Remote Ischemic Perconditioning Modulates Apelin Expression After Renal Ischemia-Reperfusion Injury.

BACKGROUND: Renal ischemia/reperfusion injury (IRI) can result in impaired ability of urine concentration and increased sodium fractional excretion. Apelin, a (neuro) vasoactive peptide, enhances diuresis by increasing the renal microcirculation and by counteracting the antidiuretic effect of arginine vasopressin on the tubules. However, changes in renal apelin expression in renal IRI rat model have not been elucidated. Remote ischemic perconditioning (RIPerC) improves renal sodium and water handling after IRI. Here, we investigated whether RIPerC prevents dysregulation of renal sodium and water handling in response to IRI by apelin signaling pathway in rats. MATERIALS AND METHODS: Renal IRI was induced by 45-min clamping of renal arteries followed by 24 h reperfusion. RIPerC was created by applying four cycles of 2-min ischemia of the left femoral artery followed by 3-min reperfusion at the start of renal ischemia. Rats were randomly divided into sham, ischemia/reperfusion, and RIPerC + ischemia/reperfusion groups. Urine and blood were sampled after reperfusion period. The kidney was harvested for mRNA isolation and histopathological study. RESULTS: IRI resulted in decreased clearance of creatinine, increased sodium fractional excretion, and reduced urine osmolality compared with sham animals. This occurred with an increase in mRNA expression levels of apelin and histological damages in both cortical and medullary regions of kidney tissues. RIPerC treatment ameliorated all these changes. CONCLUSIONS: This study showed that RIPerC has protective effects against dysregulation of renal sodium and water handling after renal IRI, which might be related with inhibition of apelin signaling pathway.

Remote ischemic per-conditioning protects against renal ischemia-reperfusion injury via suppressing gene expression of TLR4 and TNF-α in rat model.

The pathogenesis of renal ischemia-reperfusion injury (IRI) involves both inflammatory processes and oxidative stress in the kidney. This study determined whether remote ischemic per-conditioning (RIPerC) is mediated by toll-like receptor 4 (TLR4) signaling pathway in rats. Renal IR injury was induced by occluding renal arteries for 45 min followed by 24 h of reperfusion. RIPerC included 4 cycles of 2 min of ischemia of the left femoral artery followed by 3 min of reperfusion performed at the start of renal ischemia. Rats were divided into sham, IR, and RIPerC groups. At the end of the reperfusion period, urine, blood and tissue samples were gathered. IR created kidney dysfunction, as ascertained by a significant decrease in creatinine clearance and a significant increase in sodium fractional excretion. These changes occurred in concert with a decrease in the activities of glutathione peroxidase, catalase, and superoxide dismutase with an increment in malondialdehyde levels, mRNA expression levels of TLR4 and tumor necrosis factor α (TNF-α), and histological damage in renal tissues. RIPerC treatment diminished all these changes. This study demonstrates that RIPerC has protective effects on the kidney after renal IR, which might be related to the inhibition of the TLR4 signaling pathway and augmentation of antioxidant systems.

Hepatic and renal protective effects of quercetin in ferrous sulfateinduced toxicity.

Iron is a vitally important element for the maintenance of health in living organisms. But, iron overload can be toxic. This study investigated the protective efficacy of quercetin against ferrous sulfate-induced oxidative stress, hepato- and nephrotoxicity in rats. There were five experimental groups (n = 7): Sham (distilled water, 1 ml/day for 14 days, i.p.), Quer (quercetin, 50 mg/kg/day for 14 days, i.p.), DMSO (dimethyl sulfoxide 1%, 1 ml i.p.), Fe (ferrous sulfate, 30 mg/kg/day for 14 days, i.p.), Fe+Quer (ferrous sulfate, 30 mg/kg/day for 14 days; quercetin, 50 mg/kg/day for 11 days from fourth day of ferrous sulfate injection). Blood, 24-h urine and tissue samples were collected at the end of experiment. Quercetin prevented ferrous sulfate-induced hepatotoxicity and nephrotoxicity as indicated by decreased activities of serum hepatic marker enzymes and decreased serum bilirubin concentration, higher levels of serum triglyceride, cholesterol, glucose, albumin and total protein, as well as higher creatinine clearance and lower fractional excretion of sodium. Besides, quercetin decreased malondialdehyde levels and histological damages in the liver and kidney of Fe group as compared with sham, DMSO and Quer groups. The protective effect of quercetin relies, at least partially, on its antioxidative effect which leads to decreased lipid peroxidation as well as iron-chelating property.

