Reduced IP receptors in STZ-induced diabetic rat kidneys and high-glucose-treated mesangial cells.
Mesangial cells (MG) are an important source of renal PGE2 and PGI2. The purpose of this study was to examine the effects of cicaprost (CCP; PGI2 analog) on MG function and the expression of IP receptors in streptozotocin (STZ)-diabetic rats and glucose-treated MG cells. CCP increased cellular cAMP in immortalized rat MG cells. Both glucose and anisomycin attenuated CCP-cAMP, but not PMA, angiotensin II, or transforming growth factor-beta. Also, IP receptor protein was reduced in response to glucose. While CCP decreased the levels of the cell cycle inhibitor p27, it did not alter thymidine or leucine incorporation. However, CCP reduced fibronectin levels by 40% and increased matrix metalloproteinase-2 levels threefold, a key enzyme in matrix degradation. Finally, IP receptors were significantly reduced in the outer medulla of 4- and 12-wk STZ-diabetic rats and in the cortex, outer, and inner medullary regions in 6-mo uninephrectomized STZ-diabetic rats. The changes in the CCP/IP system observed in this study suggest that IP may serve as an alternate therapeutic target in diabetes.
Nasrallah
Rania
R
Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, 451 Smyth Rd., Rm. 1337, Ottawa, ON, K1H 8M5, Canada.
Hébert
Richard L
RL
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002461:Cell Line, Transformed; D000242:Cyclic AMP / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000503:physiopathology*; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D011465:Prostaglandins, Synthetic / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics* / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D005353:Fibronectins; D011465:Prostaglandins, Synthetic; D011500:Protein Synthesis Inhibitors; C545637:Ptger1 protein, rat; C545646:Ptger2 protein, rat; C545649:Ptger3 protein, rat; C545652:Ptger4 protein, rat; D012333:RNA, Messenger; D044006:Receptors, Epoprostenol; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000841:Anisomycin; D011464:Epoprostenol; D000242:Cyclic AMP; D020778:Matrix Metalloproteinase 2; D005947:Glucose; C043867:cicaprost