Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil.
Department of Nephrology (LIM 12), University of São Paulo Medical School, São Paulo, Brazil.
Am J Physiol Renal Physiol. 2021 Mar 1;320(3):F285-F296. doi: 10.1152/ajprenal.00288.2020. Epub 2020 Dec 21.
This study investigated the molecular mechanisms underlying the antiproteinuric effect of DPP4 inhibition in 5/6 renal ablation rats and tested the hypothesis that the urinary activity of DPP4 correlates with chronic kidney disease (CKD) progression. Experiments were conducted in male Wistar rats who underwent 5/6 nephrectomy (Nx) or sham operation followed by 8 wk of treatment with the DPP4 inhibitor (DPP4i) sitagliptin or vehicle. Proteinuria increased progressively in Nx rats throughout the observation period. This increase was remarkably mitigated by sitagliptin. Higher levels of proteinuria in Nx rats compared to control rats were accompanied by higher urinary excretion of retinol-binding protein 4, a marker of tubular proteinuria, as well as higher urinary levels of podocin, a marker of glomerular proteinuria. Retinol-binding protein 4 and podocin were not detected in the urine of Nx + DPP4i rats. Tubular and glomerular proteinuria was associated with the reduced expression of megalin and podocin in the renal cortex of Nx rats. Sitagliptin treatment partially prevented this decrease. Besides, the angiotensin II renal content was significantly reduced in the Nx rats that received sitagliptin compared to vehicle-treated Nx rats. Interestingly, both urinary DPP4 activity and abundance increased progressively in Nx rats. Additionally, urinary DPP4 activity correlated positively with serum creatinine levels, proteinuria, and blood pressure. Collectively, these results suggest that DPP4 inhibition ameliorated both tubular and glomerular proteinuria and prevented the reduction of megalin and podocin expression in CKD rats. Furthermore, these findings suggest that urinary DPP4 activity may serve as a biomarker of renal disease and progression.
本研究旨在探讨 DPP4 抑制在 5/6 肾切除大鼠抗蛋白尿作用的分子机制，并验证 DPP4 尿活性与慢性肾脏病（CKD）进展相关的假说。实验在雄性 Wistar 大鼠中进行，大鼠接受 5/6 肾切除术（Nx）或假手术，随后接受 DPP4 抑制剂（DPP4i）西他列汀或载体治疗 8 周。在整个观察期间，Nx 大鼠的蛋白尿逐渐增加。西他列汀显著减轻了这种增加。与对照组大鼠相比，Nx 大鼠的蛋白尿水平更高，伴随尿视黄醇结合蛋白 4（一种肾小管蛋白尿的标志物）和足细胞蛋白（一种肾小球蛋白尿的标志物）排泄量更高。Nx+DPP4i 大鼠的尿液中未检测到视黄醇结合蛋白 4 和足细胞蛋白。肾小管和肾小球蛋白尿与 Nx 大鼠肾皮质中 megalin 和 podocin 的表达减少有关。西他列汀治疗部分预防了这种减少。此外，与接受载体治疗的 Nx 大鼠相比，接受西他列汀治疗的 Nx 大鼠的肾组织中血管紧张素 II 含量显著降低。有趣的是，Nx 大鼠的尿 DPP4 活性和丰度逐渐增加。此外，尿 DPP4 活性与血清肌酐水平、蛋白尿和血压呈正相关。综上所述，这些结果表明 DPP4 抑制改善了 CKD 大鼠的肾小管和肾小球蛋白尿，并防止了 megalin 和 podocin 表达的减少。此外，这些发现表明尿 DPP4 活性可能是肾脏疾病和进展的生物标志物。
