Exosomes in renal cell carcinoma: challenges and opportunities.

Renal cell carcinoma (RCC) is the most common type of kidney cancer that accounts for approximately 2-3% of adult malignancies. Among the primary treatment methods for this type of cancer are surgery and targeted treatment. Still, due to less than optimal effectiveness, there are problems such as advanced distant metastasis, delayed diagnosis, and drug resistance that continue to plague patients. In recent years, therapeutic advances have increased life expectancy and effective treatment in renal cell carcinoma patients. One of these methods is the use of stem cells. Although the therapeutic effects of stem cells, especially mesenchymal stem cells, are still impressive, today, extracellular vesicles (EVs) as carrying molecules and various mediators in intercellular communications, having a central role in tumorigenesis, metastasis, immune evasion, and drug response, and on the other hand, due to its low immunogenicity and strong regulatory properties of the immune system, has received much attention from researchers and doctors. Despite the increasing interest in exosomes as the most versatile type of EVs, the heterogeneity of their efficacy presents challenges and, on the other hand, exciting opportunities for diagnostic and clinical interventions.In the upcoming article, we will review the various aspects of exosomes' effects in the prevention, treatment, and progress of renal cell carcinoma and also ways to optimize them to strengthen their positive sides.

Kidney injury in COVID-19 patients, drug development and their renal complications: Review study.

Since December 2019, the world was encountered a new disease called coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although SARS-CoV-2 initially causes lung damage, it also affects many other organs, including the kidneys, and on average, 5-23% of people with COVID-19 develop the symptoms of acute kidney injury (AKI), including elevated blood creatinine and urea, hematuria, proteinuria, and histopathological damages. The exact mechanism is unknown, but the researchers believe that SARS-CoV-2 directly and indirectly affects the kidneys. The direct pathway is by binding the virus to ACE2 receptor in the kidney, damage to cells, the renin-angiotensin system disturbances, activating coagulation pathways, and damaging the renal vascular endothelium. The initial evidence from studying the kidney tissue in postmortem patients is more in favor of the direct pathway. The indirect pathway is created by increased cytokines and cytokine storm, sepsis, circulatory disturbances, hypoxemia, as well as using the nephrotoxic drugs. Using renal tissue biopsy and autopsy in the patients with COVID-19, recent studies found evidence for a predominant indirect pathway in AKI induction by SARS-CoV-2. Besides, some studies showed that the degree of acute tubular injury (ATI) in autopsies from COVID-19 victims is milder compared to AKI degree. We review the mechanism of AKI induction and the renal side effects of the most common drugs used to treat COVID-19 after the overview of the latest findings on SARS-CoV-2 pathogenicity.

Protective effect of piperine in ischemia-reperfusion induced acute kidney injury through inhibition of inflammation and oxidative stress.

BACKGROUND AND AIM: Renal ischemia-reperfusion is associated with inflammation and oxidative stress. As a major compound in black pepper, piperine has anti-inflammatory and anti-oxidative properties. In present study, the protective effects of oral administration of piperine in renal ischemia-reperfusion (IR) induced acute kidney injuries (AKI) were investigated. EXPERIMENTAL PROCEDURE: Male Wistar rats received piperine (10 or 20 mg/kg.bw) or vehicle for 10 days. The artery and vein of both kidneys were then clamped for 30 min, followed by a 24-h reperfusion period. Concentrations of creatinine and urea-nitrogen in descending aorta blood were measured, and malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP) levels were measured in kidney tissue to evaluate the oxidative stress. Inflammation was evaluated by measuring the TNF-α and ICAM-1 mRNA expression levels in renal cortical tissue using Real Time PCR method and counting leukocytes infiltration to interstitium. Further measured were tissue damages in H & E stained sections. RESULTS: Renal IR reduced FRAP, while increasing the plasma concentrations of creatinine and urea-nitrogen, tissue MDA level, TNF-α and ICAM-1 mRNA expressions, leukocyte infiltration and histopathologic injuries. Piperine administration significantly reduced the plasma concentrations of creatinine and urea-nitrogen, expression of pro-inflammatory factors, oxidative stress and renal histopathologic injuries. It is to be noted that 20 mg/kg dose was more effective. CONCLUSION: Our results suggest piperine protects the kidney against ischemia-reperfusion induced acute kidney injuries by its anti-inflammatory and anti-oxidative properties.

