Increasing PKG activity protects aging kidney from ischemic-reperfusion induced injury

描述(由申请人提供)：年龄与急性肾损伤(AKI)的发病率增加有关。这种与年龄相关的AKI易感性的增加与肾功能恢复下降甚至进展为晚期慢性肾脏疾病有关，这是一个严重的全球健康问题。尽管近年来我们对AKI的细胞和分子方面的了解取得了进展，但衰老和AKI之间的关系仍然知之甚少，需要进一步的机制研究。初步研究表明，一氧化氮(NO)及其下游信号通路cGMP和cGMP依赖的蛋白激酶(PKG)在衰老肾脏中表达下调，这与衰老相关的肾功能改变有关。此外，初步研究表明，PKG对幼年小鼠肾缺血再灌注(IR)后肾小管上皮细胞的坏死和凋亡有抑制作用，并能抑制巨噬细胞的迁移，提示PKG对肾IR损伤有潜在的治疗作用。在这项提案中，我们将检验这样一种假设，即肾脏中NO/cGMP/PKG信号的下调有助于增加老年人对缺血再灌注介导的AKI的易感性。我们将在目标1中确定PKG活性的增加是否会降低老年动物对缺血介导的AKI的易感性。在目标2中将确定衰老肾脏中NO/cGMP/PKG信号减少的机制。这些研究将确立PKG在老龄人群急性肾损伤中的意义。重要的是，我们将测试西地那非在老年人群中的潜在应用。西地那非是cGMP特异性磷酸二酯酶5(PDE5)的抑制剂，也是FDA批准的治疗肺动脉高压和勃起功能障碍的药物。希望这些拟议的研究将为老年人群的急性肾损伤带来新的治疗策略。

DESCRIPTION (provided by applicant): Aging is associated with increased incidence of acute kidney injury (AKI). This age-dependent increase in susceptibility to AKI is linked to a decreased renal functional recovery and even progression to advanced chronic kidney disease, a severe health problem worldwide. Despite advances in our understanding of the cellular and molecular aspects of AKI in recent years, the relationship between aging and AKI remains poorly understood and requires further mechanistic studies. Preliminary studies demonstrated that nitric oxide (NO) and its downstream signaling pathway cGMP and cGMP-dependent protein kinase (PKG) was down-regulated in aging kidney, which was associated with aging-related renal functional changes. Moreover, preliminary data identified a novel inhibitory effect of PKG on tubular cell necrosis and apoptosis following renal ischemia reperfusion (IR) induced AKI in young mice and an inhibitory effect of PKG on macrophage migration, suggesting a therapeutic potential of PKG for renal IR injury. In this proposal, we will test the hypothesis that down-regulation of NO/cGMP/PKG signaling in the kidney contributes to increased susceptibility to ischemia reperfusion-mediated AKI in older individuals. We will determine whether genetically or pharmacologically increased PKG activity reduces the susceptibility of old animals to ischemia mediated AKI in Aim 1. The mechanisms of reduced NO/cGMP/PKG signaling in aging kidney will be determined in Aim 2. These studies will establish the significance of PKG in acute kidney injury in aging population. Importantly, we will test a novel potential application of sildenafil fr AKI in older population. Sildenafil is an inhibitor of cGMP specific phosphodiesterase 5 (PDE5) and a FDA approved drug for treatment of pulmonary hypertension and erectile dysfunction. Hopefully, these proposed studies will lead to new therapeutic strategy for acute kidney injury in aging population.