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Local cyclic adenosine monophosphate signalling cascades - roles and targets in chronic kidney disease

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Item Type:Review
Title:Local cyclic adenosine monophosphate signalling cascades - roles and targets in chronic kidney disease
Creators Name:Sholokh, A. and Klussmann, E.
Abstract:The molecular mechanisms underlying chronic kidney disease (CKD) are poorly understood and treatment options are limited, a situation underpinning the need for elucidating the causative molecular mechanisms and for identifying innovative treatment options. It is emerging that cyclic 3′,5′‐adenosine monophosphate (cAMP) signalling occurs in defined cellular compartments within nanometre dimensions in processes whose dysregulation is associated with CKD. cAMP compartmentalization is tightly controlled by a specific set of proteins, including A‐kinase anchoring proteins (AKAPs) and phosphodiesterases (PDEs). AKAPs such as AKAP18, AKAP220, AKAP‐Lbc and STUB1, and PDE4 coordinate arginine‐vasopressin (AVP)‐induced water reabsorption by collecting duct principal cells. However, hyperactivation of the AVP system is associated with kidney damage and CKD. Podocyte injury involves aberrant AKAP signalling. cAMP signalling in immune cells can be local and slow the progression of inflammatory processes typical for CKD. A major risk factor of CKD is hypertension. cAMP directs the release of the blood pressure regulator, renin, from juxtaglomerular cells, and plays a role in Na+ reabsorption through ENaC, NKCC2 and NCC in the kidney. Mutations in the cAMP hydrolysing PDE3A that cause lowering of cAMP lead to hypertension. Another major risk factor of CKD is diabetes mellitus. AKAP18 and AKAP150 and several PDEs are involved in insulin release. Despite the increasing amount of data, an understanding of functions of compartmentalized cAMP signalling with relevance for CKD is fragmentary. Uncovering functions will improve the understanding of physiological processes and identification of disease‐relevant aberrations may guide towards new therapeutic concepts for the treatment of CKD.
Keywords:CKD, Hypertension, Diabetes, Autosomal Dominant Polycystic Kidney Disease, ADPKD, Polycystic Kidney Disease, PKD, cAMP Signalling, A-Kinase Anchoring Protein, AKAP, Phosphodiesterase, PDE, Protein Kinase A, PKA, Protein-Protein Interaction, PPI, Aquaporin-2, AQP2, Arginine-Vasopressin, AVP
Source:Acta Physiologica
Page Range:e13641
Date:May 2021
Official Publication:https://doi.org/10.1111/apha.13641
PubMed:View item in PubMed

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