Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that Neuropeptide Y (NPY) was significantly down-regulated in insulin-resistant vs. insulin-sensitive mouse podocytes and in human glomeruli of patients with early and late-stage diabetic nephropathy, as well as other nondiabetic glomerular diseases. This contrasts with the increased plasma and urinary levels of NPY that are observed in such conditions. Studying NPY-knockout mice, we found that NPY deficiency in vivo surprisingly reduced the level of albuminuria and podocyte injury in models of both diabetic and nondiabetic kidney disease. In vitro, podocyte NPY signaling occurred via the NPY2 receptor (NPY2R), stimulating PI3K, MAPK, and NFAT activation. Additional unbiased proteomic analysis revealed that glomerular NPY-NPY2R signaling predicted nephrotoxicity, modulated RNA processing, and inhibited cell migration. Furthermore, pharmacologically inhibiting the NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. Our findings suggest a pathogenic role of excessive NPY-NPY2R signaling in the glomerulus and that inhibiting NPY-NPY2R signaling in albuminuric kidney disease has therapeutic potential.

蛋白尿是进展为终末期肾衰竭，心血管疾病和过早死亡的独立危险因素。因此，期望发现调节蛋白尿的信号传导途径。在这里，我们研究了糖尿病条件下足细胞的转录组，足细胞是预防白蛋白尿的关键细胞。我们发现神经肽Y（NPY）胰岛素抵抗性和胰岛素敏感性小鼠足细胞以及早期和晚期糖尿病性肾病以及其他非糖尿病性肾小球疾病患者的人肾小球中的蛋白表达明显下调。这与在这种情况下观察到的血浆和尿液中NPY水平的升高形成对比。研究NPY敲除小鼠后，我们发现，在糖尿病和非糖尿病性肾脏疾病模型中，体内NPY的缺乏令人惊讶地降低了蛋白尿和足细胞损伤的水平。在体外，足细胞NPY信号通过NPY2受体（NPY2R）发生，刺激PI3K，MAPK和NFAT激活。额外的无偏蛋白质组分析表明，肾小球NPY-NPY2R信号传导可预测肾毒性，调节RNA加工并抑制细胞迁移。此外，体内药理抑制NPY2R可以显着降低阿霉素治疗的肾小球硬化小鼠的蛋白尿。我们的发现提示肾小球中过量NPY-NPY2R信号的致病作用，而抑制蛋白尿性肾脏疾病中的NPY-NPY2R信号的治疗具有治疗潜力。