Increasing cGMP-dependent protein kinase activity attenuates unilateral ureteral obstruction-induced renal fibrosis

Abstract

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.

Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy

“…These effects have been suggested to be primarily mediated by cGMP-mediated protein kinase-G activation, secondary to phosphodiesterase type 5 inhibitor (PDE5i)-induced elevation of the NO-derived cGMP pool. 19,27,28 PF-00489791 was safe and generally well-tolerated when administered at a dose of 20 mg daily for 12 weeks in T2DM subjects with overt DN. The most commonly observed AEs in the present study were consistent with those reported in subjects with mild-to-moderate hypertension treated with PF-00489791 for 28 days, 29 including headaches and upper gastrointestinal events.…”

The soluble guanylate cyclase stimulator IW‐1973 prevents inflammation and fibrosis in experimental non‐alcoholic steatohepatitis

“…The increased liver distribution probably contributes to the antifibrotic effects observed with IW‐1973, which were achieved at doses that correspond to plasma concentrations that have no effect on systemic BP in normal mice. Our findings agree with previous publications demonstrating anti‐remodelling effects of agents modulating the cGMP pathway in in vivo and in vitro models of renal, cardiac, dermal and pulmonary fibrosis (Hohenstein et al ., ; Dunkern et al ., ; Cui et al ., ; Patrucco et al ., ; Beyer et al ., ; Wang et al ., ). Moreover, our findings are consistent with previous publications reporting the anti‐fibrotic actions of NO donors or sGC activators in vitro in renal myofibroblasts (Wang et al ., ) and in vivo in models of biliary and toxic (i.e.…”

“…() have also provided evidence that IW‐1973 is able to block TGF‐β‐induced α‐SMA protein levels in hepatic stellate cells. These findings are consistent with our results showing a significant and dose‐dependent down‐regulation of TGF‐β1 in CDAAH mice receiving IW‐1973, as well as with previous studies indicating that the blockage of the non‐canonical TGF‐β pathway by increased cGMP may be responsible for the anti‐fibrotic effects (Cui et al ., , Beyer et al ., ).…”

Sildenafil attenuates the fibrotic phenotype of skin fibroblasts in patients with systemic sclerosis

“…It has also recently been observed that NO/sGC/cGMP signaling exerts anti-fibrotic actions [21][22][23][24][25][26] and that sGC stimulation reportedly reverses the fibrotic phenotype in SSc and other fibrotic disorders in vivo and in vitro by increasing intracellular cGMP levels [12,27,28]. PDE5 inhibitors also reportedly have anti-fibrotic effects in models of various fibrotic disorders [26, 29,30].…”