Interstitial fibrosis of unilateral ureteral obstruction is exacerbated inkidneys of mice lacking the gene for inducible nitric oxide synthase

Unilateral ureteral obstruction (UUO) is characterized by decreases in rena l function and increases in interstitial fibrosis. Previous studies have in dicated that pharmacologic manipulations that increase nitric oxide (NO) ar e beneficial to the obstructed kidneys. NO is produced from arginine by nit ric oxide synthase (NOS), an enzyme that exists in both constitutive and in ducible (iNOS) forms. To determine the role of the inducible form of NOS in UUO, we used mice with a targeted deletion of iNOS (iNOS -/- mice) and com pared them with wild-type (WT) mice. Kidneys were obstructed for 2 weeks in both WT and iNOS -/- mice, and were then removed and bisected. Half of the kidney was embedded in paraffin and tissue sections were examined for inte rstitial volume or the presence of macrophages. The remainder was flash-fro zen and samples were used to measure tissue collagen (hydroxyproline) or tr ansforming growth factor-beta (TGF-beta). This study demonstrates that both cortex and medulla of obstructed kidneys of INOS -/- mice exhibit signific antly increased interstitial volume and interstitial macrophages as compare d with their WT counterparts. Furthermore tissue collagen was increased to 9.2 +/- 1.3 mug/mg tissue in WT obstructed kidneys, whereas in iNOS -/- kid neys, collagen was increased to 13.2 +/- 0.8 mug/mg tissue. The profibrotic cytokine TGF-beta was also significantly increased in obstructed kidneys o f INOS -/- mice, as compared with WT mice. No differences were noted betwee n the unobstructed kidneys of INOS -/- mice compared with WT mice in any of the parameters examined. These results demonstrate that targeted deletion of the iNOS results in exacerbation of fibrotic events in the obstructed ki dney. These results confirm previous pharmacologic studies, and suggest tha t NO produced via the inducible NOS normally serves a protective function i n UUO.