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.

Keywords: ADPKD (autosomal dominant polycystic kidney disease); GLP-1; glucagon; metabolic reprograming; metabolism & obesity; therapeutic approaches; tolvaptan.

FIGURE 1

Metabolic Pathways in ADPKD. Increased cAMP due to vasopressin (Chebib et al., 2015) but likely also to decreased phosphodiesterases (PDEs) (Pinto et al., 2016) play a key role in generating fluid-filled cysts. Defects in PC1 and PC2 mediated calcium ion influx in the primary cilia and/or in the endoplasmic reticulum (ER) (Nauli et al., 2003; Padhy et al., 2022). Decreased intracellular calcium seems to convert the antiproliferative to proliferative effect of cAMP (Yamaguchi et al., 2003) causing activation of MEK-ERK and increased cell proliferation. cAMP activates PKA and stimulates chloride secretion through the cystic fibrosis transmembrane conductance regulator (CFTR) (Sullivan et al., 1998). Tolvaptan, a vasopressin V2 receptor antagonist, was approved to preserve kidney function by targeting cAMP (Chebib and Torres, 2021). Several somatostatin analogues (SST) are being investigated to lower cAMP with Ocreotide-LAR being approved in ADPKD in Italy (Capuano et al., 2022a). Mammalian target of rapamycin (mTOR) and c-Myc are upregulated in ADPKD and suppress oxidative metabolism while enhancing glycolytic flux, lactate production and export (LDH-A and MCT4) (Rowe et al., 2013; Podrini et al., 2020).