Phosphodiesterase-5 inhibition attenuates early renal ischemia-reperfusion-induced acute kidney injury: assessment by quantitative measurement of urinary NGAL and KIM-1

Abstract

Acute kidney injury (AKI) is a common clinical problem that still lacks effective treatment. Phosphodiesterase-5 (PDE5) inhibitors possess anti-apoptotic and anti-oxidant properties, making it a promising therapy for ischemia-reperfusion (I/R) injury of various organs. The present study evaluated the early nephroprotective effects of Tadalafil, a PDE5 inhibitor, in an experimental model of renal I/R. Sprague-Dawley rats were divided into two groups: vehicle-treated I/R (n = 10), and Tadalafil (10 mg/kg po)-treated I/R group (n = 11). After removal of the right kidney and collection of two baseline urine samples, the left renal artery was clamped for 45 min followed by reperfusion for 60, 120, 180, and 240 min. Functional and histological parameters of the kidneys from the various groups were determined. In the vehicle-treated I/R group, glomerular filtration rate was significantly reduced compared with that in normal kidneys. In addition, the ischemic kidney showed remarkable cast formation, necrosis, and congestion, a consistent pattern of acute tubular necrosis. Furthermore, urinary excretion of NGAL and KIM-1, two novel biomarkers of kidney injury, substantially increased following I/R insult. In contrast, Tadalafil treatment resulted in a significant improvement in kidney function and amelioration of the adverse histological alterations of the ischemic kidney. Noteworthy, the urinary excretion of NGAL and KIM-1 markedly decreased in the Tadalafil-treated I/R group. These findings demonstrate that Tadalafil possesses early nephroprotective effects in rat kidneys subjected to I/R insult. This approach may suggest a prophylactic therapy for patients with ischemic AKI.

Protective effect of lyophilized recombinant human brain natriuretic peptide on renal ischemia/reperfusion injury in mice

“…Our results indicate that BNP can improve renal filtration function, although the underlying mechanism needs to be further explored. As a marker of renal tubular epithelial damage, the expression level of Kim-1 increases upon epithelial damage (Vaidya et al, 2010;Hu and Moe, 2012;Sohotnik et al, 2013). Our data indicate that the mRNA expression of Kim-1 significantly increases in renal tissue during I/R and then significantly decreases after BNP treatment (Figures 2C and D).…”

cGMP-Selective Phosphodiesterase Inhibitors Stimulate Mitochondrial Biogenesis and Promote Recovery from Acute Kidney Injury

“…Pretreatment with rolipram, a specific PDE4 inhibitor, blunted I/R-induced renal dysfunction in rat kidney and reduced oxidative damage (Mammadov et al, 2012). Sildenafil was shown to be protective in cisplatin-induced AKI, whereas tadalafil, a long-acting PDE5 inhibitor, protected against early I/R injury in rats (Lee et al, 2009;Sohotnik et al, 2013). However, limitations of these studies have been the lack of a clear mechanism for the renoprotective effects and the use of pretreatment protocols.…”

Phosphodiesterase type 5 inhibitors and kidney disease

“…In a rat kidney I/R injury model, tadalafil preserved the glomerular filtration rate and decreased histological injury as assessed by tubular cast formation, necrosis, and congestion as well as the urinary excretion of NGAL and KIM-1 [14]. At the same time, tadalafil also exerted renal beneficial effects regarding inflammation, oxidative stress, and tubular atrophy [37].…”

“…PDE5 is expressed by vessel walls, glomeruli, mesangial cells, cortical tubules, and inner medullary collecting duct cells of rat kidney [14]. Therefore, PDE5 inhibition modulates renal hemodynamics and excretory function, with possible long-term nephroprotection.…”