Metabolism-based approaches for autosomal dominant polycystic kidney disease

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) leads to end stage kidney disease (ESKD) through the development and expansion of multiple cysts throughout the kidney parenchyma. An increase in cyclic adenosine monophosphate (cAMP) plays an important role in generating and maintaining fluid-filled cysts because cAMP activates protein kinase A (PKA) and stimulates epithelial chloride secretion through the cystic fibrosis transmembrane conductance regulator (CFTR). A vasopressin V2 receptor antagonist, Tolvaptan, was recently approved for the treatment of ADPKD patients at high risk of progression. However additional treatments are urgently needed due to the poor tolerability, the unfavorable safety profile, and the high cost of Tolvaptan. In ADPKD kidneys, alterations of multiple metabolic pathways termed metabolic reprogramming has been consistently reported to support the growth of rapidly proliferating cystic cells. Published data suggest that upregulated mTOR and c-Myc repress oxidative metabolism while enhancing glycolytic flux and lactic acid production. mTOR and c-Myc are activated by PKA/MEK/ERK signaling so it is possible that cAMPK/PKA signaling will be upstream regulators of metabolic reprogramming. Novel therapeutics opportunities targeting metabolic reprogramming may avoid or minimize the side effects that are dose limiting in the clinic and improve on the efficacy observed in human ADPKD with Tolvaptan.

Revisiting the gene mutations and protein profile of WT 9‐12: An autosomal dominant polycystic kidney disease cell line

“…KEGG analysis linked the proteins to arginine biosynthesis, nitrogen metabolism, and proximal tubule bicarbonate reclamation (data not shown). This result supports the theory that altered cellular metabolism may be causally related to the etiology of ADPKD (Bakaj & Pocai, 2023). An investigation of mouse kidney cell lines cultivated in arginine‐replete versus arginine‐deficient medium revealed arginine‐dependent changes in the glutamine and proline pathways that drives cystogenesis in ADPKD (Trott et al, 2018).…”

Methylation analysis by targeted bisulfite sequencing in large for gestational age (LGA) newborns: the LARGAN cohort

“…MYC is a master regulator of several genes involved in cell growth and cell cycle progression [ 64 ]. Deregulated MYC expression results in a variety of oncogenic processes as well as polycystic kidney disease [ 65 ]. SOX8 is a transcription factor involved in the regulation of cell fate determination during embryonic development [ 66 ].…”

Recent progress in metabolic reprogramming in gestational diabetes mellitus: a review

“…A balanced metabolic system is essential for the structural stability of glucose and normal physiological function. Metabolic processes can adapt to changes in the environment; thus, they can be reprogrammed to support energy requirements in biosynthesis, leading to disease development such as cancer, diabetes, polycystic kidney disease, and vascular inflammatory diseases ( 15 – 18 ). Metabolic reprogramming is also important in GDM development ( 11 – 13 ).…”