sildenafil-citrate and Ureteral-Obstruction

Our previous studies support the protective effect of cGMP and cGMP-dependent protein kinase I (PKG-I) pathway on the development of renal fibrosis. Therefore, in the present studies, we determined whether pharmacologically or genetically increased PKG activity attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanisms involved. To increase PKG activity, we used the phosphodiesterase 5 inhibitor sildenafil and PKG transgenic mice. UUO model was induced in wild-type or PKG-I transgenic mice by ligating the left lateral ureteral and the renal fibrosis was observed after 14 days of ligation. Sildenafil was administered into wild-type UUO mice for 14 days. In vitro, macrophage and proximal tubular cell function was also analyzed. We found that sildenafil treatment or PKG transgenic mice had significantly reduced UUO-induced renal fibrosis, which was associated with reduced TGF-β signaling and reduced macrophage infiltration into kidney interstitial. In vitro data further demonstrated that both macrophages and proximal tubular cells were important sources of UUO-induced renal TGF-β levels. The interaction between macrophages and tubular cells contributes to TGF-β-induced renal fibrosis. Taken together, these data suggest that increasing PKG activity ameliorates renal fibrosis in part through regulation of macrophage and tubular cell function, leading to reduced TGF-β-induced fibrosis.

Topics: Actins; Angiotensin II; Animals; Cadherins; Cells, Cultured; Culture Media, Conditioned; Cyclic GMP-Dependent Protein Kinase Type I; Cytokines; Disease Models, Animal; Fibrosis; Inflammation Mediators; Kidney Diseases; Kidney Tubules, Proximal; Macrophages; Male; Mice; Mice, Transgenic; Phosphodiesterase 5 Inhibitors; Phosphorylation; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Smad2 Protein; Sulfones; Time Factors; Transforming Growth Factor beta1; Up-Regulation; Ureteral Obstruction

The aim of the present study was to evaluate the effects of phosphodiesterase 5 inhibitors on renal tubular apoptosis and also on expressions of endothelial and inducible nitric oxide synthases (eNOS and iNOS) in the ipsilateral kidney after partial unilateral ureteral obstruction (PUUO) in a rat model. Forty Wistar albino rats were divided into five groups. In Groups 1-4, left experimental PUUO was created. Sildenafil, vardenafil, and tadalafil were administrated to the rats of Groups 2-4, respectively. The pills were orally given to the rats for 30 days. Group 5 was defined as sham. After 30 days, all rats were sacrificed, and nephrectomy was performed. The renal specimens were examined histopathologically. Left hydroureteronephrosis was observed in Groups 1-4. Mean apoptotic cell count and eNOS and iNOS levels were significantly increased in Group 1 when compared with the other groups. The rats in Groups 2-4 showed significantly decreased apoptotic cell count and eNOS and iNOS values in the renal tubular tissue in accordance with Group 1 (p<0.05). There were significant differences in apoptotic cell counts between sildenafil group and the other two study groups. The sildenafil group demonstrated lesser apoptotic cell count than the vardenafil (p=0.021) and tadalafil (p=0.009) groups. PUUO increases the renal tubular apoptosis and elevates NOS concentrations in renal tubular tissue after PUUO. Phosphodiesterase 5 inhibitors have a protective effect against the tubular apoptosis.

Topics: Animals; Apoptosis; Carbolines; Ceftriaxone; Imidazoles; Kidney Tubules; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Ureteral Obstruction; Vardenafil Dihydrochloride