Arruda-Junior Daniel F, Martins Flavia L, Dariolli Rafael, Jensen Leonardo, Antonio Ednei L, Dos Santos Leonardo, Tucci Paulo J F, Girardi Adriana C C
Heart Institute (InCor), University of São Paulo Medical School São Paulo, Brazil.
Cardiology Division, Department of Medicine, Federal University of São Paulo São Paulo, Brazil.
Front Physiol. 2016 Jul 12;7:293. doi: 10.3389/fphys.2016.00293. eCollection 2016.
Circulating dipeptidyl peptidase IV (DPPIV) activity is associated with worse cardiovascular outcomes in humans and experimental heart failure (HF) models, suggesting that DPPIV may play a role in the pathophysiology of this syndrome. Renal dysfunction is one of the key features of HF, but it remains to be determined whether DPPIV inhibitors are capable of improving cardiorenal function after the onset of HF. Therefore, the present study aimed to test the hypothesis that DPPIV inhibition by vildagliptin improves renal water and salt handling and exerts anti-proteinuric effects in rats with established HF. To this end, male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were randomly divided into two groups and treated for 4 weeks with vildagliptin (120 mg/kg/day) or vehicle by oral gavage. Echocardiography was performed before (pretreatment) and at the end of treatment (post-treatment) to evaluate cardiac function. The fractional area change (FAC) increased (34 ± 5 vs. 45 ± 3%, p < 0.05), and the isovolumic relaxation time decreased (33 ± 2 vs. 27 ± 1 ms; p < 0.05) in HF rats treated with vildagliptin (post-treatment vs. pretreatment). On the other hand, cardiac dysfunction deteriorated further in vehicle-treated HF rats. Renal function was impaired in vehicle-treated HF rats as evidenced by fluid retention, low glomerular filtration rate (GFR) and high levels of urinary protein excretion. Vildagliptin treatment restored urinary flow, GFR, urinary sodium and urinary protein excretion to sham levels. Restoration of renal function in HF rats by DPPIV inhibition was associated with increased active glucagon-like peptide-1 (GLP-1) serum concentration, reduced DPPIV activity and increased activity of protein kinase A in the renal cortex. Furthermore, the anti-proteinuric effect of vildagliptin treatment in rats with established HF was associated with upregulation of the apical proximal tubule endocytic receptor megalin and of the podocyte main slit diaphragm proteins nephrin and podocin. Collectively, these findings demonstrate that DPPIV inhibition exerts renoprotective effects and ameliorates cardiorenal function in rats with established HF. Long-term studies with DPPIV inhibitors are needed to ascertain whether these effects ultimately translate into improved clinical outcomes.
循环二肽基肽酶IV（DPPIV）活性与人类及实验性心力衰竭（HF）模型中更差的心血管结局相关，这表明DPPIV可能在该综合征的病理生理学中发挥作用。肾功能不全是HF的关键特征之一，但DPPIV抑制剂在HF发病后是否能够改善心肾功能仍有待确定。因此，本研究旨在验证以下假设：维格列汀抑制DPPIV可改善已发生HF大鼠的肾水盐代谢，并发挥抗蛋白尿作用。为此，将雄性Wistar大鼠进行左心室（LV）射频消融或假手术。术后6周，将发生HF的射频消融大鼠随机分为两组，通过灌胃给予维格列汀（120 mg/kg/天）或赋形剂，治疗4周。在治疗前（预处理）和治疗结束时（治疗后）进行超声心动图检查以评估心脏功能。接受维格列汀治疗的HF大鼠（治疗后与预处理相比），其面积变化分数（FAC）增加（34±5对45±3%，p<0.05），等容舒张时间缩短（33±2对27±1毫秒；p<0.05）。另一方面，接受赋形剂治疗的HF大鼠心脏功能进一步恶化。接受赋形剂治疗的HF大鼠存在肾功能损害，表现为液体潴留、低肾小球滤过率（GFR）和高水平的尿蛋白排泄。维格列汀治疗使尿流量、GFR、尿钠和尿蛋白排泄恢复到假手术水平。DPPIV抑制使HF大鼠肾功能恢复与血清活性胰高血糖素样肽-1（GLP-1）浓度升高、DPPIV活性降低以及肾皮质蛋白激酶A活性增加有关。此外，维格列汀治疗对已发生HF大鼠的抗蛋白尿作用与顶端近端小管内吞受体巨膜蛋白以及足细胞主要裂孔隔膜蛋白nephrin和podocin的上调有关。总体而言，这些发现表明DPPIV抑制在已发生HF的大鼠中发挥肾脏保护作用并改善心肾功能。需要对DPPIV抑制剂进行长期研究以确定这些作用最终是否能转化为改善的临床结局。
