Department of Nephrology, International University of Health and Welfare, Tokyo, Japan.
Department of Nephrology, Saitama Medical University, Iruma, Japan.
Kidney Blood Press Res. 2023;48(1):326-337. doi: 10.1159/000530469. Epub 2023 Apr 5.
While recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage.
The 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.
Klotho 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).
Our 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.
尽管最近的研究表明 klotho 具有肾保护作用，但 klotho 蛋白补充是否能逆转肾损伤尚未得到充分研究。
本研究检测了皮下 klotho 补充对肾部分切除大鼠的影响。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]）：残肾补充 klotho 蛋白（20 μg/kg/天）。采用酶联免疫吸附试验和放射免疫分析法等常规方法检测血压、血液和尿液成分，肾组织学和肾脏各种基因的表达。还进行了体外研究以支持体内发现。
klotho 蛋白补充降低了蛋白尿（-43%）、收缩压（-16%）、成纤维细胞生长因子 23（FGF23）（-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%）、胶原蛋白 I 表达（-55%）和转化生长因子 β（-59%）（所有 p < 0.05）。klotho 补充增加了磷酸盐排泄分数（+45%）、肾小球滤过率（+76%）、肾脏 klotho 表达（+148%）、超氧化物歧化酶（+124%）和骨形态发生蛋白 7（BMP7）（+174%）（所有 p < 0.05）。
我们的数据表明，klotho 蛋白补充在残肾中激活了肾素-血管紧张素系统，降低了血压和蛋白尿。此外，外源性 klotho 蛋白补充增加了内源性 klotho 表达，增加了磷酸盐排泄，导致 FGF23 和血清磷酸盐减少。最后，klotho 补充逆转了残肾功能障碍和纤维化，与改善残肾中的 BMP7 有关。
