Researchers at the MRC London Institute of Medical Sciences (LMS) have shown overactivation of AMPK in mice causes the hallmark characteristics seen in humans diagnosed with early onset polycystic kidney disease.
AMP-activated protein kinase (AMPK) is known to play a vital role in maintaining cellular homeostasis. Chronic activation during development has been implicated in polycystic kidney disease (PKD), but how it does this is not understood and further research is needed to unpick whether AMPK could provide a therapeutic target.
To investigate the effects of chronic AMPK activation, researchers from the MRC LMS Cellular Stress group, led by Professor David Carling, engineered a genetically modified mouse to express active AMPK in every cell of the body. They found these mice had enlarged kidneys, which accumulated glycogen. They also observed compromised renal function, kidney damage and cyst development in the mice, which are all of the hallmarks of early-onset autosomal dominant PKD (ADPKD) in humans.
Spurred on by this observation, the LMS group bred their AMPK-mouse with a kidney-specific Cre mouse. This allowed generation of mice where the chronically activate AMPK was specifically expressed in the cells that make up the kidney tubules. This meant the researchers could observe what impact increased AMPK activity has in the kidney specifically. And they found their earlier observations were replicated, with the mice in the new model once again displaying characteristics of early-onset PKD.
Commenting on the use of a mouse model in the study, first author Dr Laura Wilson said: “Utilising a mouse model makes it easier for us to reveal cause and effect. Working in these model organisms helps to boost our understanding so that we have a better idea of where to look when we move into the more complex mechanisms of human disease.”
Approximately 70,000 people are estimated to suffer from PKD in the UK. It causes fluid-filled cysts to develop in the kidneys, which if enlarged or multiple can result in damage to the kidneys and ultimately kidney failure.
Professor David Carling, Head of the LMS Cellular Stress Group said: “Our findings reveal that chronic activation of AMPK during development leads to an early-onset PKD phenotype, with striking similarity to human ADPKD. It will be important to determine whether established genetic mutations that cause ADPKD also result in AMPK activation and whether this is required for the metabolic reprogramming seen in ADPKD, and potentially other polycystic diseases, to drive cystogenesis.”
‘Chronic Activation of AMP-Activated Protein Kinase Leads to Early-Onset Polycystic Kidney Phenotype’ was published in Clinical Science on 22 October 2021.