Sodium-Glucose Co-Transporter 2 Inhibitors: Mechanism of Action and Efficacy in Non-Diabetic Kidney Disease from Bench to Bed-Side.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently available for the management of type 2 diabetes mellitus. SGLT2i acts by inhibiting renal SGLT2, thereby increasing glucosuria and lowering serum glucose. Recent trials are emerging supporting a role for SGLT2i irrespective of the diabetic status pointing towards that SGLT2i have other mechanisms of actions beyond blood sugar control. In this review, we will shed light on the role of this group of medications that act as SGLT2i in non-diabetics focusing on pre-clinical and clinical data highlighting the mechanism of renoprotection and effects of SGLT2i in the non-diabetic kidneys.

Nephroprotective effects of diminazene on doxorubicin-induced acute kidney injury in rats.

This study aimed to investigate the potential protective effects of diminazene, an activator of angiotensin II converting enzyme (ACE2), on kidney function and structure in rats with acute kidney injury (AKI) induced by the anticancer drug doxorubicin (DOX). The impact of diminazene was compared to that of two other drugs: the ACE inhibitor lisinopril and the angiotensin II type 1 (AT1) receptor blocker valsartan. Rats were subjected to a single intraperitoneal injection of DOX (13.5 mg/kg) on the 5th day, either alone or in combination with diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), or valsartan (30 mg/kg/day) for 8 consecutive days. Various markers related to kidney function, oxidative stress, and inflammation were measured in plasma and urine. Additionally, kidney tissues were assessed histopathologically. DOX-induced nephrotoxicity was confirmed by elevated levels of plasma urea, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL). DOX also led to increased urinary N-acetyl-ß-D-glucosaminidase (NAG) activity and decreased creatinine clearance, albumin levels, and osmolality. Moreover, DOX caused a reduction in renal oxidative stress markers, including superoxide dismutase (SOD), glutathione reductase (GR), and catalase activities, while increasing malondialdehyde (MDA) levels. It also raised plasma inflammatory markers, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß). Concurrently administering diminazene significantly mitigated these DOX-induced changes, including histopathological alterations like renal tubule necrosis, tubular casts, shrunken glomeruli, and increased renal fibrosis. Similar protective effects were observed with lisinopril and valsartan. These protective effects, at least in part, appear to result from the anti-inflammatory and antioxidant properties of these drugs. In summary, this study suggests that the administration of diminazene, lisinopril, or valsartan had comparable effects in ameliorating the biochemical and histopathological aspects of DOX-induced acute kidney injury in rats.

Relative dose intensity of taxane-based chemotherapy in breast cancer patients in a tertiary hospital.

INTRODUCTION: Breast cancer (BC) is the most diagnosed tumor among women worldwide. The aim of this study was to investigate the incidence and causes of low relative dose intensity (RDI) < 85% for taxane-based chemotherapy regimens used in the treatment of BC in Sultan Qaboos University Hospital (SQUH). METHODS: This was a retrospective study that included 303 BC patients, treated with taxane-based chemotherapy protocols at SQUH. RDI was calculated for each chemotherapy regimen and causes and predictors of low RDI < 85% were identified. Prophylactic and therapeutic supportive measures for certain toxicities were studied. RESULTS: 50.8% of the patients had neoadjuvant chemotherapy, 38% had adjuvant chemotherapy, and 11.2% of patients were given palliative treatment. AC-T and AC-THP were the most used regimens (40.3% and 17.2%). Mean RDI of used taxane-based chemotherapy regimens was 93.4%. Dose delays, dose reductions, and treatment discontinuation occurred in 36.6%, 14.8%, and 11.5%, respectively. Thirty-eight patients (12.5%) had low RDI < 85% which was reduced to 9.9% after the use of an alternative taxane. Age and chemotherapy intent were significant risk factors. 83.8% received primary granulocyte colony stimulating factor. CONCLUSION: An optimal RDI greater than 85% was achieved in most cases. Furthermore, prophylactic and therapeutic supportive measures were widely used.

