Chronic activation of AMP-activated protein kinase leads to early-onset polycystic kidney phenotype

Abstract

AMP-activated protein kinase (AMPK) plays a key role in the cellular response to low energy stress and has emerged as an attractive therapeutic target for tackling metabolic diseases. Whilst significant progress has been made regarding the physiological role of AMPK, its function in the kidney remains only partially understood. We use a mouse model expressing a constitutively active mutant of AMPK to investigate the effect of AMPK activation on kidney function in vivo. Kidney morphology and changes in gene and protein expression were monitored and serum and urine markers were measured to assess kidney function in vivo. Global AMPK activation resulted in an early onset polycystic kidney phenotype, featuring collecting duct cysts and compromised renal function in adult mice. Mechanistically, the cystic kidneys had increased cAMP levels and ERK activation, increased hexokinase I expression, glycogen accumulation and altered expression of proteins associated with autophagy. Kidney tubule-specific activation of AMPK also resulted in a polycystic phenotype, demonstrating that renal tubular AMPK activation caused the cystogenesis. Importantly, human ADPKD kidney sections revealed similar protein localisation patterns to that observed in the murine cystic kidneys. Our findings show that early onset chronic AMPK activation leads to a polycystic kidney phenotype, suggesting dysregulated AMPK signalling is a contributing factor in cystogenesis.

AMPK activation protects against prostate cancer by inducing a catabolic cellular state

“…In previous studies using this model, we did not observe any overt phenotype in control mice with global or tissue-specific expression of WT γ1 because these mice showed no change in AMPK expression or activity relative to non-transgenic mice. 11 , 12 , 14 Consistent with our previous studies, we found no differences in PCa disease progression between Pten −/− and Pten −/− ; Ampk WT mice ( Figure S1A ), and we therefore combined Pten −/− and Pten −/− ; Ampk WT mice to generate a single control group, referred to as Pten −/− mice. We also confirmed that expression of the γ1 transgene had no obvious effect on the levels of endogenous α and β subunit proteins and that the transgene was expressed in anterior and dorsolateral ventral prostate lobes ( Figure S1B ).…”

The specific AMPK activator A-769662 ameliorates pathological phenotypes following mitochondrial DNA depletion

“…The targeting of a central regulator like AMPK as a treatment strategy comes with its own risks and challenges. In some studies, the chronic activation of AMPK has shown undesirable side effects such as cardiac and kidney hypertrophy and Alzheimer’s disease (Wilson et al 2021; Zimmermann et al 2020). However, clinical trials and animal studies with other AMPK agonists did not reveal harmful side effects, indicating that activating this central regulator is feasible and safe with the right compounds (López-Pérez et al 2021; Pinkosky et al 2016; Ray et al 2024; Cusi et al 2021).…”

Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease

“…Interestingly, MET (41 mg/ kg) is able to activate AMPK and slow cyst growth in a miniature pig model of ADPKD (Lian et al, 2019). Interestingly, in a mouse model expressing a constitutively active mutant of AMPK, there was early onset polycystic kidney phenotype and increased cAMP levels and ERK activation (Wilson et al, 2021). Thus, the maximal activation of p-AMPK in PKD kidneys may be insufficient to suppress mTORC1 and may even cause cystogenesis in mouse and rat models of PKD (Wilson et al, 2021).…”

“…Interestingly, in a mouse model expressing a constitutively active mutant of AMPK, there was early onset polycystic kidney phenotype and increased cAMP levels and ERK activation (Wilson et al, 2021). Thus, the maximal activation of p-AMPK in PKD kidneys may be insufficient to suppress mTORC1 and may even cause cystogenesis in mouse and rat models of PKD (Wilson et al, 2021). To inform further studies of MET in rodents and humans, elucidating the pattern of AMPK activation in the PKD kidney would be important.…”