The effect of adipose-derived mesenchymal stem cells on renal function and histopathology in a rat model of ischemia-reperfusion induced acute kidney injury.

OBJECTIVES: It has been shown that adipose-derived mesenchymal stem cells (AD-MSC) have protective effects in acute kidney injury (AKI). This study was conducted to assess the therapeutic effects of AD-MSC in rats subjected to acute kidney injury by 45 min of renal ischemia followed by 48 hr of reperfusion (I/R). MATERIALS AND METHODS: 28 male Wistar rats were divided into four groups, including control, 48-hr sham, 48-hr I/R, and 48-hr I/R receiving AD-MSC. After 48 hr of reperfusion, blood samples were taken from rats' hearts, and 24-hr urines were collected using a metabolic cage. Serum creatinine level (Cr), blood urea nitrogen (BUN), creatinine clearance (Ccr), absolute sodium excretion (UNaV°), fractional sodium excretion (FENa), absolute potassium excretion (UKV°), factional potassium excretion (FEK), and urine osmolarity were measured. Malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) levels were measured in the right kidney, while the left kidney was used for histologic study after Hematoxylin-Eosin staining. RESULTS: Renal I/R significantly increased serum Cr, BUN, UNaV°, FENa, FEK, and tissue MDA, and significantly decreased Ccr and urine osmolarity as compared with the sham group. Moreover, histologic studies showed that I/R increased Bowman capsule area, tubular necrosis, vascular congestion, and caused formation of intratubular casts. Administration of AD-MSC at the time of I/R completely or partially protected kidneys from these I/R induced injuries. CONCLUSION: Our results show that injection of AD-MSC can reduce degree of renal injury caused by 45 min of ischemia followed by 48 hr of reperfusion in rats.

Stem Cell Therapy Ameliorates Ischemia-reperfusion Induced Kidney Injury After 24 Hours Reperfusion.

INTRODUCTION: The mortality rate in patients with acute kidney injury (AKI) is high. The aim of this study was to evaluate the efficacy of treatment with adipose-derived mesenchymal stem cells (AD-MSC) in renal ischemia-reperfusion (I/R) model in rats. METHODS: In this study 28 male Wistar rats were divided into four groups of control, sham, I/R24h+PBS, and I/R24h+AD-MSC. Blocking the renal arteries for 45 minutes induced renal I/R and then reperfusion was conducted for 24 hours. Parameters including urine volume, osmolarity, plasma creatinine (Crp), and blood urea nitrogen (BUN) were evaluated and values of creatinine clearance (CCr), absolute sodium excretion (UNaV°), fractional excretion of sodium (FENa), absolute potassium excretion (UKV°) and fractional excretion of potassium (FEK) were calculated. The right kidney was removed to measure the malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP), as well as the left kidney for histological evaluation. RESULTS: I/R caused a significant increase in Crp, BUN, UNaV°, FENa, FEK, MDA, and tissue damages. In addition, the values of CCr, urine osmolarity, and FRAP level decreased significantly (P < .05). Following AD-MSC treatment, values of FENa, Crp, FEK, MDA, and tissue damages decreased significantly, while urine osmolarity increased significantly in the I/R24h + AD-MSC group compared to the I/R24h + PBS group. Furthermore, FRAP values increased significantly (P < .001). CONCLUSION: Treatment with AD-MSC reduced tissue damage and oxidative stress while increasing antioxidant activity. In addition, it improved kidney function after 45 min ischemia and 24 h reperfusion.

Piperine pretreatment attenuates renal ischemia-reperfusion induced liver injury.