The effect of diminazene, an angiotensin-converting enzyme 2 activator, on adenine-induced chronic kidney disease in rats.

The present study investigated the effect of diminazene, lisinopril, or valsartan on adenine-induced chronic kidney disease (CKD) in rats. The animals were divided into five groups (n = 6). The first and second groups received normal diet and adenine in the feed at a dose of 0.25% w/w for 35 days, respectively. The third, fourth, and fifth groups were treated as the second group but also received diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), and valsartan (30 mg/kg/day), respectively, for 35 days. Adenine significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), calcium, phosphorus, and uric acid. In addition, adenine increased urinary albumin/creatinine ratio and N-Acetyl-ß-D-glucosaminidase (NAG)/creatinine ratio and reduced creatinine clearance. Adenine also significantly increased the plasma concentrations of inflammatory cytokines (plasma tumor necrosis factor-alpha [TNF-α] and interleukin-1beta [IL-1ß]) and significantly reduced antioxidant indices (catalase, glutathione reductase [GR], and superoxide dismutase [SOD]). Histopathologically, renal tissue from adenine-treated rats showed necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. All drugs ameliorated adenine-induced biochemical and histopathological changes. The protective effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Our results show that administration of diminazene, lisinopril, or valsartan had a comparable effect on the reversal of the biochemical and histopathological indices of adenine-induced CKD in rats.

Antibiotics utilization patterns and dosage appropriateness among patients receiving hemodialysis.

Chronic kidney disease (CKD) is a global health challenge, with a reported prevalence of around 10%. Prescribing for patients receiving hemodialysis (HD) is challenging and complicated by polypharmacy, comorbidities, and changes in clearance of medications. The aim of this study was to evaluate antibiotics utilization patterns and dosage appropriateness in patients receiving HD at a tertiary hospital. A retrospective study was carried on 287 adult inpatients, who received HD and at least one antibiotic in a tertiary hospital in Oman. Data were extracted using the hospital's electronic patient information system. Dosage appropriateness was assessed by identifying the dosage and frequency of prescribed antibiotics and comparing them with international guidelines. The main outcome measures were antibiotics utilization patterns and dosing inappropriateness. The most commonly prescribed parenteral antibiotic was piperacillin + tazobactam (20%), while the most common prescribed oral antibiotic was azithromycin (41.7%). For prophylaxis, cefazolin (54.6%) was the main antibiotic prescribed. The most commonly used antibiotic for external use was mupirocin ointment (38.5%). The overall dosing inappropriateness was 29.5%. Vancomycin was the most common parenteral antibiotic subjected to dosing inappropriateness (19.8%). However, trimethoprim + sulfamethoxazole was more inappropriately prescribed among the oral route (28.6%). In conclusion, the most utilized antibiotic was piperacillin + tazobactam followed by vancomycin. The study reported some inappropriate dosing of antibiotics. Such a study opens the door for the establishment of local guidelines for the improved practice of antibiotics use in HD patients.

Nitric Oxide Modulation as a Potential Molecular Mechanism Underlying the Protective Role of NaHS in Liver Ischemia Reperfusion Injury.

BACKGROUND: Liver IR is a frequent clinical complication with high morbidity and mortality. The present study evaluated the possible protective effect of sodium hydrosulfide (NaHS), a H2S donor, in IR-induced hepatic injury and explored the mechanisms of actions of the investigated drug. METHODS: Male albino rats (200-230 g) were divided into the following groups: group 1:Sham-operated non treated rats, group 2: IR non treated rats, group 3: L-NNA + IR rats, group 4: NaHS + IR rats, group 5: L-NNA + NaHS + IR rats. Blood samples were collected for ALT determination. Liver tissue samples were used for the assessment of GPx, catalase, SOD, MDA, total nitrites and TNF- α. Parts from the liver were fixed in 10% formalin solution for histopathological examination and immunohistochemical examination of iNOS, eNOS and caspase-3. RESULTS: NaHS protected the liver against IR. This hepatoprotection was associated with normalization of antioxidant enzyme activity and decrease in hepatic MDA, TNF-α and expression of caspase- 3 and iNOS. CONCLUSION: NaHS is hepatoprotective in IR injury. The hepatoprotective effects of NaHS are associated with antioxidant, anti-inflammatory and antiapoptotic effects. These effects are probably mediated via NO modulation.

