Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease

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.

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

“…As CR has a direct impact on energy supply that involves NADH and NAD + , it thus is involved in eliciting antioxidative responses in DKD by restoring redox balance and mitigating diabetic kidney injury [ 230 , 231 ]. Such responses include AMPK activation, autophagy, ROS elimination, Nrf2 signaling pathway activation and enhancement of antioxidative capacity in the kidney [ 231 , 232 , 233 , 234 , 235 ]. In certain studies, exercise has been shown to have a synergistic effect on CR [ 236 , 237 ].…”

Identifying Therapeutic Strategies in IgA Nephropathy through Comprehensive Transcriptomic Characterization

“…57 In autosomal dominant polycystic disease, alterations of glucose, fatty acid and amino acid metabolism are suspected to contribute to cyst proliferation and growth. 58 Among our DEG clusters and co-expressed modules, cluster 6 and module 1, are a group of co-regulated and under expressed genes, and a repressed module of co-expressed genes, respectively, which show repression of amino acid metabolic pathways such as glycine-serine-threonine metabolism, alanine-aspartate-glutamate metabolism and tryptophan metabolism, in IgAN. Serine, glycine, threonine metabolism is involved in many pathways including the one-carbon cycle, which provides substrates for nucleotide synthesis, methylation reactions and antioxidant defense.…”

Non-Coding RNAs in Hereditary Kidney Disorders

“…PPARα is the key regulator of mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), suggesting that miR-17 promotes cyst growth through affecting the mitochondrial metabolism in renal epithelial cells. These findings also indicate that miR-17-PPARα axis-mediated mitochondrial dysfunction is one of the alterations leading to the pro-proliferative metabolic reprogramming of cyst epithelia, in addition to the defective glucose metabolism and dysregulated lipid and amino acid metabolism [ 58 , 59 , 60 ]. Lee et al has identified RGLS4326 by screening a chemically diverse library of anti-miR-17 oligonucleotides [ 61 ].…”