Cyclic Adenosine Monophosphate Signaling in Chronic Kidney Disease: Molecular Targets and Therapeutic Potentials
Abstract
:1. Introduction
2. Methodology
3. cAMP: Formation, Distribution, and Regulation
4. cAMP in Kidney Physiology
4.1. cAMP and AVP in the Collecting Duct
4.2. cAMP and Kidney Fibrosis
4.3. cAMP and Immune Modulation
4.4. cAMP in Nephrotic Syndrome
5. cAMP in Chronic Kidney Disease
5.1. Autosomal Polycystic Kidney Disease
5.2. Diabetic Nephropathy
5.3. cAMP and Bartter Syndrome
5.4. cAMP in Liddle Syndrome
5.5. cAMP in Renal Tubular Acidosis
5.6. cAMP and Nephrogenic Diabetes Insipidus
5.7. cAMP in Fabry Disease
5.8. The Role of cAMP in Renal Cell Carcinoma (RCC) and Implications for CKD
5.9. cAMP in AKI-to-CKD Transition
6. Therapies Targeting cAMP Signaling
6.1. Phosphodiesterase Inhibitors
6.2. Adenylate Cyclase Activators
6.3. cAMP Analogs
7. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Kidney Disease | Role of cAMP | References |
---|---|---|
Nephrotic syndrome | cAMP modulates podocyte function, affecting cytoskeletal dynamics, cell adhesion, and protein expression crucial for maintaining the filtration barrier. | [9,64] |
Diabetic nephropathy | cAMP influences the CREB-binding protein-mediated hyperacetylation of profibrotic genes, contributing to fibrogenesis and kidney damage. | [63] |
Autosomal dominant polycystic kidney disease | cAMP promotes cystogenesis by stimulating cell proliferation and fluid secretion in the cyst lumen through V2 receptor activation. | [72] |
Bartter syndrome | cAMP modulates ion transport and salt reabsorption in the thick ascending limb of the loop of Henle, impacting NKCC2 regulation. | [36] |
Liddle syndrome | cAMP regulates the ENaC activity and trafficking, with mutations in ENaC disrupting this regulation and causing hypertension. | [55] |
Renal tubular acidosis | cAMP affects proton pumps and bicarbonate transporters, regulating acid–base balance in distal tubules and influencing V-ATPase activity. | [16] |
Nephrogenic diabetes insipidus | cAMP mediates vasopressin effects on water reabsorption by promoting AQP2 trafficking to the apical membrane in the collecting ducts. | [15] |
Fabry disease | cAMP impacts lysosomal function and substrate accumulation, contributing to kidney dysfunction by modulating lysosomal enzyme activity. | [8] |
Renal cell carcinoma | cAMP influences cell proliferation, migration, and apoptosis through CREB1 regulation, impacting tumor growth and survival. | [35] |
Therapeutic Agent | Status | Mechanism of Action | Kidney Disease | Effects on Kidney Function | References |
---|---|---|---|---|---|
Pentoxifylline | On the market (off label use) | Non-selective PDE inhibitor, increases cAMP levels | Diabetic nephropathy, CKD | Reduces proteinuria, inflammation, and fibrosis; delays progression to ESKD | [101] |
Cilostazol | On the market (off label use) | PDE3 inhibitor, increases cAMP levels | Diabetic nephropathy, CKD | Prevents glomerular hypertrophy and inflammation; improves blood pressure and vascular function | [102] |
Sildenafil | On the market (off label use) | PDE5 inhibitor, increases cGMP levels | Diabetic nephropathy | Reduces progression of nephropathy and hypertension; improves hemodynamic parameters | [103] |
PF-00489791 | Clinical trials | PDE5 inhibitor, increases cGMP levels | Diabetic nephropathy | Decreases albuminuria and urine albumin-to-creatinine ratio | [104] |
GLP-1 Receptor Agonists | On the market | Activates cAMP production via GLP-1 receptor stimulation | Diabetic nephropathy | Reduces inflammation, oxidative stress, and fibrosis; improves renal function | [77] |
