Objective

Diabetic nephropathy (DN) is one of the most common complications of diabetes and a critical risk factor for developing end-stage renal disease. Activation of purinergic receptors, including P2Y2R has been associated with the pathogenesis of renal diseases, such as polycystic kidney and glomerulonephritis. However, the role of P2Y2R and its precise mechanisms in DN remain unknown. We hypothesised that P2Y2R deficiency may play a protective role in DN by modulating the autophagy signalling pathway.

Methods

We used a mouse model of DN by combining a treatment of high-fat diet and streptozotocin after unilateral nephrectomy in wild-type or P2Y2R knockout mice. We measured renal functional parameter in plasma, examined renal histology, and analysed expression of autophagy regulatory proteins.

Results

Hyperglycaemia and ATP release were induced in wild type-DN mice and positively correlated with renal dysfunction. Conversely, P2Y2R knockout markedly attenuates albuminuria, podocyte loss, development of glomerulopathy, renal tubular injury, apoptosis and interstitial fibrosis induced by DN. These protective effects were associated with inhibition of AKT-mediated FOXO3a (forkhead box O3a) phosphorylation and induction of FOXO3a-induced autophagy gene transcription. Furthermore, inhibitory phosphorylation of ULK-1 was decreased, and the downstream Beclin-1 autophagy signalling was activated in P2Y2R deficiency. Increased SIRT-1 (sirtuin-1) and FOXO3a expression in P2Y2R deficiency also enhanced autophagy response, thereby ameliorating renal dysfunction in DN.

Conclusions

P2Y2R contributes to the pathogenesis of DN by impairing autophagy and serves as a therapeutic target for treating DN.

中文翻译：

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P2Y2R通过抑制自噬反应促进糖尿病肾病的发展

客观的

糖尿病肾病 (DN) 是糖尿病最常见的并发症之一，也是发生终末期肾病的关键危险因素。嘌呤能受体（包括 P2Y2R）的激活与肾脏疾病的发病机制有关，例如多囊肾和肾小球肾炎。然而，P2Y2R 的作用及其在 DN 中的精确机制仍然未知。我们假设 P2Y2R 缺乏可能通过调节自噬信号通路在 DN 中发挥保护作用。

方法

我们通过在野生型或 P2Y2R 基因敲除小鼠的单侧肾切除术后结合高脂肪饮食和链脲佐菌素治疗来使用 DN 小鼠模型。我们测量了血浆中的肾功能参数，检查了肾脏组织学，并分析了自噬调节蛋白的表达。

结果

在野生型 DN 小鼠中诱导高血糖和 ATP 释放，并与肾功能障碍呈正相关。相反，P2Y2R 敲除显着减轻白蛋白尿、足细胞丢失、肾小球病的发展、肾小管损伤、细胞凋亡和 DN 诱导的间质纤维化。这些保护作用与抑制 AKT 介导的 FOXO3a（叉头盒 O3a）磷酸化和诱导 FOXO3a 诱导的自噬基因转录有关。此外，ULK-1 的抑制性磷酸化降低，下游 Beclin-1 自噬信号在 P2Y2R 缺陷中被激活。P2Y2R 缺乏时增加的 SIRT-1 (sirtuin-1) 和 FOXO3a 表达也增强了自噬反应，从而改善了 DN 的肾功能障碍。

结论

P2Y2R 通过损害自噬促进 DN 的发病机制，并作为治疗 DN 的治疗靶点。