Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112-2632, USA.
J Investig Med. 2011 Jun;59(5):793-802. doi: 10.2310/JIM.0b013e31821452a2.
Acute and long-term nephrotoxicity is the major dose-limiting factor for cyclosporine A (CsA). We evaluated the protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP)38 on CsA-induced nephrotoxicity in human renal proximal tubule epithelial (human kidney-2) cells and in intact mice.
Confluent (human kidney-2 cells were exposed to CsA (25-50 μmol/L) in the presence or absence of PACAP38 or vasoactive intestinal peptide (10(-10) to 10(-6) M). For studies in vivo, male BALB/c mice (n = 5 in each group) were given a single intraperitoneal injection of CsA (5 mg/kg body weight). Treatment group received 20 μg of PACAP38 2 hours before exposure to CsA and additional doses daily for 10 days.
Cyclosporine A caused oxidative injury, marked morphological alterations, apoptosis, and increased expression of transforming growth factor (TGF)-β1 in cell cultures. Pituitary adenylate cyclase-activating polypeptide 38 at 10(-8) mol/L restored cell confluency, reduced TGF-β1 secretion, and preserved cell integrity. In mice, CsA caused tubular injury characterized by loss of tubular epithelial cell brush border membranes, tubular collapse, cellular necrosis, interstitial fibrosis, increased production of TGF-β1, and elevated serum creatinine (3.39 ± 0.21 vs 0.13 ± 0.02 mg/dL in controls, P < 0.01). Treatment with PACAP38 reduced TGF-β1 and tumor necrosis factor-α production in kidney, prevented epithelial-mesenchymal transition of the renal cells, and reduced serum creatinine levels to 1.01 ± 0.18 mg/dL, P < 0.01 versus CsA group.
Pituitary adenylate cyclase-activating polypeptide 38 ameliorated renal tubular injury, reduced oxidative injury, and inhibited the expression of TGF-β1 in CsA-exposed murine kidneys. Pituitary adenylate cyclase-activating polypeptide could be a novel renoprotective and antifibrotic agent for CsA nephrotoxicity.
急性和长期的肾毒性是环孢素 A（CsA）的主要剂量限制因素。我们评估了垂体腺苷酸环化酶激活肽（PACAP）38 对 CsA 诱导的人肾近端小管上皮（人肾-2）细胞和完整小鼠的肾毒性的保护作用。
在存在或不存在 PACAP38 或血管活性肠肽（10（-10）至 10（-6）M）的情况下，将汇合的（人肾-2 细胞暴露于 CsA（25-50μmol/L）。在体内研究中，雄性 BALB/c 小鼠（每组 5 只）单次腹腔注射 CsA（5mg/kg 体重）。治疗组在接触 CsA 前 2 小时给予 20μg PACAP38，并在 10 天内每天给予额外剂量。
环孢素 A 导致氧化损伤、明显的形态改变、细胞凋亡和 TGF-β1 的表达增加在细胞培养物中。10（-8）mol/L 的垂体腺苷酸环化酶激活肽 38 恢复细胞一致性，减少 TGF-β1 的分泌，并保持细胞完整性。在小鼠中，CsA 导致肾小管损伤，特征为肾小管上皮细胞刷状缘膜丢失、肾小管塌陷、细胞坏死、间质纤维化、TGF-β1 产生增加和血清肌酐升高（3.39±0.21 与对照组 0.13±0.02mg/dL，P<0.01）。用 PACAP38 治疗可减少肾组织中 TGF-β1 和肿瘤坏死因子-α的产生，防止肾脏细胞的上皮-间充质转化，并将血清肌酐水平降低至 1.01±0.18mg/dL，与 CsA 组相比 P<0.01。
垂体腺苷酸环化酶激活肽 38 改善了 CsA 暴露小鼠肾脏的肾小管损伤，减少了氧化损伤，并抑制了 TGF-β1 的表达。垂体腺苷酸环化酶激活肽可能是 CsA 肾毒性的一种新型肾保护和抗纤维化药物。