MR-L2 | Research stage | Activates long forms of PDE4, reduces cAMP levels | Polycystic kidney disease | Suppresses cyst development and progression | [105] |
Forskolin | On the market | AC activator, increases cAMP levels | CKD | Promotes protective cellular responses, reduces fibrosis | [106] |
PACAP38 | Research stage | AC activator, reduces off-target effects | CKD | Prevents renal injury by suppressing proinflammatory cytokine production, inhibits p38 MAPK and NF-κB pathways | [107] |
(Rp)-8-Br-cAMPS, (Rp)-8-Cl-cAMPS | Research stage | cAMP analogs, selectively inhibit cAMP-dependent protein kinase I | CKD | Target specific signaling pathways, reduce off-target actions | [108] |
Rolipram | Research stage | PDE4 inhibitor, increases cAMP levels | Renal fibrosis | Activates Epac1/Rap1 pathway, reduces tubular epithelial cell damage and fibrosis | [43] |
PDE Isoform | Localization in the Kidney | Role in CKD | References |
---|---|---|---|
PDE1 (cAMP) PDE1 (cGMP) | Cortical tubules + Proximal tubule epithelial cells +/++ Inner medullary collecting duct cells ++ Glomeruli ++++ Mesangial cells +++ Cortical tubules +++ Proximal tubule epithelial cells +/++ Inner medullary collecting duct cells + | Inhibition of PDE1 causes greater stimulation of ERK and proliferation of ADPKD cells. | [113,125] |
PDE2 | Glomeruli ++++ Proximal tubule epithelial cells + | cGMP-stimulated PDE2 mediates the inhibitory effect of nitric oxide on NaCl absorption by the medullary thick ascending limb of the loop of Henle. | [113,126] |
PDE3 | Glomeruli ++ Glomerular epithelial cells +/− Mesangial cells +++ Cortical tubules ++ Proximal tubule epithelial cells +/− Inner medullary collecting duct cells + | PDE3-linked cAMP–PKA pathway modulates mitogenesis. | [113,127,128] |
PDE4 | Glomeruli ++ Glomerular epithelial cells ++++ Mesangial cells ++++ Cortical tubules +++ Proximal tubule epithelial cells ++++ Inner medullary collecting duct cells +++ | PDE4 inhibition suppresses oxidative stress, fibrosis, and inflammation in mesangial cells and podocyte cells, which protect podocyte loss, which leads to albuminuria and glomerulosclerosis. In tubulointerstitial lesions, PDE4 inhibition suppresses inflammation and epithelial–mesenchymal transition, which leads to tubulointerstitial fibrosis. PDE4-linked cAMP–PKA pathway modulates generation of reactive oxygen species. | [113,128,129,130] |
PDE5 | Glomeruli +++ Mesangial cells +++ Cortical tubules +++ Proximal tubule epithelial cells +/++ Inner medullary collecting duct cells + | PDE5 inhibition regulates the excretory function and hemodynamics of the kidney. PDE5 contributes to the regulation of renal vascular blood flow by limiting the vascular relaxation caused by cGMP. PDE5 contributes to the regulation of natriuresis through the degradation of cGMP. | [113,131] |
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Delrue, C.; Speeckaert, R.; Moresco, R.N.; Speeckaert, M.M. Cyclic Adenosine Monophosphate Signaling in Chronic Kidney Disease: Molecular Targets and Therapeutic Potentials. Int. J. Mol. Sci. 2024, 25, 9441. https://doi.org/10.3390/ijms25179441
Delrue C, Speeckaert R, Moresco RN, Speeckaert MM. Cyclic Adenosine Monophosphate Signaling in Chronic Kidney Disease: Molecular Targets and Therapeutic Potentials. International Journal of Molecular Sciences. 2024; 25(17):9441. https://doi.org/10.3390/ijms25179441
Chicago/Turabian StyleDelrue, Charlotte, Reinhart Speeckaert, Rafael Noal Moresco, and Marijn M. Speeckaert. 2024. "Cyclic Adenosine Monophosphate Signaling in Chronic Kidney Disease: Molecular Targets and Therapeutic Potentials" International Journal of Molecular Sciences 25, no. 17: 9441. https://doi.org/10.3390/ijms25179441