Antifibrotic effects of bezafibrate and pioglitazone against thioacetamide-induced liver fibrosis in albino rats.

Activation of hepatic stellate cells is a central event in hepatic fibrogenesis that offers multiple potential sites for therapeutic interventions. Peroxisome proliferator-activated receptors are implicated in liver fibrosis. We aimed to evaluate the effect of bezafibrate and pioglitazone on a thioacetamide (TAA) rat model of liver fibrosis and to clarify the possible underlying mechanisms. Rats received intraperitoneal injections of TAA for 6 weeks. Daily oral treatments with bezafibrate or pioglitazone were started with the first day of TAA intoxication. Serum liver function tests, hepatic malondialdehyde (MDA), total nitrite and nitrate (NOx), superoxide dismutase, and hepatic histopathology were assessed to evaluate hepatic damage. Alpha smooth muscle actin (α-SMA) and tissue inhibitor metalloproteinase-1 (TIMP-1) and caspase-3 were also assessed. The TAA group experienced significant deterioration of liver functions, increased oxidative stress, and increased liver tissue NOx. Administration of bezafibrate or pioglitazone resulted in significant improvement of all liver functions and reduced oxidative stress in hepatic tissues. Only administration of bezafibrate significantly reduced NOx levels. Liver tissues from the TAA-treated group showed disrupted normal architecture. Administration of bezafibrate or pioglitazone attenuated this picture. Stronger α-SMA expression was detected in the TAA group. Treatment with bezafibrate or pioglitazone decreased the α-SMA expression.

Effect of levosimendan, an inodilator, on streptozotocin-induced diabetic nephropathy in rats.

This study examined the effect of levosimendan on streptozotocin-induced early diabetic nephropathy. Rats were distributed into four groups and treated for six weeks. The first and third group received either vehicle or levosimendan (1 mg/kg/day) for the last three weeks, respectively. The second and fourth groups were rendered diabetic by a single intraperitoneal injection of streptozotocin (60 mg/kg) and were treated as the first and third groups, respectively. In the untreated diabetic group, there was a significant decrease in body weight, polyuria and hyperglycemia as well as, increased urinary albumin/creatinine ratio (UACR) and N-acetyl-ß-D-glucosaminidase (NAG)/creatinine ratio (UNCR) with no change in creatinine clearance. In addition, diabetes was associated with increased oxidative stress as evidenced by reduced plasma total antioxidant capacity (TAC) and catalase activity and increased plasma malondialdhyde (MDA) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-α). Kidneys from streptozotocin-treated rats showed focal clear renal tubular cells affecting proximal convoluted tubules and mild interstitial fibrosis at the cortico-medullary junction. Levosimendan significantly attenuated the streptozotocin-induced physiological and biochemical changes and there was less clear renal tubular cells. This study shows that levosimendan ameliorated some of the changes seen in streptozotocin-induced early diabetic nephropathy in rats. This could be partly due to its antioxidative and anti-inflammatory effects.

Effect of infliximab, a tumor necrosis factor-alpha inhibitor, on doxorubicin-induced nephrotoxicity in rats.