BACKGROUND: Remote organ injury is one of the complications which are developed following ischemia-reperfusion induced acute kidney injury (AKI), dramatically increasing its mortality rate. The aim of the present study was to investigate the effect of piperine pretreatment on liver dysfunction following ischemia-reperfusion induced AKI. MATERIALS AND METHODS: Acute kidney injury was induced by 30 min-bilateral renal ischemia followed by 24 h of reperfusion. To investigate liver damages, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) enzymes were measured in plasma. In order to study oxidative stress, malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) levels were measured. Furthermore, the expression of intercellular adhesion molecule-1 (ICAM-1) mRNA along with infiltration of leukocytes in the liver tissue was measured for inflammation assessment. Histopathological damages were studied through measuring the extent of cellular fibrosis, sinusoidal dilatation, and vascular congestion in liver tissue. RESULTS: Following acute kidney injury, AST, ALT, and ALP levels in plasma, MDA level and ICAM-1 expression in the liver tissue, infiltration of leukocytes into the interstitium, and hepatic histopathologic damages increased significantly, while FRAP decreased. Pretreatment with piperine at 10 and 20 mg/kg body weight was able to improve these damages, such that some of them reached its value in the sham group, though piperine in the 20 mg/kg was more effective. CONCLUSIONS: The results of this study suggest that ischemia-reperfusion induced AKI result in hepatic damages, and pretreatment with piperine can prevent development of these damages through its antioxidant and anti-inflammatory properties.

Amelioration of renal and hepatic function, oxidative stress, inflammation and histopathologic damages by Malva sylvestris extract in gentamicin induced renal toxicity.

BACKGROUND: Gentamycin, contrary to its wide range of antimicrobial effects, has a high potential for nephrotoxicity, and renal injury can have effects on other organs such as the liver. OBJECTIVES: The aim of the present study was to assess the effects of hydro alcoholic Malva sylvestris(MS) extract on nephrotoxicity induced by gentamicin, and also its remote organ injury in the liver. METHODS: Renal and hepatic functions were evaluated through measurement of creatinine, urea-nitrogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in plasma. Oxidative stress was assessed through measuring malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP) levels, and histopathologic injuries were evaluated using H & E stained sections. For evaluation of inflammation, TNF-α and ICAM-1 mRNA expression levels were measured in the renal tissue using Real-time PCR method. RESULTS: Gentamicin resulted in an increase in the levels of creatinine, urea-nitrogen, AST, ALT, and ALP in the plasma, as well as an increase in TNF-α and ICAM-1 mRNA expression levels in the renal tissue, renal and hepatic histopathologic injuries and MDA level, and a decrease in FRAP. Administration of MS led to improvement in the function of kidney and liver, a decrease in the expression levels of proinflammatory factors, reduction of oxidative stress, and also a decrease in tissue injuries. CONCLUSION: MS extract can protect the kidney against toxic effects of gentamicin, and thus, the degree of harmful effects of nephrotoxicity on remote organs including the liver will be decreased.

Reduction of cisplatin-induced renal and hepatic side effects in rat through antioxidative and anti-inflammatory properties of Malva sylvestris L. extract.

BACKGROUND: Cisplatin is widely used in the chemotherapy of solid organ cancers. However, its application is associated with serious side effects in various organs including the kidneys and liver. OBJECTIVES: The aim of this study was to investigate the effects of mallow extract on the side effects of cisplatin in the kidneys and liver. METHODS: Hydroalcoholic extract of mallow, at doses of 200, 400, and 600 mg/kg BW, was administered to the animals for seven days intraperitoneally (ip). Animals in the Cis + Mallow group received a dose of cisplatin (8 mg/kg, ip) on the third day. Renal and hepatic functional disturbances were evaluated by measuring concentrations of creatinine, urea-nitrogen, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in the plasma. In order to assess oxidative stress, malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) levels were measured in the kidney tissue. Then, degree of mRNA expressions of TNF-α and ICAM-1 were measured to examine renal inflammation. Hematoxylin and Eosin (H & E) staining of kidney and liver tissues was performed to study tissue damage and leukocyte infiltration. RESULTS: Cisplatin increased levels of plasma creatinine, urea-nitrogen, AST, and ALT; levels of tissue damage and leukocytes infiltration in the kidneys and liver; and MDA level and expression of pro-inflammatory factors in the kidney tissue. Meanwhile, it decreased FRAP level in the kidney tissue. Pretreatment by mallow extract resulted in significant improvement in all measured variables although 200-mg and 400-mg doses yielded better results. CONCLUSION: Results showed that mallow supplement protects the kidneys and liver against side effects of cisplatin, and reduces the resultant oxidative stress and inflammation.

