Ali Badreldin H, Al Salam Suhail, Al Suleimani Yousuf, Al Za'abi Mohammed, Abdelrahman Aly M, Ashique Mohammed, Manoj Priyadarsini, Adham Sirin A, Hartmann Christina, Schupp Nicole, Nemmar Abderrahim
Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman,
Cell Physiol Biochem. 2019;52(1):27-39. doi: 10.33594/000000003. Epub 2019 Feb 18.
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).
CKD was induced in rats by feeding them adenine (0.25% 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.
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-1β, 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.
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.
背景/目的：钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂已被证明在糖尿病中具有肾脏保护作用。在此，我们研究了其中一种药物（卡格列净）是否也能改善非糖尿病慢性肾脏病（CKD）。
通过给大鼠喂食腺嘌呤（0.25%，持续35天）诱导CKD，并在有或无腺嘌呤的情况下给予卡格列净（10或25mg/kg，经口灌胃）。使用几种传统和新型的血浆及尿液生物标志物以及组织形态学来研究卡格列净对肾脏结构和功能的影响。
喂食腺嘌呤的大鼠表现出CKD的典型特征，包括血压升高、食物摄入量和生长减少、水摄入量和尿量增加、肌酐清除率降低、尿白蛋白/肌酐比值、肝型脂肪酸结合蛋白、N-乙酰-β-D-氨基葡萄糖苷酶以及血浆尿素、肌酐、尿酸、钙、硫酸吲哚酚和磷浓度升高。腺嘌呤还增加了几种炎症生物标志物的浓度，如中性粒细胞明胶酶相关脂质运载蛋白、白细胞介素-6、肿瘤坏死因子α、簇集素、胱抑素C和白细胞介素-1β，并降低了肾脏匀浆中的一些氧化生物标志物，如超氧化物歧化酶、过氧化氢酶、谷胱甘肽还原酶、总抗氧化活性，以及尿8-异前列腺素和尿8-羟基-2-脱氧鸟苷。腺嘌呤显著增加了肾组织中核因子E2相关因子2（Nrf2）的蛋白含量，导致肾小管坏死和纤维化。单独使用时，所使用的两种剂量的卡格列净均未显著改变上述任何参数。当卡格列净与腺嘌呤同时给予时，它能显著且剂量依赖性地改善所有测量的腺嘌呤诱导的作用。
卡格列净通过降低几种炎症和氧化应激参数以及其他指标（如尿毒症毒素），并拮抗转录因子Nrf2在肾脏中的含量增加，改善了腺嘌呤诱导的大鼠CKD。该药物未引起明显或显著的不良影响，因此可能有必要在CKD患者中进行试验。
