The Protective Effect of Apocynin on Cyclosporine A‐Induced Hypertension and Nephrotoxicity in Rats

Abstract

Cyclosporine A (CsA) is the prototype of immunosuppressant drugs that has provided new perspectives in human and veterinary medicine to prevent organ transplant rejection and to treat certain autoimmune diseases and dermatologic diseases. Unfortunately, the treatment with CSA is often limited by severe adverse effects such as hypertension and nephrotoxicity. Some data suggest that reactive oxygen species (ROS) and the oxidative stress play an important role in its pathogenesis, in particular the superoxide (O2 (-)) that is the most powerful free radical generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase present mainly in the kidney. The present study has been designed to investigate the role of Apocynin a selective inhibitor of NADPH oxidase activity on cyclosporine-induced adverse effect. In this study, we have evaluated the effect of CsA, used alone or in association with Apocynin on blood pressure (BP), on glomerular filtration rate (GFR), on absoluted fluid reabsorption (Jv) in proximal tubule (PT), on O2 (-) concentration, and on nitric oxide (NO) production. We have demonstrated that CsA administration increases superoxide concentration in the aorta, decreases the NO concentration, reduces GFR and the Jv in PT, and induces a significant increase in BP. Moreover, we have shown that Apocynin treatment restores these hemodynamic alterations, as well as NO and superoxide productions. In conclusion, the reported data indicate that CsA induced nephrotoxicity and hypertension are related to NADPH oxidase activity, in fact Apocynin protects the kidney function and BP from toxic effects induced by CsA through the inhibition of NADPH oxidase activity.

Recombinant Mitochondrial Manganese Containing Superoxide Dismutase Protects Against Ochratoxin A‐Induced Nephrotoxicity

“…In fact, it has been demonstrated in various experimental models of hypertension, that the increase of blood pressure is linked to ROS increase and it is prevented by the treatment with antioxidants [Gill and Wilcox, ; Palabiyik et al, ]. In an our previous article we have shown that the use of antioxidant apocynin in CsA hypertensive rats restored blood pressure and levels of ROS [Ciarcia et al, ]. Here we have shown that treatment with the new recombinant rMnSOD prevents hypertension induced by OTA and, in addiction, restores lipid peroxidation levels.…”

“…The mechanism of chronic nephrotoxic diseases has been previously investigated by our research group. In particular, we have demonstrated, in a rat animal model of hypertension induced by cyclosporine, that the increase in ROS production, in particular the O 2 − , was linked to a strong reduction of glomerular filtration rate (GFR) [Ciarcia et al, ]. Since the reduction of antioxidants expression has been shown to be related to an increase of oxidative damage [Klaunig et al, ; Marin‐Kuan et al, ] which contribute to OTA toxicity.…”

Ochratoxin A induces ER stress and apoptosis in mesangial cells via a NADPH oxidase-derived reactive oxygen species-mediated calpain activation pathway

“…NADPH oxidase inhibitor apocynin significantly inhibited the OTA-induced mesangial cytotoxicity and apoptosis. Several studies have demonstrated that apocynin has therapeutic effect on multiple animal disease model including chemically-induced colitis in mice [28], testicular ischemia-reperfusion injury in rats [29], bleomycin-induced lung fibrosis in rats [30], Cyclosporine A-Induced hypertension and nephrotoxicity in rats [31], established alcoholic steatohepatitis rat model [32], and contrast-induced nephropathy in the diabetic rats [33]. Therefore, these findings indicate that the concentrations of OTA used in this cellular toxicological study are reasonable and effectively induce mesangial cell cytotoxicity via a NADPH oxidase-derived ROS-mediated pathway.…”

“…Superoxide production was measured in total cell homogenates by using lucigenin-derived chemiluminescence as described previously [31]. Briefly, 50 μg of protein was diluted in 500 μl of 50 mM phosphate buffer containing 1 mM EGTA and 150 mM sucrose.…”

Cyclosporine-A induced nephrotoxicity in male and female rats: Is zinc a suitable protective supplement?

“…In addition, many research studies have been conducted to suggest supplemental agents to confer additional protection for the kidney against CYCinduced toxicity. These supplemental agents may include herbal drugs [3][4][5] , endothelin-1 receptor antagonists 6 , antihypertensive drugs or β-blockers [7][8][9] , NADPH oxidase activity inhibitor 10 , antioxidants 11 , omega-3 fatty acids 12 , apelin peptide 13 , and/or renin inhibitor 14 . Gender and sex hormones are also important factors that influence the effects of CYC [15][16][17][18][19] .…”