Protective effect of Malva sylvestris L. extract in ischemia-reperfusion induced acute kidney and remote liver injury.

Mallow (Malva sylvestris L.) has had medicinal and therapeutic uses in addition to its oral consumption. The present study was conducted to examine the protective effect of Malva sylvestris L. extract on ischemia-reperfusion-induced kidney injury and remote organ injuries in the liver. Before ischemia-reperfusion, rats in the different groups received intraperitoneal normal saline or mallow extract at the doses of 200, 400 or 600 mg/kg of body weight. After 30-minutes of bilateral renal ischemia followed by 24-hours of reperfusion, tissue damage in the kidney and liver samples were determined through studying H&E-stained slides under a light microscope. The degree of leukocyte infiltration and tissue mRNA expressions of TNF- and ICAM-1 were then measured to examine the degree of renal inflammation. The renal tissue MDA and FRAP levels were measured for determining the amount of oxidative stress. Plasma concentrations of creatinine, urea, ALT and ALP were also measured. Ischemia-reperfusion led to a significant increase in plasma concentrations of creatinine, urea, ALT and ALP, and renal tissue MDA, and a significant decrease in renal tissue FRAP. The expression of pro-inflammatory factors in the kidney tissue, the level of leukocyte infiltration and the amount of tissue damage in the kidney and liver also increased. Pretreatment by mallow extract led to a significant improvement in all the variables measured. The 200- and 400-mg doses yielded better results in most parameters compared to the 600-mg dose. The findings showed that mallow extract protects the kidney against ischemia-reperfusion and reduces remote organ injury in the liver.

Antioxidant activity of omega-3 derivatives and their delivery via nanocages and nanocones: DFT and experimental in vivo investigation.

The antioxidant properties of omega-3 were investigated via experimental in vivo and theoretical methods. For experimental evaluation, oxidative stress was induced by 30 min bilateral renal ischemia and 24 h of reperfusion in male Sprague Dawley rats. The oxidative stress was evaluated through measuring malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP) levels in renal tissue. In theoretical methods, the reaction enthalpies of antioxidant mechanisms of omega-3 were calculated and the effects of NHMe, OMe, OH, Cl, and Me substituents on its antioxidant activity were investigated. Moreover, the omega-3 delivery potential by carbon and boron nitride nanocages and naocones were evaluated. The experimental results showed that omega-3 administration decreases MDA and increases FRAP levels after their changes by ischemia/reperfusion. Theoretical results indicated that NHMe and OMe substituents can significantly improve the antioxidant activity of omega-3. Also, boron nitride nanocone (BNNC) has higher |∆Ead| values, so it has higher potential for omega-3 delivery. Taken together, the new findings presented here indicate that omega-3 has anti-oxidative properties and NHMe and OMe substituents can improve its antioxidant activity. Moreover, adsorption of omega-3 on the surface of the studied nanostructures was exothermic, and BNNC with higher |∆Ead| values has higher potential for omega-3 delivery. Graphical abstract The interaction and adsorption of BNNC with omega-3 is exothermic and experimentally possible from the energetic viewpoint, so the BNNC with higher |∆Ead| and |∆Gad| values has higher potential for omega-3 delivery.

Crocin has anti-inflammatory and protective effects in ischemia-reperfusion induced renal injuries.

