title: Prostaglandin I2 Receptor Agonism Preserves β-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms.
abstract: Discovery of common pathways that mediate both pancreatic β-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 I2 (IP) receptor in pancreatic β-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 β-cells. Its prodrug form, selexipag, augmented GSIS and preserved islet β-cell mass in diabetic mice. Determining that this preservation of β-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.
authors: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Sri N
authors: SN
authors: Batchu
authors: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Syamantak
authors: S
authors: Majumder
authors: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Bridgit B
authors: BB
authors: Bowskill
authors: Electron Microscopy Research Services, Newcastle University, Newcastle upon Tyne, U.K.
authors: Kathryn E
authors: KE
authors: White
authors: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Suzanne L
authors: SL
authors: Advani
authors: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Angela S
authors: AS
authors: Brijmohan
authors: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Youan
authors: Y
authors: Liu
authors: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Kerri
authors: K
authors: Thai
authors: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Paymon M
authors: PM
authors: Azizi
authors: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Warren L
authors: WL
authors: Lee
authors: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada advania@smh.ca.
authors: Andrew
authors: A
authors: Advani
mesh_terms: D000081:Acetamides / Q000627:therapeutic use; D000085:Acetates / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000819:agonists / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D011355:Prodrugs / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D044006:Receptors, Epoprostenol / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: D000081:Acetamides; D000085:Acetates; D007004:Hypoglycemic Agents; D007328:Insulin; D008565:Membrane Proteins; C113936:PTGIR protein, human; D011355:Prodrugs; C491910:Ptgir protein, mouse; D011719:Pyrazines; D044006:Receptors, Epoprostenol; C113267:nephrin; C523468:selexipag; C531934:(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid