Kim J S, Yang J W, Han B G, Kwon H J, Kim J H, Choi S O
Department of Nephrology, Yonsei University, Wonju College of Medicine, Wonju, Republic of Korea.
Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Republic of Korea.
Transplant Proc. 2017 Jul-Aug;49(6):1499-1509. doi: 10.1016/j.transproceed.2017.03.080.
Cyclosporine (CsA) usually reduces glomerular filtration rate (GFR) but also can induce tubular injury without resulting in GFR reduction. Apelin is an endogenous ligand for the apelin receptor and has diverse physiologic roles related to hemodynamic or metabolic processes. We investigated the renoprotective role of apelin against CsA-induced tubular toxicity in rats.
Rats were given CsA (15 mg/kg/day) and/or apelin-13 (15 μg/kg/day) for 7 days via subcutaneous injection. We performed serum and urinary assays of creatinine and neutrophil gelatinase-associated lipocalin (NGAL) to estimate renal injury and performed Western blotting for endothelial nitric oxide synthase and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) to document the underlying mechanism.
The CsA-treated group showed increased urinary creatinine excretion, polyuria, and renal glycosuria without GFR reduction, suggesting adequate CsA-induced renal tubular injury. Urinary NGAL excretion also increased significantly in the CsA group. Conversely, apelin attenuated CsA-induced tubular injury and had no effect on urinary NGAL excretion. In histopathologic examination, the apelin-treated group had lower tubulo-interstitial injury scores compared with those in the CsA group. Regarding the effects of apelin, our results indicate that apelin provides protection against CsA-induced tubular injury by activating nitric oxide and/or the NFATc1 pathway. Notably, we also found that CsA inhibits renal glucose reabsorption by reducing Na-K ATPase expression and that apelin reverses reduced renal glucose reabsorption by CsA in tubular cells.
Our study demonstrates the renoprotective effect of apelin against CsA-induced renal tubular toxicity and provides novel insights into the effects of CsA and apelin on renal tubular cells.
环孢素（CsA）通常会降低肾小球滤过率（GFR），但也可在不导致GFR降低的情况下诱导肾小管损伤。Apelin是apelin受体的内源性配体，在血流动力学或代谢过程中具有多种生理作用。我们研究了apelin对CsA诱导的大鼠肾小管毒性的肾脏保护作用。
通过皮下注射给予大鼠CsA（15mg/kg/天）和/或apelin-13（15μg/kg/天），持续7天。我们进行了血清和尿液肌酐及中性粒细胞明胶酶相关脂质运载蛋白（NGAL）检测以评估肾损伤，并进行了内皮型一氧化氮合酶和活化T细胞核因子细胞质1（NFATc1）的蛋白质印迹分析以阐明潜在机制。
CsA治疗组出现尿肌酐排泄增加、多尿和肾性糖尿，而GFR未降低，提示CsA诱导了充分的肾小管损伤。CsA组尿NGAL排泄也显著增加。相反，apelin减轻了CsA诱导的肾小管损伤，且对尿NGAL排泄无影响。在组织病理学检查中，apelin治疗组的肾小管间质损伤评分低于CsA组。关于apelin的作用，我们的结果表明apelin通过激活一氧化氮和/或NFATc1途径对CsA诱导的肾小管损伤起到保护作用。值得注意的是，我们还发现CsA通过降低Na-K ATP酶表达来抑制肾葡萄糖重吸收，而apelin可逆转CsA对肾小管细胞肾葡萄糖重吸收的降低作用。
我们的研究证明了apelin对CsA诱导的肾小管毒性具有肾脏保护作用，并为CsA和apelin对肾小管细胞的作用提供了新的见解。