Treatment with the chemotherapeutic agent, doxorubicin (DOX), is limited by nephrotoxicity. We investigated the possible protective effect of infliximab, a tumor necrosis factor alpha (TNF-α) inhibitor on DOX-induced nephrotoxicity. Rats were treated with a single intraperitoneal (ip) injection of DOX (17.5 mg/kg) in the absence or presence of infliximab (5 mg/kg, i.p.). Plasma and urinary markers of kidney function, oxidative stress, and inflammation were measured. Kidney and heart tissue was evaluated histopathologically. DOX-induced nephrotoxicity was confirmed by increased plasma urea, creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and clusterin concentrations. In addition, DOX increased urinary albumin/creatinine ratio, N-acetyl-ß-D-glucosaminidase (NAG) activity, kidney injury molecule (KIM-1) concentrations, and reduced creatinine clearance. DOX significantly reduced renal antioxidants and increased plasma inflammatory markers and adiponectin concentrations. Concomitant treatment with infliximab did not significantly affect DOX-induced changes in plasma creatinine, cystatin C, or creatinine clearance. However, infliximab significantly reduced DOX-induced action on plasma urea, NGAL, clusterin, and adiponectin. Infliximab also significantly reduced urinary albumin/creatinine ratio, NAG activity, and KIM-1 concentrations, as well as the occurrence of fibrotic lesions in kidney tissue. Fibrosis detected in the heart was unchanged. In addition, infliximab reduced DOX-induced effects on plasma inflammatory markers, renal superoxide dismutase (SOD) and total antioxidant capacity. Our results show that infliximab is partially effective in mitigating DOX-induced nephrotoxicity in rats.

Effect of tocilizumab, an interleukin-6 inhibitor, on early stage streptozotocin-induced diabetic nephropathy in rats.

The aim of this study was to examine the effect of tocilizumab, an interleukin-6 (IL-6) inhibitor on streptozotocin-induced diabetic nephropathy. Male Sprague-Dawley rats (n = 36) were distributed into six groups and treated for 4 weeks. Groups 1, 3, 5 received either saline, tocilizumab (2 mg/kg), or tocilizumab (8 mg/kg) injection intraperitoneally (i.p.), every 2 weeks, respectively. Groups 2, 4, 6 were rendered diabetic by a single i.p. injection of streptozotocin (65 mg/kg) and were treated as in groups 1, 3, 5, respectively. Biochemical parameters were measured in plasma, urine, and kidneys. In the untreated diabetic group, there was a significant decrease in body weight, polyuria, and increased kidney weight. There was increased urinary albumin/creatinine ratio (UACR) and N-acetyl-ß-D-glucosaminidase (NAG)/creatinine ratio (UNCR). Streptozotocin also induced a significant increase in creatinine clearance. In addition, diabetes was associated with increased oxidative stress [reduced renal glutathione reductase (GR), superoxide dismutase (SOD), catalase activities, and increased malondialdhyde (MDA)] and increased plasma tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) concentrations. Kidneys from streptozotocin-treated rats showed marked vacuolation of the proximal tubular epithelium with focal tubular necrosis and the glomeruli showing increase in mesangial cells. Tocilizumab significantly mitigated the increase in UACR and UNCR, renal MDA, plasma TNF-α, IL-6 and NO levels, and the decrease in renal SOD and catalase activities in diabetic rats. Tocilizumab did not significantly improve creatinine clearance; however, it attenuated the histopathological changes induced by streptozotocin. This study shows that tocilizumab was able to ameliorate some of the changes seen in streptozotocin-induced early diabetic nephropathy in rats. This is mainly due to its anti-inflammatory and antioxidative effects.

Effect of levosimendan, a calcium sensitizer, on cisplatin-induced nephrotoxicity in rats.