OBJECTIVES: Crocus sativus (saffron) has been widely used in traditional medicine. It has also been found to possess many beneficial properties in modern medicine. The most important ingredients of saffron are crocin, crocetin, safranal, and picrocrocin. This study evaluated the protective effects of crocin against the inflammation, oxidative stress, and functional disturbances of the kidney induced by renal ischemia/reperfusion (I/R). MATERIALS AND METHODS: Different doses of crocin (0, 100, 200, and 400 mg/kg) were administered intraperitoneally 30 min before I/R. The rats of the sham group were also injected with normal saline before the sham surgery. For induction of I/R, both renal artery and vein clamped for 30 min, bilaterally. The I/R-induced renal injuries were assessed by measuring leukocyte infiltration, intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF-α) mRNA expression levels, malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP) levels in the kidney tissue, and plasma creatinine and urea-nitrogen concentrations. RESULTS: Except for the tissue level of FRAP which decreased, all other measured parameters increased following I/R induction. Pretreatment with all doses of crocin significantly reduced the severity of these disturbances (P<0.05 to P<0.001). In fact, while there was no significant differences between MDA and FRAP levels, plasma creatinine and urea-nitrogen concentrations of the crocin-treated animals and the sham group, crocin administration reduced leukocyte infiltration and ICAM-1 and TNF-α mRNA expression levels in a dose-dependent manner. CONCLUSION: The present study clearly demonstrated the anti-inflammatory, antioxidant, and protective effects of crocin, a main constituent of saffron, against renal damages resulted from I/R in rats.

Theoretical and Experimental in vivo Study of Antioxidant Activity of Crocin in Order to Propose Novel Derivatives with Higher Antioxidant Activity and Their Delivery via Nanotubes and Nanocones.

In this study, the antioxidant activity of crocin via experimental and theoretical methods was investigated. In order to induce oxidative stress, 30-min renal ischemia and 24-h reperfusion were used in male Wistar rats. Oxidative stress was assessed by measuring tissue malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP). The results showed that following ischemia/reperfusion, the level of MDA was increased and FRAP decreased. Both of these changes were alleviated by crocin administration. The bond dissociation enthalpy and ionization potential values as enthalpies of mechanism of antioxidant activity of crocin were calculated by density functional theory method. According to obtained results, the novel structures of crocin with higher antioxidant activity for synthesis were proposed. Results indicated that NH2, OMe, and F substituents can improve the antioxidant activity of crocin. The crocin delivery via carbon and boron nitride nanotubes and nanocones was investigated. The results confirm that the calculated adsorption and free Gibbs energies of crocin on the surface of studied nanostructures were negative meaningfully, so these processes were exothermic and experimentally possible from the energetic viewpoint.

Anti-inflammatory and protective effects of saffron extract in ischaemia/reperfusion-induced acute kidney injury.

AIM: Inflammation is one of the major challenges in the management of ischaemia/reperfusion (I/R)-induced acute kidney injury. Our aim was to assess the anti-inflammatory and protective effects of saffron extract against I/R-induced renal disturbances. METHODS: A total of 35 male Wistar rats were randomly divided into five groups (n = 7) as sham, I/R and three groups of I/R that were pretreated with different doses of saffron extract (5 mg/kg, 10 mg/kg, or 20 mg/kg) intraperitoneally. The I/R-induced renal inflammation was assessed by measuring leukocyte infiltration and mRNA expression levels of intercellular adhesion molecule-1 and tumour necrotic factor-alpha. For the assessment of oxidative stress, thiobarbituric acid reactive species and antioxidant capacity of kidneys were measured in the right kidneys. In addition, plasma creatinine and urea-nitrogen concentrations were determined for renal functional disturbances. Statistical analysis was performed using one-way analysis of variance using the Duncan post hoc test. RESULTS: The I/R increased all of the measured parameters, except for the tissue level of ferric reducing/antioxidant power, which decreased. Pretreatment with saffron extract in all doses significantly reduced the severity of these disturbances in such a way that there were no significant differences between the FRAP level and urea-nitrogen concentrations between the sham and all three saffron extract-treated groups. However, the saffron extract could decrease the plasma creatinine concentration, malondialdehyde level, tumour necrotic factor-alpha and intercellular adhesion molecule-1 expression and leukocyte infiltration in a dose-dependent manner. CONCLUSION: The present study showed anti-inflammatory, anti-oxidative and protective effects for the hydro-ethanolic extract of saffron in I/R-induced acute kidney injury.

