Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is the third most common cause of end stage kidney disease after diabetes mellitus and hypertension. Over the last 3 decades there has been great progress in understanding its pathogenesis. This allows the stratification of therapeutic targets into four levels, gene mutation and polycystin disruption, proximal mechanisms directly caused by disruption of polycystin function, downstream regulatory and signaling pathways, and non-specific pathophysiologic processes shared by many other diseases. Dysfunction of the polycystins, encoded by the PKD genes, is closely associated with disruption of calcium and upregulation of cyclic AMP and protein kinase A (PKA) signaling, affecting most downstream regulatory, signaling, and pathophysiologic pathways altered in this disease. Interventions acting on G protein coupled receptors to inhibit of 3′,5′-cyclic adenosine monophosphate (cAMP) production have been effective in preclinical trials and have led to the first approved treatment for ADPKD. However, completely blocking cAMP mediated PKA activation is not feasible and PKA activation independently from cAMP can also occur in ADPKD. Therefore, targeting the cAMP/PKA/CREB pathway beyond cAMP production makes sense. Redundancy of mechanisms, numerous positive and negative feedback loops, and possibly counteracting effects may limit the effectiveness of targeting downstream pathways. Nevertheless, interventions targeting important regulatory, signaling and pathophysiologic pathways downstream from cAMP/PKA activation may provide additive or synergistic value and build on a strategy that has already had success. The purpose of this manuscript is to review the role of cAMP and PKA signaling and their multiple downstream pathways as potential targets for emergent therapies for ADPKD.

Molecular mechanisms underlying polycystic kidney disease: From the smallest bricks to the big scenario

“…Tolvaptan has been shown to exhibit a partial agonist activity on β-arrestin recruitment whose expression is increased in human ADPKD kidneys . These data suggest that there is space for safer and tolerated best in class cAMP lowering approaches in ADPKD either targeting additional pathways regulating cAMP (PKA inhibition, PDE activation), biased V2R antagonists or combination with targets that may provide an additive or synergistic effect such as the calciumsensing receptor Zhou and Torres, 2022).…”

Metabolism-based approaches for autosomal dominant polycystic kidney disease

“…Tolvaptan has been shown to exhibit a partial agonist activity on β-arrestin recruitment whose expression is increased in human ADPKD kidneys ( Xu et al, 2018 ). These data suggest that there is space for safer and tolerated best in class cAMP lowering approaches in ADPKD either targeting additional pathways regulating cAMP (PKA inhibition, PDE activation), biased V2R antagonists or combination with targets that may provide an additive or synergistic effect such as the calcium-sensing receptor ( Di Mise et al, 2021 ; Zhou and Torres, 2022 ).…”

Clinical findings, underlying pathogenetic processes and treatment of vascular dysfunction in autosomal dominant polycystic kidney disease

“…It is estimated to have an incidence rate ranging from 1/1000 to 1/2500 [ 1 , 2 ]. ADPKD is the third most common cause of end-stage renal disease (ESRD), following diabetes and hypertension [ 3 ]. One aspect that has attracted widespread attention is the abnormal changes associated with vasculature, particularly vascular dysfunction.…”

“…These proteins play critical roles in maintaining the normal structure and function of the renal tubules and blood vessels. Together with these genetic changes, dysregulation of various signaling pathways, such as the cAMP [ 3 , 7 , 8 ], mTOR [ 9 , 10 ], and Wnt pathways [ 11 , 12 ], has been suggested to be involved in the development and progression of ADPKD. These pathways interact with polycystins and other proteins involved in cyst formation and growth, leading to altered cell proliferation, apoptosis, and differentiation [ 13 ].…”