We investigated the effect of levosimendan on cisplatin (Cis)-induced nephrotoxicity. Rats were divided into four groups (n = 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) cisplatin (6 mg/kg) on day 7, respectively. The third and fourth groups received a single intraperitoneal (i.p.) injection of Cis on day 7 and levosimendan (1 mg/kg/day, orally) or vehicle for 10 days, respectively. At day 11, animals were anaesthetized and blood collected and kidneys removed. Another four groups were treated the same as the previous four groups to measure renal blood flow. Cis induced nephrotoxicity as evidenced by biochemical, histopathological and hemodynamic changes. Levosimendan partially reduced Cis-induced increase in plasma urea, creatinine and neutrophil gelatinase-associated lipocalin (NGAL) levels and decrease in creatinine clearance. Levosimendan partially reduced Cis-induced increase in urinary albumin/creatinine ratio, N-Acetyl-ß-D-Glucosaminidase (NAG) and kidney Injury Molecule-1 (KIM-1). Levosimendan significantly attenuated the effect of Cis on plasma concentration of plasma tumor necrosis factor-alpha (TNF-α), antioxidant indices [catalase and superoxide dismutase (SOD)] and lipid peroxidation. Cis induced acute tubular necrosis with tubular dilatation, interstitial edema and congestion. Levosimendan attenuated the remarkable renal damage and reduced renal blood flow induced by Cis. In conclusion this study shows that levosimendan has a partial protective effect on Cis-induced nephrotoxicity. The protective effect of levosimendan is shown to be related to its anti-inflammatory, antioxidant and vasodilator effects.

Effects of the SGLT-2 Inhibitor Canagliflozin on Adenine-Induced Chronic Kidney Disease in Rats.

BACKGROUND/AIMS: SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD). METHODS: CKD was induced in rats by feeding them adenine (0.25%w/w for 35 days) and canagliflozin (10 or 25 mg/kg, by gavage) was given with or without adenine. Several conventional and novel plasma and urine biomarkers and tissues morphology were used to investigate the canagliflozin effect on kidney structure and function. RESULTS: Rats fed adenine showed the typical features of CKD that included elevation of blood pressure, decreased food intake and growth, increased water intake and urine output, decrease in creatinine clearance, and increase in urinary albumin/creatinine ratio, liver-type fatty acid binding protein, N-acetyl-beta-D-glucosaminidase, and plasma urea, creatinine, uric acid, calcium, indoxyl sulfate and phosphorus concentrations. Adenine also increased concentrations of several biomarkers of inflammation such as neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor alpha, clusterin, cystatin C and interleukin-1ß, and decreased some oxidative biomarkers in kidney homogenate, such as superoxide dismutase, catalase, glutathione reductase, total antioxidant activity, and also urinary 8-isoprostane and urinary 8-hydroxy-2-deoxy guanosine. Adenine significantly increased the renal protein content of Nrf2, caused renal tubular necrosis and fibrosis. Given alone, canagliflozin at the two doses used did not significantly alter any of the parameters mentioned above. When canagliflozin was given concomitantly with adenine, it significantly and dose - dependently ameliorated all the measured adenine - induced actions. CONCLUSION: Canagliflozin ameliorated adenine - induced CKD in rats, through reduction of several inflammatory and oxidative stress parameters, and other indices such as uremic toxins, and by antagonizing the increase in the renal content of the transcription factor Nrf2. The drug caused no overt or significant untoward effects, and its trial in patients with CKD may be warranted.

Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on cisplatin-induced nephrotoxicity in mice.

Canagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor that is currently available for the management of type 2 diabetes mellitus. The present study investigated the effect of canagliflozin on cisplatin (CP)-induced nephrotoxicity in mice. The animals were divided into four groups (n = 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) cisplatin (20 mg/kg) on day 7, respectively. The third and fourth groups were given a single intraperitoneal (i.p.) injection of CP (20 mg/kg) on day 7 and canagliflozin (10 mg/kg/day) and (30 mg/kg/day), for 10 days, respectively. At day 11, animals were anesthetized and blood collected and kidneys were removed. CP significantly increased the plasma urea, creatinine, cystatin C, and clusterin concentrations and neutrophil gelatinase-associated lipocalin (NGAL) activity. In addition, CP increased urinary albumin/creatinine ratio, N-acetyl-ß-D-glucosaminidase (NAG) activity, and liver-type fatty acid-binding protein (L-FABP) concentrations and reduced creatinine clearance. CP also significantly increased the plasma concentration of inflammatory cytokines [plasma tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1ß)] and significantly reduced antioxidant indices [catalase, glutathione reductase (GR), and superoxide dismutase (SOD)]. Histopathologically, CP caused a remarkable renal damage compared with control. Canagliflozin significantly ameliorated CP-induced biochemical and histopathological changes. The protective effect of canagliflozin is most likely due to anti-inflammatory and antioxidant effects. Our results show that administration of canagliflozin reversed the biochemical and histopathological indices of CP-induced nephrotoxicity in mice.

