The effects of PDE5 inhibitory drugs on renal ischemia/reperfusion injury in rats.

Department of Physiology, Medical Faculty, Dumlupinar University, Central Campus, Tavsanlı Road, 43270 Kutahya, Turkey.
Molecular Biology Reports (Impact Factor: 2.51). 06/2012; 39(10):9775-82. DOI: 10.1007/s11033-012-1843-1
Source: PubMed

ABSTRACT The aim of the present study was to evaluate the effects of phosphodiesterase type 5 (PDE5) inhibitory drugs, Tadalafil and Sildenafil, on inducible NOS (iNOS), endothelial NOS (eNOS) and p53 genes expressions and apoptosis in ischemia/reperfusion (I/R) induced oxidative injury in rat renal tissue. Eighty Sprague-Dawley rats (300-350 g) were divided into four groups. In ischemia/reperfusion group, rats were subjected to renal ischemia by clamping the left pedicle for 60 min, and then reperfused for 90 min. On the other hand, in other two groups the rats were individually pretreated with Tadalafil and Sildenafil 1 h before the induction of ischemia. Malondialdehyde (MDA) is determined in renal tissue homogenates by high-performance liquid chromatography, the number of apoptotic cell were calculated by TUNEL method and p53 and eNOS expression were detected with immunohistochemistry. On the other hand, myeloperoxidase (MPO) levels were measured by spectrophotometric method and the mRNA level of iNOS in renal tissue was determined by Real-time PCR (RT-PCR). Our results indicate that MDA and MPO levels were increased in the I/R group than those in the control group. Both Tadalafil and Sildenafil treatment decreased the MDA levels in ischemia/reperfusion group, whereas this effect was more potent with Sildenafil. RT-PCR results showed that, iNOS gen expression increased in the I/R group, but decreased in the PDE5 inhibitory drugs treated group. Apoptotic cells, eNOS levels and p53 positive cells were also decreased in PDE5 inhibitory drugs treated group. We suggest that Tadalafil and Sildenafil have beneficial effects against I/R related renal tissue injury and this protective effect is clearer for Sildenafil than Tadalafil.

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    ABSTRACT: Oxidative stress and DNA damage have been implicated in the pathogenesis of renovascular hypertension induced by renal artery stenosis in the two-kidney, one-clip (2K1C) Goldblatt model. Considering our previous report indicating that the chronic blockade of phosphodiesterase 5 with sildenafil (Viagra (R)) has marked beneficial effects on oxidative stress and DNA damage, we tested the hypothesis that sildenafil could also protect the stenotic kidneys of 2K1C hypertensive mice against oxidative stress and genotoxicity. The experiments were performed with C57BL6 mice subjected to renovascular hypertension by left renal artery clipping. Two weeks after clipping, the mice were treated with sildenafil (40 mg/kg/day for 2 weeks, 2K1C-sildenafil group) or the vehicle (2K1C). These mice were compared with control mice not subjected to renal artery clipping (Sham). After hemodynamic measurements, the stenotic kidneys were assessed using flow cytometry to evaluate cell viability and the comet assay to evaluate DNA damage. Measurements of intracellular superoxide anions and hydrogen peroxide levels as well as nitric oxide bioavailability were also obtained. Sildenafil treatment significantly reduced mean arterial pressure (15%), heart rate (8%), intrarenal angiotensin II (50%) and renal atrophy (36%). In addition, it caused a remarkable decrease of reactive oxygen species production. On the other hand, sildenafil increased nitric oxide levels relative to those in the nontreated 2K1C mice. Sildenafil treatment also significantly reduced the high level of kidney DNA damage that is a characteristic of renovascular hypertensive mice. Our data reveal that sildenafil has a protective effect on the stenotic kidneys of 2K1C mice, suggesting a new use of phosphodiesterase 5 inhibitors for protection against the DNA damage observed in the hypoperfused kidneys of individuals with renovascular hypertension. Further translational research is necessary to delineate the mechanisms involved in the prevention of renal stenosis in the clinical setting.
    Journal of Translational Medicine 02/2014; 12(1):35. · 3.46 Impact Factor


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