The clinical efficacy of cGMP-specific sildenafil on mitochondrial biogenesis induction and renal damage in cats with acute on chronic kidney disease.

Abstract

BACKGROUND: Mitochondrial biogenesis (MB) induction has recently emerged as potential therapeutic approaches in kidney pathology and the mitochondria-targeted therapies should be investigated to improve treatment of animals with kidney diseases. This study aimed to investigate the effects of MB induction with sildenafil citrate on the cGMP/NO pathway, glomerular filtration, and reduction of kidney damage and fibrosis (TGF-&#x3b2;/SMAD pathway) in cats with acute on chronic kidney disease (ACKD). Thirty-three cats were divided into the non-azotemic (healthy) group (n:8) and the ACKD group (n:25), comprising different breeds, sexes, and ages. Sildenafil citrate was administered to the non-azotemic and ACKD groups (2.5&#xa0;mg/kg, PO, q12 hours) for 30 days. Serum and urine NO, MDA, NGAL, KIM-1, TGF-&#x3b2;1, IL-18, FGF 23, PGC-1&#x3b1; and cGMP concentrations were measured. RESULTS: Serum cGMP concentrations increased (P&#x2009;<&#x2009;0.05) in the non-azotemic group during the 2(median 475.99 pmol/mL) and 3(median 405.01 pmol/mL) weeks of the study, whereas serum cGMP concentrations decreased in the ACKD group during the 4(median 188.52 pmol/mL) week compared to the non-azotemic group (P&#x2009;<&#x2009;0.05). No difference was observed in serum biomarker concentrations except NO, which increased in the 4week (P&#x2009;<&#x2009;0.05). The urinary concentrations of NO, MDA, PGC-1&#x3b1;, TGF-&#x3b2;1, NGAL, KIM-1, IL-18, and FGF 23 in the ACKD group were found to be higher compared to those in the non-azotemic group from the 1to the 4week (P &#x2009;<&#x2009;0.05). In the ACKD group, the urine PGC-1&#x3b1; concentration in the 2(median 6.10 ng/mL) week was lower compared to that in the 0 and 1(median 7.65 and 7.21 ng/mL, respectively) week, and the NO concentration in the 3(median 28.94 &#xb5;mol/mL) week was lower than that in the 0(median 37.43 &#xb5;mol/mL) week (P&#x2009;<&#x2009;0.05). CONCLUSIONS: While sildenafil citrate has been determined to induce a low level of MB and to have a beneficial effect on glomerular filtration, it is observed to be ineffective in mitigating renal damage and fibrosis via the TGF-&#x3b2;/SMAD pathway in cats with ACKD.