Hepatorenal protection during renal ischemia by quercetin and remote ischemic perconditioning.

BACKGROUND: Pathogenesis of renal ischemia/reperfusion injury (IRI) involves oxidative stress response in the kidney and remote organs. Both quercetin and remote ischemic perconditioning (RIPerC) can protect partially against IRI. This study determined whether combined quercetin and RIPerC could provide an augmented hepatorenal protection against renal IRI. MATERIALS AND METHODS: I/R was induced by clamping renal arteries for 45 min followed by 24-h reperfusion. RIPerC consisted of four cycles of 2 min of left femoral artery ischemia followed by 3 min of reperfusion administered at the beginning of renal ischemia. Rats were divided into five groups: sham, I/R, RIPerC, quercetin (Q + I/R), and combined quercetin and RIPerC (Q + RIPerC). At the end of reperfusion period, blood, urine, and tissue samples were collected. RESULTS: I/R caused kidney dysfunction, as proved by significant decrease in creatinine clearance, and a significant increase in liver functional indicators as evidenced by increased plasma alanine aminotransferase and aspartate aminotransferase activity. This was accompanied by a decrease of glutathione peroxidase and catalase activities with an increase of malondialdehyde levels and histological damages in renal and hepatic tissues. Treatment with RIPerC and quercetin reduced all these changes. However, the measure of improvements was enhanced by combined quercetin and RIPerC treatment. CONCLUSIONS: This study demonstrated protective effects of quercetin and RIPerC strategy on the both kidney and liver after renal I/R. The results suggest that combined quercetin and RIPerC provides an enhanced protection against renal IRI by reduction of lipid peroxidation and augmentation of antioxidant systems.

Berberis integerrima hydro-alcoholic root extract and its constituent berberine protect against cisplatin-induced nephro- and hepato-toxicity.

BACKGROUND: This study determined the potential hepato- and renal protective role of berberine and hydroalcohol extract of Berberis integerrima (barberry) against cisplatin-induced acute liver and kidney injury. METHODS: Animals were dedicated into six groups (n = 7 per group): control, control+Ber (berberine, 0.4 mg/kg/day during 10 days, i.p.), control+B.E (barberry extract, 160 mg/kg/day during 10 days, i.p.), Cis (cisplatin, 8 mg/kg on 7th day, i.p.), Cis+Ber (berberine, 100 mg/kg/day during 10 days; cisplatin, 8 mg/kg on 7th day), Cis+B.E (barberry extract, 160 mg/kg/day during 10 days; cisplatin, 8 mg/kg on 7th day). After placing the rats in metabolic cages for 24 h, blood, urine, liver and kidney tissue samples were collected. RESULTS: Compared to control, control+Ber and control+B.E groups, cisplatin administration led to kidney and liver dysfunction. These happened with diminished activities of antioxidant enzymes, increased levels of malondialdehyde, Toll-like receptor 4 gene expression and histological damages in hepatic and renal tissues. Berberine and barberry extract administration decreased all the changes. CONCLUSIONS: An intensification in enzymatic oxidant status, decrease in lipid peroxidation with decrease in TLR4 gene expression level indicate that barberry extract may be a potential candidate in combating cisplatin-induced oxidative stress and inflammation in liver and kidney tissues through its constituent berberine.

Protective effect of genistein in a rat model of ischemic acute kidney injury.

