title: Early diabetes as a model for testing the regulation of juxtaglomerular NOS I.
abstract: Dysregulation of kidney nitric oxide synthase (NOS) I may alter renal hemodynamics in diabetes. Four types of studies were performed in anesthetized 1- to 2-wk-streptozotocin diabetic rats. 1) Glomerular filtration rate (GFR) was measured before and during NOS I blockade. Subsequent addition of nonspecific NOS blocker tested for residual NO from other isoforms. Acute systemic NOS I blockade reduced GFR only in diabetics. Nonspecific NOS blockade had no additional effect on NOS I-blocked diabetics. 2) Renal blood flow (RBF) was monitored for evidence that tubuloglomerular feedback (TGF) resets during 1 h of continuous activation with benzolamide. NOS I blockade was added to test for the role of NOS I in TGF resetting. During 1 h of TGF activation in controls, RBF initially declined and then returned to baseline. In diabetic and NOS I-blocked rats, RBF declined and remained low. 3) The ability of NOS I blockade to increase the homeostatic efficiency of TGF in diabetes was tested by micropuncture in free-flowing nephrons. The addition of NOS I blocker to the tubular fluid increased TGF efficiency in control and diabetic rats. 4) The influence of distal salt delivery on local NOS I activity was tested by micropuncture. Henle's loop was perfused at varying rates with NOS I blocker while single-nephron GFR (SNGFR) from the late proximal tubule was measured. In controls, NOS I blockade mainly reduced SNGFR when flow through Henle's loop was high. In diabetics, NOS I blockade reduced SNGFR independently of flow through Henle's loop. In conclusion, normally, salt delivered to the macula densa (MD) exerts immediate control over MD NOS I activity. In diabetes, there is ongoing overactivity of NOS I that is not regulated by MD salt.
authors.affiliation: Department of Medicine, Division of Nephrology-Hypertension, University of California and Veterans Affairs San Diego Health Care System, San Diego, CA 92161, USA. sthomson@ucsd.edu
authors.forename: Scott C
authors.initials: SC
authors.lastname: Thomson
authors.forename: Aihua
authors.initials: A
authors.lastname: Deng
authors.forename: Norikuni
authors.initials: N
authors.lastname: Komine
authors.forename: John S
authors.initials: JS
authors.lastname: Hammes
authors.forename: Roland C
authors.initials: RC
authors.lastname: Blantz
authors.forename: Francis B
authors.initials: FB
authors.lastname: Gabbai
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000502:physiology; D007191:Indazoles / Q000494:pharmacology; D007606:Juxtaglomerular Apparatus / Q000201:enzymology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C080122:7-nitroindazole