Pathophysiology of unilateral ureteral obstruction: studies from Charlottesville to New York.
OBJECTIVE
More than 30 years ago the decreased renal blood flow and glomerular filtration rate characteristic of unilateral ureteral obstruction (UUO) was described. In the ensuing time, much has been learned about the involvement of nitric oxide (NO) and transforming growth factor-beta (TGF-beta) in the pathophysiology of UUO.


METHODS
We measured renal blood flow and glomerular filtration rate in dogs and rats, and assessed the effect of altering the availability of NO on these parameters. In rats and mice we used an antibody to TGF-beta, NO synthase gene deletion and inducible nitric oxide synthase gene therapy to assess the role of TGF-beta and NO in renal fibrosis.


RESULTS
Results of our studies suggest 2 strategies that have the potential to be incorporated into clinical trials. The first would be replenishment of the NO system with arginine (or a NO donor) to decrease renovascular resistance and increase renal nitric oxide. Either in addition to the first strategy or separately, interstitial fibrosis could be targeted. Strategies for inhibiting fibrosis include antibody to TGF-beta, use of antisense oligonucleotides to TGF-beta, use of drugs that inhibit other pro-fibrotic mediators or gene therapy to inhibit fibrosis.


CONCLUSIONS
While these studies have primarily centered on acute UUO, the findings in this model of renal injury may potentially be transferable to other entities that are characterized by decreased renal function and increased renal fibrosis such as different forms of interstitial nephropathy or diabetic glomerulopathy.
Vaughan
E Darracott
ED
James Buchanan Brady Department of Urology, Weill Cornell Medical College, New York, New York, USA.
Marion
Donald
D
Poppas
Dix P
DP
Felsen
Diane
D
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015316:Genetic Therapy; D005919:Glomerular Filtration Rate; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D007678:Kidney Glomerulus / Q000000981:diagnostic imaging; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D012039:Regional Blood Flow; D012084:Renin-Angiotensin System / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D014463:Ultrasonography; D014513:Ureter / Q000503:physiopathology; D014517:Ureteral Obstruction / Q000503:physiopathology* / Q000628:therapy; D014662:Vasoconstrictor Agents / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase