NDT Advance Access originally published online on August 25, 2006
Nephrology Dialysis Transplantation 2006 21(11):3074-3081; doi:10.1093/ndt/gfl444
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Chronic inhibition of NOS-2 ameliorates renal injury, as well as COX-2 and TGF-ß1 overexpression in 5/6 nephrectomized rats
1Department of Nephrology, 2Department of Pathology and 3Department of Immunology, lnstituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
Correspondence and offprint requests to: Laura G. Sánchez-Lozada PhD, Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, 14080-Mexico City, Mexico. Email: lgsanchezlozada{at}hotmail.com
Background. Chronic renal damage is associated with inflammatory infiltration, fibrosis and vascular lesion, coupled with increased expression of cyclo-oxygenase 2 (COX-2) and transforming growth factor-ß1 (TGF-ß1). However, the role of inducible nitric oxide synthase (NOS-2) is still controversial. Thus, we studied the contribution of NOS-2 to the expression levels of COX-2 and TGF-ß1, as well as the structural renal injury in rats with subtotal renal ablation (5/6 Nx).
Methods. Four groups of rats were studied: sham, 5/6 Nx, 5/6 Nx + aminoguanidine (AG) and 5/6 NX + L-NIL (L-N6-iminoethyl-lysine). Systolic blood pressure (SBP), proteinuria and creatinine (Cr) clearance were measured. NOS-2, COX-2 and TGF-ß1 gene expression was determined by real-time reverse transcription–polymerase–chain reaction. Protein expression was evaluated by western blot and ELISA (TGF-ß1). Immunohistochemistry and morphometry were performed for NOS-2, microvascular thickening and fibrosis.
Results. Systemic hypertension and marked proteinuria, increased expression of NOS-2, COX-2 and TGF-ß1, thickening of arteriolar wall and tubulointerstitial fibrosis were produced in 5/6 Nx rats. Chronic inhibition of NOS-2 did not prevent arterial hypertension or the fall in Cr clearance, but partially reduced proteinuria. Nevertheless, AG and L-NIL preserved arteriolar morphology and the administration of both selective inhibitors of inducible NOS (AG and L-NIL) prevented NOS-2 overexpression.
Conclusion. This study shows that NOS-2 was markedly enhanced in renal tissue of 5/6 Nx rats. Moreover, treatment with AG and L-NIL prevented the morpho-functional changes induced by subtotal renal ablation, despite persistence of systemic hypertension, suggesting that high concentrations of nitric oxide produced by NOS-2 could act as a positive modulator of the proinflammatory and profibrotic pathways involved in the progression of renal disease.
Keywords: aminoguanidine and L-NIL; COX-2; 5/6 nephrectomy; NOS-2; TGF-ß1
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