Pimpinella anisum L. ethanolic extract ameliorates the gentamicin- induced nephrotoxicity in rats.

AIM: Gentamicin (GM) is one of the commonest causes of drug-induced nephrotoxicity. Moreover, oxidative stress plays an important role in gentamicin-induced nephrotoxicity. The current study aimed to explore the antioxidant and protective effects of Pimpinella anisum (P. anisum) on the alleviation of GM-induced damage. METHODS: Forty male wistar rats were divided into four groups: control, sham that was administrated normal saline orally and intraperitoneally (i.p.), GM that received 100 mg/kg bw/day i.p., GM and ethanolic extract of P. anisum that was administrated at an oral dose of 300 mg/kg bw/day for 8 days. Creatinine, Na+ , K+ and blood urea nitrogen (BUN) levels were measured. The levels of ferric-reducing-antioxidant-power (FRAP) and malondialdehyde (MDA) were measured to evaluate the oxidative stress induced by GM. Kidney tissues were stained to determine the degree of tissue damage. RESULTS: The plasma levels of creatinine, BUN, MDA and the absolute excretion of sodium and potassium were increased in the GM group, while FRAP level was reduced compared to the sham group. In addition, congestion of renal Vessels and tubular cell necrosis was observed. We found that 300 mg/kg bw/day P. anisum significantly reduced the plasma concentrations of renal function markers in the group receiving GM (P < 0.05). Additionally, gentamicin-induced tubule damage was improved by P. anisum. CONCLUSION: We demonstrated the potential therapeutic impact of P. anisum to attenuate GM-induced nephrotoxicity. Therefore, the simultaneous use of ethanolic extract of P. anisum during GM administration is recommended to reduce its nephrotoxicity effects.

Protective effect of crocin on gentamicin-induced nephrotoxicity in rats.

OBJECTIVES: Gentamicin is used for the treatment of Gram-negative bacterial infections. However, gentamicin administration is limited because of nephrotoxicity. The aim of the present study was to evaluate the protective effect of crocin against gentamicin-induced nephrotoxicity in rats. MATERIALS AND METHODS: Thirty two male Wistar rats received gentamicin (100 mg/kg, IP), with or without crocin (100 mg/kg, IP) for seven consecutive days. Plasma creatinine and urea-nitrogen concentrations, oxidative stress and histopathological changes of kidney tissues were monitored. RESULTS: Administration of gentamicin resulted in significant increases in plasma creatinine and urea-nitrogen concentrations and renal tissue malondialdehyde (MDA) level, and a decrease in the renal tissue ferric reducing/antioxidant power (FRAP) level. Crocin decreased plasma creatinine and urea-nitrogen concentrations and tissue MDA level, but increased the level of tissue FRAP. In addition, gentamicin led to cellular damages including glomerular atrophy, cellular desquamation, tubular necrosis and fibrosis, epithelial oedema of proximal tubules, perivascular edema, vascular congestion and intra-tubular proteinaceous casts, all of which were partially recovered by crocin. CONCLUSION: Crocin has protective effects against functional disturbances, oxidative stress and tissue damages induced by gentamicin.

A1 -Adenosine receptor activation has biphasic roles in development of acute kidney injury at 4 and 24 h of reperfusion following ischaemia in rats.

