Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease: Evidence and Therapeutic Potential

Abstract

Autosomal dominant polycystic kidney disease is characterized by progressive development and enlargement of kidney cysts, leading to ESKD. Because the kidneys are under high metabolic demand, it is not surprising that mounting evidence suggests that a metabolic defect exists in in vitro and animal models of autosomal dominant polycystic kidney disease, which likely contributes to cystic epithelial proliferation and subsequent cyst growth. Alterations include defective glucose metabolism (reprogramming to favor aerobic glycolysis), dysregulated lipid and amino acid metabolism, impaired autophagy, and mitochondrial dysfunction. Limited evidence supports that cellular kidney metabolism is also dysregulated in humans with autosomal dominant polycystic kidney disease. There are notable overlapping features and pathways among metabolism, obesity, and/or autosomal dominant polycystic kidney disease. Both dietary and pharmacologic-based strategies targeting metabolic abnormalities are being considered as therapies to slow autosomal dominant polycystic kidney disease progression and are attractive, particularly given the slowly progressive nature of the disease. Dietary strategies include daily caloric restriction, intermittent fasting, time-restricted feeding, a ketogenic diet, and 2-deoxy-glucose as well as alterations to nutrient availability. Pharmacologic-based strategies include AMP-activated kinase activators, sodium glucose cotransporter-2 inhibitors, niacinamide, and thiazolidenediones. The results from initial clinical trials targeting metabolism are upcoming and anxiously awaited within the scientific and polycystic kidney disease communities. There continues to be a need for additional mechanistic studies to better understand the role of dysregulated metabolism in autosomal dominant polycystic kidney disease and for subsequent translation to clinical trials. Beyond single-intervention trials focused on metabolic reprograming in autosomal dominant polycystic kidney disease, great potential also exists by combining metabolic-focused therapeutic approaches with compounds targeting other signaling cascades altered in autosomal dominant polycystic kidney disease, such as tolvaptan.

Keywords: AMP-activated protein kinases; animal models; animals; autophagy; autosomal dominant polycystic kidney; caloric restriction; chronic kidney failure; cysts; deoxyglucose; diet; fasting; glucose; glycolysis; humans; ketogenic diet; kidney; lipids; metabolism; mitochondria; niacinamide; obesity; polycystic kidney disease; sodium-glucose transporter 2 inhibitors; tolvaptan; type 2 diabetes mellitus.

Figure 1.

Autosomal dominant polycystic kidney disease (ADPKD) and nutrient metabolisms have converging pathways. Central cellular processes that are known to be impaired in ADPKD pathology and are characteristic of metabolic reprogramming include autophagic flux, glycolysis, fatty acid oxidation, and mitochondrial function. Central signaling nodes that overlap between ADPKD and metabolic response include mammalian target of rapamycin (mTOR), AMP-activated kinase (AMPK), sirtuin-1 (SIRT-1), IGF-I, and peroxisome proliferator–activated receptor-α/γ (PPARα/γ). Alteration in diet intake or composition can affect many of these overlapping processes/pathways. Similarly, multiple pharmacologic approaches that are known to alter metabolic reprogramming target these central processes/signaling hubs. Collectively, this suggests that such interventions have high potential in alleviating ADPKD in humans. Dotted arrows indicate that signaling cascade is more complex than depicted. AKT, protein kinase B; BHB, β-hydroxybutyrate; BMI, body mass index; CFTR, cystic fibrosis transmembrane conductance regulator; cMYC, cellular mycelocytomatosis; CR, caloric restriction; 2-DG, 2-deoxyglucose; 4E-BP1, eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1; ERK1/2, extracellular signal–regulated kinase; FAO, fatty acid oxidation; HNF4α, hepatocyte nuclear factor 4α; IMF, intermittent fasting; IRS, insulin receptor substrate; MAM, mitochondria associated membranes; MEK, mitogen-activated protein kinase kinase; OXPHOS, oxidative phosphorylation; PC, polycystin; PI3K, phosphoinositide 3-kinase; Rheb, ras homolog enriched in brain; ROS, reactive oxygen species; S6K, ribosomal protein S6 kinase; SGLT1/2, sodium glucose cotransporter-1/2; STAT3, signal transducer and activator of transcription 3; TCA, tricarboxylic acid cycle; TRF, time-restricted feeding; TSC1/2, tuberous sclerosis 1/2; TZD, thiazolidinedione.

Figure 2.

Dietary and pharmacologic-based strategies may target dysregulated metabolism in ADPKD. A summary is provided regarding whether dietary and pharmacologic-based strategies to potentially target dysregulated metabolism in ADPKD have been evaluated in nonpolycystic kidney disease (non-PKD) models (rodents and humans) and in PKD models (rodents and humans).