BACKGROUND: This study determined the possible anti-inflammatory and antioxidant renal protective effect of genistein, a soy isoflavone, against kidney damage and functional disorders following renal ischemia/reperfusion (I/R) in male rats. MATERIALS AND METHODS: The animals were dedicated to five groups (n = 7 per group): Sham, Sham + Geni (genistein, 15 mg/kg in 1 ml 1% DMSO, i.p.), Sham + DMSO (1 ml 1% DMSO, i.p.), I/R (bilateral renal ischemia for 45 min followed by 24 h reperfusion), I/R + Geni (genistein, 15 mg/kg). 24-h urine samples, blood and tissue samples of the kidney were collected at the end of 24 h reperfusion period. RESULTS: Compared to sham, sham + Geni and sham + DMSO groups, IR injury (IRI) ended in kidney dysfunction (decreased creatinine clearance, and increased fractional excretion of sodium), increased levels of malondialdehyde, decreased activities of antioxidant enzymes (superoxide dismutase, gluthatione peroxidase, and catalase), increased gene expression levels of TLR4 (Toll-like receptor 4) and TNF-α (tumor necrosis factor-alpha), as well as histological damages in kidney tissue. Genistein administration decreased all the changes. Therefore, genistein apparently protects the kidney against IRI by mitigating both oxidative stress and inflammation. The antioxidant and anti-inflammatory properties of genistein probably exert important roles in improving functional disorders and offer renal protection against IRI.

Amelioration of testicular damages in renal ischemia/reperfusion by berberine: An experimental study.

BACKGROUND: Ischemic acute kidney injury is associated with an inflammatory reaction. OBJECTIVE: In the current study, berberine was assessed for its effect on the functional disorders and histological damages of testis induced by renal ischemia/reperfusion (I/R). MATERIALS AND METHODS: Twenty-eight adult male Wistar rats (260-300 gr) were equally divided into four groups (n = 7/each): sham and I/R groups which received distilled water as well as berberine (BBR) and BBR + I/R groups which received berberine (15 mg/kg/day) orally seven days before the surgery. In both groups of sham and BBR, renal arteries were not clamped. Renal I/R was induced by occluding right and left renal artery for 45 min followed by a 24 hr reperfusion period. Blood samples were taken for determining the plasma levels of creatinine, urea nitrogen, FSH (follicle stimulating hormone), LH (luteinizing hormone), and testosterone. Then the rats were killed under deep anesthesia and the left testis was immediately isolated and preserved. RESULTS: The renal I/R injury led to testicular histological damages accompanied with increased plasma levels of creatinine, urea nitrogen, LH, and FSH, as well decrease of plasma testosterone concentration at the end of 24 hr reperfusion (All p < 0.001, except for FSH p < 0.01). Berberine diminished histological damage to the testis and attenuated the increase in plasma creatinine, urea nitrogen, LH, FSH, and decrease in plasma testosterone concentration in the BBR + I/R group (All p < 0.001). CONCLUSION: These results suggest that ischemic acute renal failure induces functional disorders and tissue damages in testis of rat, which was improved through the administration of berberine.

Berberine protects the liver and kidney against functional disorders and histological damages induced by ferrous sulfate.

OBJECTIVES: Iron is an essential element for living organisms. Iron overload can have detrimental effects on health. This study pertains to the protective role of berberine against ferrous sulfate-induced hepatic and renal functional disorders and histological damages in rats. MATERIALS AND METHODS: The rats were divided into four groups (n=7): Sham, Ber (10 mg/kg/day for 14 days, by gavage), FS (ferrous sulfate, 30 mg/kg/day for 14 days, intraperitoneally), FS + Ber (ferrous sulfate, 30 mg/kg/day for 14 days; berberine, 10 mg/kg/day for 11 days from fourth day of ferrous sulfate injection). After 24 hr, blood, urine, and tissue samples were collected. RESULTS: Compared with sham and Ber groups, administration of ferrous sulfate resulted in liver and kidney dysfunction as evidenced by significantly higher levels of serum hepatic markers and bilirubin, and lower levels of serum albumin, total protein, triglyceride, cholesterol, and glucose, as well as lower creatinine clearance and higher fractional excretion of sodium. This was accompanied by increased malondialdehyde levels and histological damages. Berberine treatment significantly reversed the levels of serum hepatic markers, renal functional markers and lipid peroxidation marker in the FS + Ber group. Furthermore, it restored the levels of serum total protein, albumin, glucose, triglycerides, and cholesterol with a decrease in bilirubin concentration in the blood. All these changes were corroborated by histological observations of the liver and kidney. CONCLUSION: Berberine protects the liver and kidneys against ferrous sulfate-induced toxicity by reduction in lipid peroxidation and ability to chelate iron.

