By Daniella Gimbosh
Scientists have been elucidating the role of thousands of enzymes, genes and molecules present in the body since the dawn of time. One of these substances is an enzyme called AMP-activated protein kinase (AMPK). AMPK is an enzyme that plays a vital role in metabolism regulation and has been referred to as the cell’s “fuel gauge”. It is a key cellular sensor and is strongly implicated in a myriad of diseases including obesity, diabetes, metabolic syndrome and even cancer.1 When low amounts of energy molecules are present in a cell, for example due to conditions including hypoxia, hypoglycemia, and metabolic stress, AMPK is activated and works to restore their normal cellular levels.2 Overall, AMPK activation usually leads to a restoration of cellular homeostasis by promoting an increase in catalytic reactions that release energy by breaking down large molecules, and similarly, a decrease in anabolic reactions that require energy to build them up. It does this through various signalling pathways such as by phosphorylating specific substrates and regulators of transcription that play a vital role in cellular metabolism.3 This has made the enzyme an attractive candidate for treating metabolic diseases, such as obesity and type 2 diabetes.
In the kidney, due to its action on various membrane channels, AMPK activation has been suggested as a potential therapeutic target to tackle polycystic kidney disease (PKD).4 PKD is a disorder that causes multiple fluid-filled cysts to develop in the kidneys, also known as cystogenesis. If these cysts become enlarged or if too many cysts develop, this could result in damage to the kidneys and, eventually, kidney failure.5 Moreover, there are two subtypes of PKD in humans: autosomal dominant PKD (ADPKD), usually caused by mutations in the genes PKD1 or PKD2, and autosomal recessive PKD (ARPKD), usually caused by a mutation in the PKHD1 gene.1 ADPKD is currently the most prevalent monogenic kidney disease, affecting approximately 1 in 1000 people worldwide. It ultimately leads to kidney failure in the majority of affected individuals due to cyst development and has been linked to an increased risk of brain aneurysms.6 However, the pathobiology of ADPKD is still not clear and more research is needed for scientists to uncover the exact mechanisms behind the disease. Moreover, the role of the AMPK enzyme in the kidney, in PKD, and the long-term effects of AMPK activation on kidney function, remain largely unknown.
To investigate this, recent research7 used a genetically modified mouse model with a continuously active version of AMPK in all cells of the mice. The research found that this chronic activation of AMPK led to the kidneys acquiring hallmark properties of PKD. This included an increase in kidney size, accumulation of the sugar glycogen, and altered signalling pathways, amongst others. Such changes ultimately resulted in compromised renal function, kidney damage and cyst development. The acquired characteristics of the mouse kidneys also strikingly resembled those of early-onset human ADPKD. The researchers also found that when AMPK was chronically activated in just the kidney tubules (structures of the kidney that help to filter fluids), the same results were replicated. These findings suggested that it was specifically the renal activation of AMPK that caused the cystogenesis.
Notably, as the results showed that chronic AMPK activation led to early-onset PKD characteristics, the study’s overall conclusion suggested that altered AMPK signalling is a contributing factor in cystogenesis. These findings have remarkable implications not only for further research investigating the mechanisms of human kidney disease, but also for potential therapeutic intervention for disease treatment. Authors of the paper commented on the importance of determining whether established genetic mutations causing ADPKD lead to AMPK activation or not, as well as investigating whether this process plays a role in the metabolic changes present in ADPKD to drive cyst development.8
Other studies have also investigated the potential of AMPK activators for the treatment of ADPKD, both through pharmacological and non-pharmacological approaches.1 For example, multiple pharmacological compounds have been proven to lead to an increase in AMPK activity both directly and indirectly, and are currently going through the preclinical drug testing phases. Additionally, non-pharmacological methods, such as caloric restriction9, have been researched and show great therapeutic potential for AMPK activation.
Needless to say, the therapeutic potential of AMPK activation in various diseases is enormous. Although much more research is needed to fully understand the role AMPK plays in cystogenesis, PKD and other polycystic diseases, the exciting possibilities of this enzyme may change the face of disease treatment in the near future.
References:
1. Song X, Tsakiridis E, Steinberg GR, Pei Y. Targeting AMP-activated protein kinase (AMPK) for treatment of autosomal dominant polycystic kidney disease. Cellular Signalling. [Online] 2020;73: 109704. Available from: doi:10.1016/j.cellsig.2020.109704 [Accessed: 15th February 2022]
2. Steinberg GR, Carling D. AMP-activated protein kinase: the current landscape for drug development. Nature Reviews Drug Discovery. [Online] 2019;18(7): 527–551. Available from: doi:10.1038/s41573-019-0019-2 [Accessed: 16th February 2022]
3. Hardie DG. AMPK: A Target for Drugs and Natural Products With Effects on Both Diabetes and Cancer. Diabetes. [Online] 2013;62(7): 2164–2172. Available from: doi:10.2337/db13-0368 [Accessed: 16th February 2022]
4. Hwang Y-H, Conklin J, Chan W, Roslin NM, Liu J, He N, et al. Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease. Journal of the American Society of Nephrology : JASN. [Online] American Society of Nephrology; 2016;27(6): 1861–1868. Available from: doi:10.1681/ASN.2015060648 [Accessed: 17th February 2022]
5. Grantham JJ. Clinical practice. Autosomal dominant polycystic kidney disease. The New England Journal of Medicine. [Online] 2008;359(14): 1477–1485. Available from: doi:10.1056/NEJMcp0804458 [Accessed: 18th February 2022]
6. Lanktree MB, Haghighi A, Guiard E, Iliuta I-A, Song X, Harris PC, et al. Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing. Journal of the American Society of Nephrology. [Online] 2018;29(10): 2593–2600. Available from: doi:10.1681/ASN.2018050493 [Accessed: 17th February 2022]
7. Wilson L, Pollard Alice E, Penfold L, Muckett Phillip J, Whilding C, Bohlooly-Y. M, et al. Chronic activation of AMP-activated protein kinase leads to early-onset polycystic kidney phenotype. Clinical Science. [Online] 2021;135(20): 2393–2408. Available from: doi:10.1042/cs20210821 [Accessed: 18th February 2022]
8. MRC London Institute of Medical Sciences. LMS researchers demonstrate novel role for AMP-activated protein kinase in kidney disease. [Online] LMS London Institute of Medical Sciences. Available from: https://lms.mrc.ac.uk/lms-researchers%e2%80%afdemonstrate-novel-role-for-amp-activated-protein-kinase%e2%80%afin-kidney-disease/ [Accessed: 16th February 2022]
9. Cantó C, Auwerx J. Calorie Restriction: Is AMPK a Key Sensor and Effector? Physiology. [Online] 2011;26(4): 214–224. Available from: doi:10.1152/physiol.00010.2011 [Accessed: 16th February 2022]
Imperial Bioscience Review 