Ketosis as a therapy for polycystic kidney disease

项目摘要/摘要 我们之前已经证明，轻度减少食物摄入量会强烈抑制多囊肾的进展。 疾病(PKD)在一个直系小鼠模型，但我们不知道其机制。现在，我们发现 酮症的代谢状态是重要的，而不是卡路里限制本身。饮食干预导致 酮病对同种和非同种异体小鼠、大鼠PKD进展的抑制甚至逆转作用 和猫的PKD模型。值得注意的是，仅用酮β-羟丁酸酯(BHb)治疗几乎 在防止PKD进展方面100%有效。初步结果表明，BHB通过以下途径作用于PKD肾脏 它的受体Gpr109a是一种抑制cAMP信号的GPCR。我们的结果表明，PKD中的囊性细胞 代谢能力不强，依赖葡萄糖，不能利用脂肪酸和酮体。 这项提案的主旨是产生令人信服的结果，以证明临床试验是合理的，以调查 对ADPKD患者进行饮食干预和/或BHB补充，并为此类试验的设计提供信息。 这一建议的主要意义是临床翻译的巨大潜力。饮食干预措施 诱导酮症是公认的。因为饮食干预在临床实践中经常失败，因为 坚持下去，我们认为BHB(一种FDA标准的膳食补充剂)具有明显的益处 迅速导致一种高度可行的治疗方法。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中毒(限时喂养或生酮饮食)或通过以下方式模仿酮中毒 补充BHB。EF？Cacy对PKD进展参数及分子机制的影响 将会被评估。为了确定BHB是否通过Gpr109a发挥作用，我们将Gpr109a-/-小鼠与FAST- 以及进展缓慢的PKD1小鼠模型。我们将测试Gpr109a基因敲除是否会影响疾病 进展和预防生酮饮食干预或BHB的效果。圆满完成 拟议的工作可能导致ADPKD治疗的颠覆性变化，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.