Impaired nitric oxide-dependent cyclic guanosine monophosphate generation in glomeruli from diabetic rats. Evidence for protein kinase C-mediated suppression of the cholinergic response.
Nitric oxide (NO)-dependent cyclic guanosine monophosphate (cGMP) generation was examined in glomeruli isolated from 1-2-wk and 2-mo streptozotocin diabetic (D) and control (C) rats. After 1-2 wk of diabetes, ex vivo basal cGMP generation and cGMP responses to carbamylcholine (CCh) were significantly suppressed in glomeruli from D compared with those from C, whereas cGMP responses to the calcium ionophore A23187 and nitroprusside (NP) did not differ in glomeruli from D vs. those from C. After 2 mo, glomeruli from D did not respond to CCh, and responses to A23187 and NP were suppressed compared with those from C. Differences in basal, CCh, and A23187-responsive cGMP between D and C were abolished by the NO synthetase inhibitor NG-monomethyl-L-arginine. Soluble glomerular guanylate cyclase prepared from either D or C responded indistinguishably to NP, suggesting a role for NO quenching in the suppression of cGMP in intact glomeruli from D. Compared with those from C, glomeruli isolated from D demonstrated increased generation of thromboxane A2 (TXA2) and activation of protein kinase C (PKC). Both the TXA2/endoperoxide receptor antagonist Bay U3405 and inhibitors of PKC activity restored a cGMP response to CCh in glomeruli from D. Conversely, in glomeruli from C, the TXA2/endoperoxide analogue U46619 activated PKC and suppressed the cGMP response to CCh. Both of those actions were blocked by inhibitors of PKC. The results indicate a progressive impairment of NO-dependent cGMP generation in glomeruli from D which may be mediated in part by TXA2 and activation of PKC. This impairment may participate in glomerular injury in diabetes.
Craven
P A
PA
Department of Medicine, Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15240.
Studer
R K
RK
DeRubertis
F R
FR
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000470:Alkaloids / Q000494:pharmacology; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D019323:omega-N-Methylarginine
D000470:Alkaloids; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D008565:Membrane Proteins; D010710:Phosphates; D010879:Piperazines; D011450:Prostaglandin Endoperoxides, Synthetic; D011506:Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000001:Calcimycin; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002217:Carbachol; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D011493:Protein Kinase C; D006152:Cyclic GMP; D019311:Staurosporine; D015056:1-Methyl-3-isobutylxanthine