Yousuf M. Al Suleimani

Interaction of nimesulide, a cyclooxygenase-2 inhibitor, with cisplatin in normotensive and spontaneously hypertensive rats.

We investigated the effect of administration of nimesulide, a selective cyclooxygenase-2 (COX-2) inhibitor, on cisplatin (CP)-induced nephrotoxicity in rats. WKY rats and SHRs were divided into four groups, each. The first and second groups received saline and oral nimesulide (20mg/kg/day for 6 days), respectively, whereas the third and fourth groups received a single intraperitoneal (i.p.) injection of CP (5mg/kg) and CP (5mg/kg) and nimesulide (20mg/kg/day for 5 days), respectively. At the end of the experiment, rats were anesthetized and blood pressure and renal blood flow (RBF) were monitored, followed by intravenous (i.v.) injection of norepinephrine (NE). Nephrotoxicity was evaluated histopathologically and biochemically. CP caused a reduction in baseline RBF in both WKY and SHRs. It increased the concentrations of urea and creatinine and kidney relative weight, and decreased body weight in both WKY and SHRs. Histopathologically, CP caused remarkable renal damage in both WKY rats and SHRs. Treatment with nimesulide alone did not produce any significant change in any of the above measurements. However, nimesulide aggravated CP-induced renal tissue damage in SHRs, but not in WKY rats. The results show that administration nimesulide augmented the histopathological indices of nephrotoxicity in SHRs, but not in WKY rats.

Effect of aqueous extract and anthocyanins of calyces of Hibiscus sabdariffa (Malvaceae) in rats with adenine-induced chronic kidney disease

The aim of this work was to assess the possible beneficial effects of aqueous extracts of Hibiscus sabdariffa L. calyces and anthocyanins isolated therefrom in an adenine‐induced chronic kidney disease (CKD) model.

Curcumin Ameliorates Kidney Function and Oxidative Stress in Experimental Chronic Kidney Disease

Chronic kidney disease (CKD) is known to involve inflammation, oxidative stress and apoptosis. Here, we investigated the impact of curcumin (diferuloyl methane, a phenolic turmeric pigment), which has strong antioxidant, anti‐inflammatory and anti‐apoptotic activities on kidney structure and function in rats with adenine‐induced CKD. Rats were treated for 5 weeks with adenine to induce CKD‐like renal damage and combined with three doses of curcumin. Markers of kidney function and oxidative stress were quantified in plasma, urine, renal homogenates and on kidney tissue. Curcumin was found to significantly abate adenine‐induced toxic effects such as reduced creatinine clearance, elevated neutrophil gelatinase‐associated lipocalin levels and raised urinary N‐acetyl‐β‐D‐glucosaminidase activities. Curcumin markedly reduced renal morphological damage and histopathological markers of inflammation, fibrosis and apoptosis. Curcumin further reduced adenine‐induced hypertension, urinary albumin, the inflammatory cytokines IL‐1β, IL‐6 and TNF‐α, cystatin C and adiponectin. It restored plasma sclerostin concentrations and lowered oxidative stress in renal homogenates. In animals treated with the two higher curcumin concentrations, alone or in combination with adenine, an increased expression of the antioxidative transcription factor Nrf2 was found as well as up‐regulation of the activity of its direct target glutathione reductase, and of an indirect target, the glutathione level. In conclusion, curcumin exhibits salutary effects against adenine‐induced CKD in rats by reducing inflammation and oxidative stress via up‐regulation of the transcription factor Nrf2.

Four-week administration of nimesulide, a cyclooxygenase-2 inhibitor, improves endothelial dysfunction in the hindlimb vasculature of streptozotocin-induced diabetic rats

