Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7.
Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7.
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DOI：
10.1038/srep44584
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发表时间：
2017-03-15
影响因子：
4.6
通讯作者：
Venneri MA
中科院分区：
文献类型：
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作者：
Pofi R;Fiore D;De Gaetano R;Panio G;Gianfrilli D;Pozza C;Barbagallo F;Xiang YK;Giannakakis K;Morano S;Lenzi A;Naro F;Isidori AM;Venneri MA
糖尿病肾病（DN）是终末期肾病的主要原因。临床前和实验研究表明，PDE5 抑制剂 (PDE5is) 对 DN 发挥保护作用，改善血管周围炎症。我们使用糖尿病肾损伤小鼠模型研究了 PDE5is 对肾血流动力学的保护特性及其相关分子机制。 PDE5i治疗可预防DN相关高血压的发生（P < 0.001）、尿白蛋白肌酐比值升高（P < 0.01）、肾小球滤过率下降（P < 0.001），并改善肾抵抗指数（P < 0.001）和肾脏微循环。此外，PDE5i 减弱了肾病生物标志物、可溶性尿激酶型纤溶酶原激活剂受体、suPAR 和中性粒细胞明胶酶相关脂质运载蛋白、NGAL 的上升。在接受治疗的动物中，血管灌注得到改善，血管渗漏减少，表明肾内皮完整性得以保留，这一点通过较高的毛细血管密度、CD31+细胞数量和周细胞覆盖率得到证实。对相关机制的分析揭示了通过 PDE5i 依赖性下调 miR-22 诱导骨形态发生蛋白 7 (BMP7) 表达，骨形态发生蛋白 7 (BMP7) 是血管生成和肾脏稳态的关键调节因子。总之，PDE5i 可以减缓小鼠 DN 的进展，改善血流动力学参数和血管完整性。 miR-22/BMP7 的调节是 PDE5 在肾血管保护中的一种未知机制，可能代表治疗糖尿病并发症的一种新的治疗选择。
Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease. Preclinical and experimental studies show that PDE5 inhibitors (PDE5is) exert protective effects in DN improving perivascular inflammation. Using a mouse model of diabetic kidney injury we investigated the protective proprieties of PDE5is on renal hemodynamics and the molecular mechanisms involved. PDE5i treatment prevented the development of DN-related hypertension (P < 0.001), the increase of urine albumin creatinine ratio (P < 0.01), the fall in glomerular filtration rate (P < 0.001), and improved renal resistive index (P < 0.001) and kidney microcirculation. Moreover PDE5i attenuated the rise of nephropathy biomarkers, soluble urokinase-type plasminogen activator receptor, suPAR and neutrophil gelatinase-associated lipocalin, NGAL. In treated animals, blood vessel perfusion was improved and vascular leakage reduced, suggesting preserved renal endothelium integrity, as confirmed by higher capillary density, number of CD31+ cells and pericyte coverage. Analysis of the mechanisms involved revealed the induction of bone morphogenetic protein-7 (BMP7) expression, a critical regulator of angiogenesis and kidney homeostasis, through a PDE5i-dependent downregulation of miR-22. In conclusion PDE5i slows the progression of DN in mice, improving hemodynamic parameters and vessel integrity. Regulation of miR-22/BMP7, an unknown mechanism of PDE5is in nephrovascular protection, might represent a novel therapeutic option for treatment of diabetic complications.