NEW FINDINGS: What is the central question of this study? A1 -Adenosine receptor (A1 AR) blockade before renal ischaemia aggravated kidney injury after 24 h reperfusion in several studies, whereas we previously observed a renoprotective effect of A1 AR blockade during a 4 h reperfusion period. What are the underlying mechanisms for this biphasic effect of pretreatment with an A1 AR antagonist at 4 and 24 h reperfusion? What is main finding and its importance? A1 -Adenosine receptor blockade protects the kidney against ischaemia-induced injury during the early hours of reperfusion by attenuating the reduction in renal blood flow and lowering energy expenditure, whereas its inflammatory effects gradually dominate over 24 h reperfusion to intensify kidney injury. We previously reported that selective blockade of the A1 -adenosine receptor (A1 AR) with an antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), had protective effects on renal ischaemia-induced structural and functional disruption during a 4 h reperfusion period. In contrast, several studies demonstrated that endogenous and exogenous A1 AR activation before renal ischaemia had a renoprotective role 24 h after reperfusion, through mechanisms that reduced inflammation, necrosis and apoptosis. In this study, we investigated potential mechanisms underlying this biphasic action of A1 AR in renal ischaemia-reperfusion injury. Anaesthetized male Sprague-Dawley rats underwent 30 min of bilateral renal ischaemia, and biphasic effects of pretreatment with DPCPX at 4 and 24 h reperfusion were studied on the kidney injury. Pretreatment with DPCPX attenuated at 4 h but augmented at 24 h reperfusion the renal ischaemia-induced histological damage, reductions in creatinine clearance, urea excretion and free-water reabsorption, and increases in bicarbonate excretion and tissue malondialdehyde. The DPCPX increased tumour necrosis factor-α expression and migration of lymphocytes in the postischaemic kidney at both time points, but with a different pattern; lymphocytes mostly aggregated in cortical periarterial spaces at 4 h reperfusion but had infiltrated into the interstitium at 24 h reperfusion. In conclusion, A1 AR activation contributes to ischaemia-induced acute kidney injury during the early hours of reperfusion by causing a greater reduction in renal haemodynamics and by elevating tubular energy expenditure, which overcome its anti-inflammatory effect. However, its anti-inflammatory actions are exerted by reducing lymphocyte infiltration and cytokine production that begins to dominate from 4 to 24 h of reperfusion, which is reflected in attenuation of renal structural and functional disruption.

Therapeutic effects of curcumin on the functional disturbances and oxidative stress induced by renal ischemia/reperfusion in rats.

OBJECTIVE: Curcumin has anti-inflammatory and antioxidative properties. The objective of this study was to investigate the therapeutic effects of curcumin on functional disturbances, oxidative stress, and leukocyte infiltration induced by renal ischemia/reperfusion (I/R). MATERIALS AND METHODS: Animals were randomly divided into 9 groups. The groups with 24-h reperfusion consisted of sham-24h, I/R-24h, and three I/R groups treated with curcumin at 10, 20, or 30 mg kg(-1), i.p. after the ischemic period. The 72-h reperfusion groups also included Sham-72h, I/R-72h, I/R treated with curcumin at single dose of 20 mg kg(-1), i.p., and I/R group which received three doses of curcumin at 20 mg kg(-1), i.p., consecutively. Renal functional injury was assessed by measuring serum creatinine and urea-nitrogen concentrations. Oxidative stress was evaluated by assessment tissue malondialdehyde (MDA) and the ferric reducing/antioxidant power (FRAP) levels. Moreover, renal tissue leukocyte infiltration was measured by histopathology examination. RESULTS: Ischemia/reperfusion resulted in a significant increase in serum concentration of creatinine, urea-nitrogen, tissue MDA level, and leukocytes infiltration as well as reduced FRAP level. Treatment with curcumin in 24-h reperfusion groups could only lead to a significant change in the levels of MDA and FRAP. However, in 72-h reperfusion groups, curcumin was able to correct all functional disturbances, oxidative stress, and leukocytes infiltration with more effectiveness in groups that received three doses of curcumin. CONCLUSION: The administration of curcumin during 72-h reperfusion following 30 minutes of ischemia can decrease renal oxidative stress and leukocytes infiltration as well as improve kidney function. However, during first 24-h reperfusion, curcumin only decreased oxidative stress.

Protective effects of Tribulus terrestris L extract against acute kidney injury induced by reperfusion injury in rats.

