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Cisplatin (CP) is nephrotoxic, and this side effect is used as an animal model for acute kidney injury (AKI). Earlier research has been focused on CP-induced AKI, with relatively little attention being paid to its ability to progress to chronic kidney disease (CKD) on repeated administration. We aimed here to test the dose dependency of its nephrotoxic actions by comparing various physiological, biochemical, molecular, and histopathological indices using repeated increasing doses of CP in rats. Furthermore, we investigated whether these doses of CP would result in the development of CKD. Biochemical, molecular, and histopathological measurements were conducted in plasma, urine, and/or kidneys of rats treated with increasing doses of CP at 1.6, 3.2, and 4.8 mg kg−1 weekly for four consecutive weeks. These doses induced significant and dose-dependent elevations in most of the measured renal indices. These included increased renal fibrosis, as suggested histopathologically and biochemically by the significant increase in transforming growth factor-β1, significant decrease in actin alpha 2, and variable actions of collagen I and IV. CP also dose-dependently increased nuclear factor (erythroid-derived 2)-like 2 and caspase-3. Multiple repeated doses of CP (1.6 to 4.8 mg kg−1) induced multiple episodes of AKI, leading to CKD after the 4th weekly dose and confirmed that this dosage regimen could be used as an experimental animal model of AKI progressing to CKD. These actions were driven by inflammation, oxidative, and nitrosative stress.

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-β-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.

Cisplatin (CP) is commonly used in the treatment of various solid tumors. Its use, however, is hampered by nephrotoxicity. In this study, we compared the effect of betaine and melatonin given singly, with that of a combination of these two agents on CP-induced nephrotoxicity in mice. CP (20 mg/kg, given intraperitoneally on the 8th day of 12 days of the experiment) showed the typical physiological, biochemical, and histologic features of nephrotoxicity. CP-treated mice showed a significant reduction in food intake, body weight, and urine and fecal output. It also induced significant increases in the plasma concentrations of urea, creatinine, uric acid, phosphorous, adiponectin, interleukin-1β, interleukin-6, transforming growth factor -β1, tumor necrosis factor-α, and cystatin C. All these effects were significantly reduced by daily administration of betaine or melatonin at oral doses of 200 mg/kg and 10 mg/kg, respectively. Furthermore, using the two agents in combination caused further significant reductions in the above parameters. These findings suggest that betaine and melatonin concomitant use is likely to provide greater protection against CP-induced nephrotoxicity than when they are given singly, rendering them potentially suitable and safe agents to use in clinical trials to assess their possible beneficial actions in cancer patients receiving CP.

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-β-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-1β)] 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 aim of this study was to investigate some biochemical indices of inflammation and oxidative and nitrosative stresses in the gastrointestinal tract of mice with experimental chronic kidney disease (CKD) and treated with gum arabic (GA). Male CD1 mice (n = 28) were randomly distributed into four groups and treated for four consecutive weeks: group 1: Control: received the same diet without treatment until the end of the study; group 2: Adenine: switched to a powder diet containing adenine (0.2% w/w in feed); group 3: Gum acacia (GA): given normal feed and GA in drinking water at a concentration of 15% w/v; and group 4: Adenine + GA: given adenine in the feed as in the second group plus GA in the drinking water at concentration of 15% w/v. CKD was induced to mice by adenine feeding and concomitantly treated with the prebiotic dietary fiber gum acacia, GA (15% in drinking water). Duodenal mucosa from CKD mice had significantly higher concentrations of TNF-alfa, IL- 6, and TGF-beta-1 and lipid peroxidation. Moreover, low concentrations of IL-10, some antioxidants (catalase, glutathione reductase, total antioxidant capacity, and superoxide dismutase), and nuclear factor erythroid 2–related factor 2 were found in the duodenum. The levels of nitrosative stress (nitrite, nitrate, and total nitrate) were significantly increased by CKD, as well as the concentrations of ammonia and urea creatinine in the cecal content. Concomitant GA treatment significantly mitigated these harmful effects. Taken together, GA reduces inflammation and duodenal oxidative and nitrosative stress in the gastrointestinal tract of mice with CKD.

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-β-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.