Torres Jacob A, Holznecht Nickolas, Asplund David A, Kroes Bradley C, Amarlkhagva Tselmeg, Haeffner Matthias M, Sharpe Elizabeth H, Koestner Stella, Strubl Sebastian, Schimmel Margaret F, Kruger Samantha, Agrawal Shagun, Aceves Brina A, Thangaraju Muthusamy, Weimbs Thomas
Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA.
Department of Biochemistry and Molecular Biology, University of Augusta, Augusta, GA, USA.
iScience. 2024 Aug 20;27(9):110773. doi: 10.1016/j.isci.2024.110773. eCollection 2024 Sep 20.
Autosomal-dominant polycystic kidney disease (ADPKD) is a common monogenic disease characterized by the formation of fluid-filled renal cysts, loss of mitochondrial function, decreased fatty acid oxidation, increased glycolysis, and likely renal failure. We previously demonstrated that inducing a state of ketosis ameliorates or reverses PKD progression in multiple animal models. In this study, we compare time-restricted feeding and 48-h periodic fasting regimens in both juvenile and adult Cy/+ rats. Both fasting regimens potently prevent juvenile disease progression and partially reverse PKD in adults. To explore the mechanism of fasting, we administered β-hydroxybutyrate (BHB) to Cy/+ rats and orthologous mouse models of PKD ( , ). BHB recapitulated the effects of fasting in these models independent of stereoisomer, suggesting the effects of BHB are largely due to its signaling functions. These findings implicate the use of ketogenic metabolic therapy and BHB supplementation as potential disease modifiers of PKD and point toward underlying mechanisms.
常染色体显性多囊肾病（ADPKD）是一种常见的单基因疾病，其特征是形成充满液体的肾囊肿、线粒体功能丧失、脂肪酸氧化减少、糖酵解增加，并可能导致肾衰竭。我们之前证明，在多种动物模型中，诱导酮症状态可改善或逆转多囊肾病的进展。在本研究中，我们比较了幼年和成年Cy/+大鼠的限时进食和48小时周期性禁食方案。两种禁食方案都能有效预防幼年疾病进展，并部分逆转成年大鼠的多囊肾病。为了探究禁食的机制，我们给Cy/+大鼠和多囊肾病的直系同源小鼠模型施用了β-羟基丁酸（BHB）。BHB在这些模型中重现了禁食的效果，且与立体异构体无关，这表明BHB的作用很大程度上归因于其信号传导功能。这些发现表明，生酮代谢疗法和补充BHB可作为多囊肾病的潜在疾病修饰剂，并指向其潜在机制。