INTRODUCTION: This study aimed to investigate the protective effect of aerial parts of the Tribulus terrestris L extract on acute kidney injury (AKI) induced by ischemia for 30 minutes and reperfusion for 24 hours in rats. MATERIALS AND METHODS: Ten male Sprague-Dawley rats in the AKI and 10 in the Tribulus terrestris groups received the extract solvent and extract of the plant (11 mg/kg), respectively, for 13 days (oral administration). On day 14, ischemia for 30 minutes and reperfusion for 24 hours were induced on the rats. In the last 6 hours of the reperfusion period (24 hours), urine samples were collected in metabolic cages. At the end of this period, blood samples were also taken to determine plasma urea nitrogen, creatinine, and electrolyte concentrations. The kidney tissues were collected for measuring the level of oxidative stress and histological studies. They were compared with the sham operation group and a control group with normal diet and no operation. RESULTS: In the Tribulus terrestris group, the increase in plasma creatinine and urea nitrogen concentrations was significantly less following reperfusion, and their values reached the same level as that in the sham group. Creatinine clearance and urine osmolarity in the Tribulus terrestris group was higher in comparison with the AKI group, whereas sodium absolute excretion, fractional excretion of potassium, oxidative stress, and cellular damages were less. CONCLUSIONS: Oral administration of Tribulus terrestris extract for 2 weeks can decrease kidney functional disturbance, oxidative stress, and cellular damages following reperfusion injury in rats.

Calcium dobesilate for prevention of gentamicin-induced nephrotoxicity in rats.

INTRODUCTION: Calcium dobesilate is an antioxidant drug and this study is aimed to investigate the effects of calcium dobesilate on gentamicin-induced nephrotoxicity. MATERIAL AND METHODS: This experimental study was conducted on 40 male Sprague-Dawley rats. The rats were randomly divided into the following 5 groups: control, sham, gentamicin (100 mg/kg/d, intraperitoneal), gentamicin and calcium dobesilate (50 mg/kg body weight), gentamicin and calcium dobesilate (50 mg/kg body weight). Treatment was provided once a day in a 7-day period. At the end of the 7th day, plasma and urine samples were taken and the concentrations of creatinine, urea nitrogen, sodium, potassium, and osmolarity were measured in both samples. The level of oxidative stress in the left kidney tissue samples was also assessed by measuring malondialdehyde and ferric reducing antioxidant power. RESULTS: Calcium dobesilate intake with both doses led to a significant decrease in the elevated concentration of creatinine, urea nitrogen, and fractional excretion of sodium by gentamicin, and an increase in creatinine clearance and absolute excretion of potassium as compared to the gentamicin group. Furthermore, calcium dobesilate decreased tissue malondialdehyde and increased tissue ferric reducing antioxidant power at both doses, in comparison to those in the gentamicin group. CONCLUSIONS: Calcium dobesilate is capable of protecting rats against gentamicin-induced nephrotoxicity. This protective effect of calcium dobesilate is probably dependent on its antioxidant properties.

Protective effects of Rosa canina L fruit extracts on renal disturbances induced by reperfusion injury in rats.

INTRODUCTION: This study aimed to investigate the effects of Rosa canina L fruit extracts on histological damages, oxidative stress, and functional disturbances induced by bilateral renal ischemia and reperfusion. MATERIALS AND METHODS: Ischemia and reperfusion were induced on the kidneys of anesthetized male Sprague-Dawley rats. The rats in the reperfusion and Rosa canina groups were administered extract solvent and Rosa canina extract, respectively. In addition, in the sham group, surgery was done without ischemia. In the last 6 hours of the reperfusion period, urine sample were collected using metabolic cage and at the end of this period, blood samples were taken from the descending aorta. The kidney tissues were collected and subjected to microscopic study for histological damages, while oxidative stress was measured by determining malondialdehyde and ferric reducing/antioxidant power levels. RESULTS: The comparison between the reperfusion and sham groups indicated reductions in creatinine clearance, absolute excretion of potassium, urine osmilarity, and increase in absolute excretion of sodium in the reperfusion group. These changes were less pronounced with Rosa canina fruit extract. In addition, blood creatinine and urea concentrations which increased in the reperfusion group, were significantly lower in the Rosa canina group. In this group, the degree of histological damages and the level of malondialdehyde were lower than the reperfusion group, while ferric reducing/antioxidant power level was significantly higher. CONCLUSIONS: The findings of this study showed that Rosa canina fruit extract possesses protective effects against kidney function disturbances, oxidative stress, and histological damages.