The aim of this study was to examine the effect of chronic administration of nimesulide, a cyclooxygenase-2 inhibitor, on endothelial dysfunction in streptozotocin-induced diabetic rats. Three groups of Sprague-Dawley rats (300–350 g, n = 6) were used. The first group served as normoglycemic control and the second and third groups were rendered diabetic by an intraperitoneal injection of streptozotocin (60 mg/kg). The third group received the selective COX-2 inhibitor, nimesulide (20 mg/kg/day), orally by gavage for 4 weeks while the second group received only drinking water and served as diabetic control. At the end of the treatment period, the rats were anesthetized with urethane (1.2 g/kg) and mean arterial pressure, heart rate and hindlimb blood flow were monitored. This was followed by the injection of acetylcholine (endothelium-dependent vasodilator, 0.1–0.8 μg/kg) and sodium nitroprusside (endothelium-independent vasodilator 1–4 μg/kg). Mean arterial pressure was significantly reduced and hindlimb vascular conductance was not significantly affected in the control diabetic group when compared to the normoglycemic control group. Nimesulide treatment did not cause any significant change in any of the measured hemodynamic parameters. Acetylcholine and sodium nitroprusside induced dose-dependent increases in hindlimb vascular conductance in control normoglycemic rats which were attenuated in diabetic control rats. Nimesulide reversed the attenuation of acetylcholine-induced increase in hindlimb vascular conductance. In conclusion, chronic administration of the selective COX-2 inhibitor, nimesulide improved endothelial dysfunction in the hindlimb vasculature of streptozotocin induced diabetic rats. This suggests that COX-2 products might be involved in the pathogenesis of endothelial dysfunction in streptozotocin-induced diabetic rats.

Gum Acacia Improves Renal Function and Ameliorates Systemic Inflammation, Oxidative and Nitrosative Stress in Streptozotocin-Induced Diabetes in Rats with Adenine-Induced Chronic Kidney Disease

Background/Aims: The effect of treatment with gum acacia (GA), a prebiotic shown previously to ameliorate chronic kidney disease (CKD), in diabetic and non – diabetic rats with adenine – induced CKD has been investigated using several conventional and novel physiological, biochemical, and histopathological parameters. Methods: Diabetes mellitus was induced in rats by a single injection of streptozotocin (STZ). Diabetic and non – diabetic rats were randomly divided into several groups, and given either normal food or food mixed with adenine (0.25% w/w, for five weeks) to induce CKD. Some of these groups were also concomitantly treated orally with GA in the drinking water (15% w/w). Results: Rats fed adenine alone exhibited physiological (decreased body weight, increased food and water intake and urine output), biochemical (increase in urinary albumin/creatinine ratio, plasma urea and, creatinine, indoxyl sulfate and phosphorus), inflammatory biomarkers (increased in neutrophil gelatinase-associated lipocalin, transforming growth factor beta -1, tumor necrosis factor alpha, adiponectin, cystatin C and interleukin-1β), oxidative biomarkers (8-isoprostane, 8 -hydroxy -2-deoxy guanosine), nitrosative stress biomarkers (nitrite and nitrate) and histopathological (increase in tubular necrosis and fibrosis) signs of CKD. STZ - induced diabetes alone worsened most of the renal function tests measured. Administration of adenine in STZ – diabetic rats further worsened the renal damage induced by adenine alone. GA significantly ameliorated the renal actions of adenine and STZ, given either singly or in combination, especially with regards to the histopathological damage. Conclusion: GA is a useful dietary agent in attenuating the progression of CKD in rats with streptozotocin-induced diabetes.

The effect of the dipeptidyl peptidase-4 inhibitor sitagliptin on gentamicin nephrotoxicity in mice

This study aimed at investigating the possible ameliorative effects of sitagliptin in mice with gentamicin (GEN) nephrotoxicity. Sitagliptin was given to the animals at an oral dose of 10mgkg-1 per day for 10days, and in some of these mice, GEN was injected intraperitoneally at a dose of 100mgkg-1 per day during the last seven days of the treatment. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically by measuring several indices in plasma, urine and renal cortex homogenates. GEN treatment induced nephrotoxicity as evidenced by significantly (P<0.0001) increasing the plasma concentrations of urea, creatinine, circulatory cytokines, cystatin C, sclerostin, and TNFα. Treatment with GEN also significantly elevated urinary N-acetyl-β-d glucosaminidase (NAG) concentration (P<0.0001). Moreover, GEN caused significant increase in oxidative stress in the kidneys (P<0.0001). Histopathological examination revealed massive tubular injury, necrosis, infiltration of inflammatory cells and intraluminal hyaline casts in mice treated with GEN. Sitagliptin alone did not significantly affect any of the indices measured. However, concomitant treatment with sitagliptin and GEN significantly mitigated most of the nephrotoxic actions of GEN. Pending further studies, sitagliptin may potentially be useful as a nephroprotectant agent.

