Impaired nitric oxide-dependent cyclic guanosine monophosphate generation in glomeruli from diabetic rats : evidence for protein kinase C-mediated suppression of the cholinergic response

• Published in: The Journal of clinical investigation 1994, Vol.93 (1), p.311-320
• Main Authors: CRAVEN, P. A, STUDER, R. K, DERUBERTIS, F. R
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; 1-Methyl-3-isobutylxanthine - pharmacology; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alkaloids - pharmacology; Amino Acid Oxidoreductases - antagonists & inhibitors; Animals; Arginine - analogs & derivatives; Arginine - pharmacology; Associated diseases and complications; Biological and medical sciences; Calcimycin - pharmacology; Carbachol - pharmacology; Cyclic GMP - metabolism; Diabetes Mellitus, Experimental - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Isoquinolines - pharmacology; Kidney Glomerulus - drug effects; Kidney Glomerulus - metabolism; Kinetics; Medical sciences; Membrane Proteins; Myristoylated Alanine-Rich C Kinase Substrate; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - physiology; Nitric Oxide Synthase; omega-N-Methylarginine; Phosphates - metabolism; Phosphorylation; Piperazines - pharmacology; Prostaglandin Endoperoxides, Synthetic - pharmacology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Proteins - metabolism; Rats; Rats, Sprague-Dawley; Staurosporine; Thromboxane A2 - analogs & derivatives; Thromboxane A2 - pharmacology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci116961

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.