The role of nitric oxide in the protective action of remote ischemic per-conditioning against ischemia/reperfusion-induced acute renal failure in rat.

OBJECTIVES: We investigated the role of nitric oxide (NO) in the protective effects of remote ischemic per-conditioning (rIPerC) on renal ischemia/reperfusion (I/R) injury in male rats. MATERIALS AND METHODS: I/R treatment consisted of 45 min bilateral renal artery ischemia and 24 hr reperfusion interval. rIPerC was performed using four cycles of 2 min occlusions of the left femoral artery and 3 min reperfusion at the beginning of renal ischemia. The animals were given normal saline (vehicle), NG-nitro-L-arginine methyl ester (L-NAME) or L-arginine. Following the reperfusion period, renal functional- and oxidative stress- parameters, as well as histopathological changes were assessed. RESULTS: In comparison with the sham group, I/R resulted in renal dysfunction, as indicated by significantly lower creatinine clearance and higher fractional excretion of sodium. This went along with decreased glutathione peroxidase (GPX) and catalase (CAT) activity in the I/R group, increased malondialdehyde (MDA) contents and histological damages. In comparison with the I/R group, the rIPerC group displayed improved renal function, increased activity of GPX and CAT enzymes, and decreased MDA level. However, these effects were abrogated by L-NAME injection and augmented by L-arginine treatment. CONCLUSION: According to the results, the functional and structural consequences of rIPerC against I/R-induced kidney dysfunction, which is associated with reduction of lipid peroxidation and intensification of anti-oxidant systems, is partially dependent on NO production.

The protective effect of hydroalcoholic extract of Ginger (Zingiber officinale Rosc.) against iron-induced functional and histological damages in rat liver and kidney.

OBJECTIVE: Iron overload in the body is related with toxic effects and threatens the health. The aim of this study was to evaluate the protective role of hydroalcoholic extract of ginger (Zingiber officinale) against ferrous sulfate-induced hepatic and renal functional disorders and histological damages in rats. MATERIALS AND METHODS: The rats were divided into four groups (n=7): Sham, Sham + G.E (ginger extract, 400 mg/kg/day for 14 days), FS (ferrous sulfate, 30 mg/kg/day for 14 days), FS+G.E (ferrous sulfate, 30 mg/kg/day for 14 days; ginger extract, 400 mg/kg/day for 11 days from the fourth day of ferrous sulfate injection). After 24 hr, blood, urine and tissue samples were collected. RESULTS: Compared with Sham and Sham + G.E groups, administration of ferrous sulfate resulted in liver and kidney dysfunction as evidenced by significantly higher levels of serum hepatic markers and bilirubin, and lower levels of serum albumin, total protein, triglyceride, cholesterol and glucose, as well as lower creatinine clearance and higher fractional excretion of sodium (p<0.001). This was accompanied by increased malondialdehyde levels and histological damages (p<0.001). In the FS + G.E, ginger extract significantly (p<0.01) reversed the levels of serum hepatic markers, renal functional markers and lipid peroxidation marker. Furthermore, it restored the levels of serum total protein, albumin, glucose, triglycerides and cholesterol and decreased bilirubin concentration in the blood. All these changes were corroborated by histological observations of liver and kidney. CONCLUSION: In conclusion, ginger extract appears to exert protective effects against ferrous sulfate-induced hepatic and renal toxicity by reducing lipid peroxidation and chelating iron.