Klotho supplementation reverses renal dysfunction and interstitial fibrosis in remnant kidney.
Klotho supplementation reverses renal dysfunction and interstitial fibrosis in remnant kidney.
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DOI：
10.1159/000530469
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发表时间：
2023-04-05
影响因子：
2.8
通讯作者：
Hayashi，Matsuhiko
中科院分区：
文献类型：
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作者：
Takenaka，Tsuneo;Hasan，Arif;Hayashi，Matsuhiko
IntroductionWhile最近的调查表明，klotho发挥肾保护作用，它还没有完全解决是否klotho蛋白补充逆转renal damage.MethodsThe影响皮下klotho补充大鼠肾次全切除术进行了检查。将动物分为3组：第1组（短残肾[SR]）：残肾4周，第2组（长残肾[LR]）：残肾12周，第3组（klotho补充[KL]）：在残肾上补充klotho蛋白（20 μg/kg/天）。采用酶联免疫吸附试验和放射免疫分析等常规方法对血压、血液和尿液成分、肾脏组织学和肾脏各种基因的表达进行分析。结果Klotho蛋白补充剂降低了蛋白尿（− 43%）、收缩压（− 16%）、成纤维细胞生长因子（FGF）23（− 51%）和血清磷酸盐水平（− 19%）、肾血管紧张素II浓度（− 43%）、纤维化指数（− 70%）、肾胶原蛋白I表达（− 55%）、和转化生长因子β（-59%）（p< 0.05）。补充Klotho可提高磷酸盐排泄分数（+ 45%）、肾小球滤过率（+ 76%）、肾脏表达Klotho（+ 148%）、超氧化物歧化酶（+ 124%）和骨形态发生蛋白（BMP）7（+ 174%）。结论klotho蛋白补充可使肾组织的肾素-血管紧张素系统失活，降低残肾血压和蛋白尿。此外，外源性klotho蛋白补充提高了内源性klotho表达，以增加磷酸盐排泄，从而降低FGF 23和血清磷酸盐。最后，klotho补充逆转了与残肾中改善的BMP 7相关的肾功能不全和纤维化。
IntroductionWhile recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage.MethodsThe impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined. Animals were divided into 3 groups: group 1 (short remnant [SR]): remnant kidney for 4 weeks, group 2 (long remnant [LR]): remnant kidney for 12 weeks, and group 3 (klotho supplementation [KL]): klotho protein (20 μg/kg/day) supplementation on the remnant kidney. Blood pressure, blood and urine compositions with conventional methods such as enzyme-linked immunosorbent assay and radioimmunoassay, kidney histology, and renal expressions of various genes were analyzed. In vitro studies were also performed to support in vivo findings.ResultsKlotho protein supplementation decreased albuminuria (− 43%), systolic blood pressure (− 16%), fibroblast growth factor (FGF) 23 (− 51%) and serum phosphate levels (− 19%), renal angiotensin II concentration (− 43%), fibrosis index (− 70%), renal expressions of collagen I (− 55%), and transforming growth factor β (− 59%)(p< 0.05 for all). Klotho supplementation enhanced fractional excretion of phosphate (+ 45%), glomerular filtration rate (+ 76%), renal expressions of klotho (+ 148%), superoxide dismutase (+ 124%), and bone morphogenetic protein (BMP) 7 (+ 174%)(p< 0.05 for all).ConclusionOur data indicated that klotho protein supplementation inactivated renal renin-angiotensin system, reducing blood pressure and albuminuria in remnant kidney. Furthermore, exogenous klotho protein supplementation elevated endogenous klotho expression to increase phosphate excretion with resultant reductions in FGF23 and serum phosphate. Finally, klotho supplementation reversed renal dysfunction and fibrosis in association with improved BMP7 in remnant kidney.