natural Sciences and Engineering Research Council of Canada