The renoprotective effect of the dipeptidyl peptidase-4 inhibitor sitagliptin on adenine-induced kidney disease in rats.

We assessed the effect of treatment with the dipeptidyl peptidase-4 inhibitor, sitagliptin, on adenine-induced chronic kidney disease (CKD). Six equal groups of rats were 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 simultaneously treated with sitagliptin (2.5 and 10 mg/kg/day, by gavage). Rats given adenine showed elevation of blood pressure, decreased body weight and increased relative kidney weight. Adenine also significantly increased plasma urea, creatinine, cystatin C, liver-type fatty acid-binding protein concentrations and neutrophil gelatinase-associated lipocalin activity by 404%, 354%, 667%, 91% and 281% respectively and reduced plasma α-Klotho by 50%. In addition, adenine significantly increased albumin/creatinine ratio and N-acetyl-ß-d-glucosaminidase activity by 3553% and 400% respectively and reduced creatinine clearance by 91%. Adenine feeding also significantly elevated the plasma concentration of inflammatory cytokines (plasma tumor necrosis factor-alpha, interleukin-1beta and transforming growth factor beta-1) and significantly reduced antioxidant indices (catalase, glutathione reductase and superoxide dismutase). Histopathologically, adenine caused renal fibrosis, inflammation and atrophy. When given concomitantly with adenine, sitagliptin ameliorated all the measured adenine-induced physiological and biochemical changes but not the histopathological changes. Sitagliptin (10 mg/kg/day) reduced plasma urea and creatinine by 32% and 25% respectively and increased creatinine clearance by 248%. These findings suggest a renoprotective action of sitagliptin on adenine-induced CKD.

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 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-ß-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.

Effect of captopril and telmisartan on methotrexate-induced hepatotoxicity in rats: impact of oxidative stress, inflammation and apoptosis.

Methotrexate (MTX) is a commonly used antineoplastic and anti-rheumatoid drug whose efficacy is limited by its hepatotoxicity. The aim of this study was to investigate the possible protective role of captopril (100 mg/kg/day, p.o. for seven days), an angiotensin converting enzyme inhibitor, and telmisartan (10 mg/kg/day p.o. for seven days), an angiotensin II receptor blocker with peroxisome proliferative receptor gamma (PPARγ) agonism, in a model of MTX (single dose 20 mg/kg i.p. at the fifth day) induced hepatotoxicity in rats. Results of the present study revealed MTX-induced hepatotoxicity as demonstrated by increased level of liver enzymes and confirmed by histopathology. Pretreatment with captopril or telmisartan produced a significant hepatic protection manifested as a significant (p < 0.05) decrease in serum levels of alanine transferase (ALT) and aspartate transferase (AST) and alkaline phosphatase (ALP) enzymes; hepatic malondialdehyde (MDA) and total nitrites and nitrates (NOx) levels; as well as a significant increase in hepatic superoxide dismutase (SOD) activity. In addition, there was a remarkable improvement in the histopathological features and a significant reduction in the expression of COX-2, iNOS and caspase-3 enzymes as compared with the MTX group. We recommend considering captopril/Telmisartan, if tolerated and not contraindicated, as preferable antihypertensive agents in patients receiving MTX in their chemotherapy protocols.

Possible Protective Effect of Diacerein on Doxorubicin-Induced Nephrotoxicity in Rats.

