Selective phosphodiesterase-5 (PDE-5) inhibitor vardenafil ameliorates renal damage in type 1 diabetic rats by restoring cyclic 3′,5′ guanosine monophosphate (cGMP) level in podocytes

Abstract

Our data suggest that a dysfunctional NO-cGMP pathway exacerbates podocyte damage in diabetes. In conclusion, vardenafil treatment preserves podocyte function and reduces glomerular damage, which indicates therapeutic potential in patients with DN.

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

“…In addition, a large set of preclinical studies conducted in animal models of diabetic and nondiabetic kidney disease have demonstrated the beneficial effect of PDE5 inhibition on pathophysiological pathways implicated in albuminuria, glomerulosclerosis, and tubulointerstitial injury. The data most relevant to the present study population come from the streptozotocin-induced diabetic rat, 15,18 the Long-Evans noninsulin dependent diabetic rat, 16 and the alloxan-induced diabetic rabbit, 17 models of DN in which chronic inhibition of PDE5 reduced podocyte damage contributing to lowered albuminuria and reduced inflammation, oxidative stress, and fibrosis in the kidney in turn accompanied by improved renal structure and function. 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.…”

“…Preclinical in vivo studies demonstrate that restoring the NO pathway by elevating the intracellular pool of cGMP, through inhibition of the cGMP-hydrolyzing enzyme phosphodiesterase type 5 (PDE5), is renoprotective, with reductions in albuminuria, inflammation, fibrosis, and improvement in creatinine clearance. [15][16][17] Specifically, PDE5 inhibition-mediated elevation of cGMP in podocytes attenuates podocyte damage in diabetic rats, resulting in decreased albuminuria, 18 likely through correction of podocyte dysmotility as suggested by in vitro data. 19 The first clinical study to suggest translation of the PDE5-related preclinical findings was conducted by Grover-Páez et al who demonstrated that administration of a PDE5 inhibitor once daily for 30 days to microalbuminuric T2DM patients significantly reduced albuminuria.…”

Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes

“…The effect of PDE5 inhibitors has been investigated in animal models of diabetic nephropathy. The PDE5 inhibitors sildenafil and vardenafil ameliorated matrix accumulation and albuminuria in rats with streptozotocin-induced type 1 or spontaneous type 2 diabetes (51,65,66). However, these studies did not explore whether H 2 S was involved in the salutary effects of PDE5 inhibitors.…”

Hydrogen Sulfide in Renal Physiology and Disease

“…These observations emphasize the fact that whether iNOS mediates or ameliorates tissue injury is highly context dependent. PDE-5 inhibitors have been reported to ameliorate diabetic kidney injury in rodent models (20); however, whether H2S mediates the salutary effect of PDE-5 inhibitor was not examined in those studies.…”