Ketosis as a therapy for polycystic kidney disease

项目总结/摘要 我们以前已经表明，轻度减少食物摄入量强烈抑制多囊肾的进展 在orthopathic小鼠模型中，我们发现了PKD，但我们不了解其机制。我们发现 酮症的代谢状态很重要，而不是热量限制本身。饮食干预导致 酮病在直立和非直立小鼠、大鼠中显著抑制甚至逆转PKD进展 和PKD的猫科动物模型。值得注意的是，单独使用酮β-羟基丁酸酯（BHB）的治疗几乎 100%有效预防PKD进展。初步结果表明，BHB作用于PKD肾脏， 其受体GPR 109 a，一种抑制cAMP信号传导的GPCR。我们的研究结果表明，PKD中的囊肿细胞是 在代谢？易变性，依赖葡萄糖，不能转化为利用脂肪酸和酮体。 该提案的主旨是产生令人信服的结果，以证明临床试验的合理性， ef？饮食干预和/或BHB补充剂在ADPKD中的准确性，并为此类试验的设计提供信息。 主要标志？这一建议的好处是临床翻译的巨大潜力。膳食干预 诱导酮症是公认的。由于饮食干预在临床实践中经常失败， 坚持，我们？发送BHB（FDA级？艾德膳食补充剂）有贝内？社会影响可以 快速地导致高度可行的疗法。为了实现我们的目标，我们将治疗PKD的啮齿动物和猫科动物模型， 通过饮食干预诱导酮症（限时喂养或生酮饮食）或模拟酮症， 补充BHB。Ef？PKD进展参数的准确性及其对分子机制的影响 将被评估。为了确定BHB是否通过GPR 109 a起作用，我们将GPR 109 a-/-小鼠与快速- 和缓慢进展的Pkd 1小鼠模型。我们将测试Gpr 109 a基因敲除是否会影响疾病 并防止EF？生酮饮食干预或BHB。成功完成 拟议的工作可能会导致ADPKD治疗的破坏性变化，通过利用饮食干预和/或 不需要药物干预的膳食补充剂。

Project Summary/Abstract We have previously shown that a mild reduction in food intake strongly inhibits progression of polycystic kidney disease (PKD) in an orthologous mouse model but we did not understand the mechanism. Now, we discovered that the metabolic state of ketosis is important, not caloric restriction per se. Dietary interventions leading to ketosis profoundly inhibit - and even reverse - PKD progression in orthologous and non-ortholgous mouse, rat and feline models of PKD. Remarkably, treatment with the ketone β-hydroxybutyrate (BHB) alone is almost 100% effective in preventing PKD progression. Preliminary results suggest that BHB acts on PKD kidneys via its receptor GPR109a, a GPCR that suppresses cAMP signaling. Our results suggest that cyst cells in PKD are metabolically in?exible, depend on glucose and are unable to shift to utilizing fatty acids and ketone bodies. The main thrust of this proposal is to generate compelling results to justify clinical trials to investigate the ef?cacy of dietary interventions and/or BHB supplementation in ADPKD, and to inform the design of such trials. The main signi?cance of this proposal is the enormous potential for clinical translation. Dietary interventions to induce ketosis are well-established. Because dietary interventions frequently fail in clinical practice due to poor adherence, our ?nding that BHB (an FDA-classi?ed dietary supplement) has a dominant bene?cial effect could rapidly lead to a highly feasible therapy. To achieve our goals, we will treat rodent and feline models of PKD, with dietary interventions to induce ketosis (time-restricted feeding or ketogenic diets) or mimic ketosis by supplementation with BHB. Ef?cacy on parameters of PKD progression and effects on molecular mechanisms will be assessed. To determine whether BHB acts via GPR109a, we have crossed Gpr109a-/- mice with fast- and slowly-progressing Pkd1 mouse models. We will test whether Gpr109a knock-out affects disease progression and prevents the ef?cacy of ketogenic dietary intervention or BHB. Successful completion of the proposed work could lead to a disruptive change in ADPKD therapy by utilizing dietary interventions and/or dietary supplements without the need for pharmacological intervention.