Nephrotoxicity is one of the limiting factors for using doxorubicin (DOX). Interleukin 1 has major role in DOX-induced nephrotoxicity, so we investigated the effect of interleukin 1 receptor antagonist diacerein (DIA) on DOX-induced nephrotoxicity. DIA (25 and 50 mg/kg/day) was administered orally to rats for 15 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of DOX (15 mg/kg) at the 11th day. We measured levels of serum urea, creatinine, renal reduced glutathione (GSH), malondialdehyde (MDA), total nitrites (NO x ), catalase, and superoxide dismutase (SOD). In addition, caspase-3, tumor necrosis factor alpha (TNFα), nuclear factor kappa B (NFκB) expressions, and renal histopathology were assessed. Our results showed that DOX-induced nephrotoxicity was ameliorated or reduced by both doses of DIA, but diacerein high dose (DHD) showed more improvement than diacerein low dose (DLD). This protective effect was manifested by significant improvement in all measured parameters compared to DOX treated group by using DHD. DLD showed significant improvement of creatinine, MDA, NO x , GSH, histopathology, and immunohistochemical parameters compared to DOX treated group.

Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats.

Methotrexate (MTX), a chemotherapeutic and immunosuppressant drug, is generally well-tolerated by most patients. However, its cytotoxic nature contributes to life-threatening side effects including hepatotoxicity and nephrotoxicity. The present study investigated the possible role of tumor necrosis factor-alpha (TNF-α) inhibitor, etanercept and inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine, on MTX-induced hepatotoxicity and nephrotoxicity in rats. Rats were divided into 7 groups: control group, etanercept group, aminoguanidine group, MTX group, MTX+etanercept group, MTX+aminoguanidine group, and MTX+etanercept+aminoguanidine group. MTX caused hepatotoxicity and nephrotoxicity as evidenced biochemically by significant increase in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and creatinine, respectively as well as by histopathological changes. Such effects were associated with significant changes in oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), catalase, and glutathione (GSH)) as well as by upregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. Etanercept and aminoguanidine significantly attenuated MTX-hepatotoxicity and nephrotoxicity. The protective effect of either agent was associated with significant improvement in oxidative stress parameters as well as by downregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. The study suggested that inhibitors of either TNF-α and/or iNOS have protective effect in MTX-induced hepatotoxicity and nephrotoxicity. The protective effect of either agent relies, at least partially, on their antioxidant effects and decreased TNF-α, iNOS, and caspase-3 expressions.

Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia-reperfusion-induced hepatic injury in rats.

AIM: Ischemia-reperfusion (IR) injury represents an important pathological process of liver injury during major hepatic surgery. The role of cyclooxygenase (COX) enzymes in the pathogenesis of ischemia-reperfusion (IR)-induced liver injury is not clear. This study investigated the effect of a selective COX-2 inhibitor, celecoxib, versus non-selective, indomethacin, on hepatic IR injury in rats. MATERIALS AND METHODS: Hepatic IR was induced in adult male rats. The animals were divided into 4 groups: normal control (sham group), IR non-treated group; IR-indomethacin-treated group; and IR-celecoxib-treated group. Liver injury was evaluated by serum alanine aminotransferase (ALT) and a histopathological examination of liver tissues. Hepatic tissue content of oxidative stress parameters glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase, malondialdehyde (MDA), nitric oxide (NO) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-α) were measured. Moreover, the immunohistochemical detection of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), and caspase-3 in the hepatic tissue was performed. KEY FINDINGS: Celecoxib, but not indomethacin, significantly attenuated hepatic IR injury as evidenced by reduction in serum ALT as well as by improvement in the histopathological scoring. Such effect was associated with attenuation in oxidative stress and TNF-α, along with modulation of immunohistochemical expression of eNOS, iNOS and caspase-3 in the hepatic tissue. SIGNIFICANCE: The present study concluded that selective COX-2 inhibition (but not non-selective), is hepatoprotective against liver IR injury; indicating a differential role of COX-1 versus COX-2. Modulation of iNOS, eNOS and caspase-3 might participate in the protective effect of selective COX-2-inhibitors.