期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 320, 期 3, 页码 F285-F296出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00288.2020
关键词
angiotensin II; biomarker; dipeptidyl peptidase-4; glomeruli; proteinuria; proximal tubule
资金
- Sao Paulo State Research Foundation (FAPESP) [2016/22140-7]
- Brazilian National Council for Scientific and Technological Research
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [16/22140-7] Funding Source: FAPESP
The study found that DPP4 inhibition can alleviate proteinuria in rats with chronic kidney disease and prevent the reduction of important protein expression. Furthermore, the urinary DPP4 activity may serve as a biomarker for renal disease and progression.
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.
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