The effect of sildenafil on rats with adenine—Induced chronic kidney disease

The erectile dysfunction drug sildenafil has cardiopulmonary protective actions, and a nephroprotective action in cisplatin and ischemia-reperfusion-induced acute kidney injury. Here, we assessed its possible ameliorative action in a model of chronic kidney disease (CKD) using adenine feeding. Eight groups of rats were treated with saline (controls), adenine (0.25% w/w in feed daily for 5 weeks), and oral sildenafil (0.1, 0.5 or 2.5 mg/kg), either alone, or concomitantly with adenine. Urine was collected 24 h after the end of the treatments from all rats and blood pressure measured, followed by collection of blood and kidneys for the measurement of several functional, biochemical and histopathological parameters. Adenine treatment reduced body weight, creatinine renal clearance, and increased water intake and urine output, as well as the plasma concentrations of urea and creatinine, neutrophil gelatinase-associated lipocalin, and N-acetyl-β-D-glucosaminidase activity, and albumin in urine. Adenine also increased the concentrations of the uremic toxins indoxyl sulfate, uric acid and phosphate, and a number of proteins and inflammatory cytokines, and decreased that of several anti - oxidant indices. Renal histopathological markers of damage (inflammation and fibrosis) were significantly increased by adenine. Sildenafil, given simultaneously with adenine, induced a dose - dependent improvements in most of the above parameters, suggesting its possible use as adjunct treatment for CKD in humans.

Effect of infliximab and tocilizumab on fructose-induced hyperinsulinemia and hypertension in rats.

Fructose administration can induce hypertension, insulin resistance and hypertriglyceridemia. Here, we investigated the possible protective effect of infliximab (IFX), a tumor necrosis factor alpha (TNF-α) inhibitor, or tocilizumab (TOC), an interleukin-6 (IL6) inhibitor, on fructose-induced increase in blood pressure, insulin resistance and hyperlipidemia in rats. The animals were fed a 60% fructose diet in the absence or presence of IFX (5 mg/kg, i.p., once weekly) or TOC (8 mg/kg, i.p., once every two weeks). Fructose significantly increased blood pressure, heart rate and homeostatic model assessment of insulin resistance (HOMA-IR). Fructose also significantly raised the concentrations of fasting plasma insulin, triglycerides, total cholesterol, uric acid, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), malondialdhyde (MDA) and nitric oxide. Fructose also significantly decreased plasma superoxide dismutase (SOD) and catalase activities. In addition, fructose significantly increased aortic endothelin and nitric oxide concentrations. Both IFX and TOC attenuated the fructose-induced increase in blood pressure, insulin resistance, and the concentrations of uric acid, MDA and IL-6. TOC significantly reduced fructose-induced increase in triglycerides and cholesterol. In addition, IFX increased plasma SOD and catalase activities. Our results showed that both IFX and TOC were partially successful in reversing fructose - induced changes.

The effect of swimming exercise on adenine-induced kidney disease in rats, and the inffuence of curcumin or lisinopril thereon

Patients with chronic kidney disease (CKD) have been reported to benefit from different types of exercises. It has also been shown that the ACE inhibitor lisinopril, and the natural product curcumin are also beneficial in different models of CKD in rats. We assessed the influence of moderate swimming exercise (SE) on rats with adenine-induced CKD, and tested the possible effects of lisinopril and/or curcumin thereon using several physiological, biochemical, histopathological and immunohistochemical parameters. Rats (either sedentary or subjected to SE) were randomly divided into several groups, and given for five weeks either normal food or food mixed with adenine (0.25% w/w) to induce CKD. Some of these groups were also concomitantly treated orally with curcumin (75 mg/kg), or lisinopril (10 mg/kg) and were subjected to moderate SE (45 min/day three days each week). Rats fed adenine showed the typical biochemical, histopathological signs of CKD such as elevations in blood pressure, urinary albumin / creatinine ratio, and plasma urea, creatinine, indoxyl sulfate and phosphorus. SE, curcumin or lisinopril, given singly, significantly ameliorated all the adenine-induced actions. Administering curcumin or lisinopril with SE improved the histopathology of the kidneys, a salutary effect not seen with SE alone. Combining SE to the nephroprotective agents’ curcumin or lisinopril might offer additional nephroprotection.