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

描述（由申请人提供）：衰老与急性肾损伤（AKI）发生率增加有关。AKI易感性的年龄依赖性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，这是全球范围内严重的健康问题。尽管近年来我们对AKI的细胞和分子方面的理解有所进展，但衰老与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依赖性蛋白激酶（PKG）在衰老肾脏中下调，与衰老相关的肾功能改变有关。此外，初步数据发现PKG对幼鼠肾缺血再灌注（IR）诱导的AKI后小管细胞坏死和凋亡具有新的抑制作用，并对巨噬细胞迁移具有抑制作用，表明PKG对肾IR损伤具有治疗潜力。在本研究中，我们将验证肾脏NO/cGMP/PKG信号下调导致老年人对缺血再灌注介导的AKI易感性增加的假设。我们将在Aim 1中确定基因或药理学上增加PKG活性是否会降低老年动物对缺血介导的AKI的易感性。NO/cGMP/PKG信号在衰老肾脏中降低的机制将在Aim 2中确定。这些研究将确立PKG在老年人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治疗AKI的一种新的潜在应用。西地那非是一种cGMP特异性磷酸二酯酶5 （PDE5）抑制剂，是FDA批准用于治疗肺动脉高压和勃起功能障碍的药物。希望这些建议的研究将为老年人急性肾损伤的治疗提供新的策略。

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.