AMP-activated protein kinase (AMPK) is widely regarded as a master regulator of energy homeostasis, functioning to maintain energy levels under conditions of metabolic stress. Activation of AMPK has emerged as an attractive therapeutic strategy for treatment of many diseases including metabolic, cardiovascular (CV) and renal pathologies. Consistent with this novel, direct AMPK activators have recently been developed that provide evidence for the amelioration of metabolic diseases in vivo. Despite numerous studies demonstrating beneficial effects of AMPK activation, there are also concerns as to the negative impact AMPK activation could have on physiology. Activating mutations in AMPKγ2 (one of three potential AMPKγ subunits that can be incorporated into the enzymatic complex) are known to cause the inherited cardiac disease Wolff-Parkinson White (WPW) syndrome, which is characterised by cardiac hypertrophy, glycogen accumulation and electrical conductance defects. Furthermore, a recent transgenic mouse model of AMPKγ2 activation indicated that AMPK activation could lead to the development of a polycystic kidney (PKD) phenotype in some circumstances. However, the effect of AMPKγ1 activation on cardio-renal physiology is currently largely unknown.
To address this question, a novel transgenic mouse model of AMPKγ1 activation was generated by expressing a gain-of-function D316A mutation in the AMPKγ1 subunit, resulting in a constitutively active AMPK complex. The model was generated using the Cre-LoxP system to enable tissue-specific AMPKγ1 activation. Initial observations in a global AMPKγ1 activation model revealed a striking PKD phenotype and an enlarged heart phenotype. Subsequent characterisation of the heart phenotype demonstrated increased cardiac hypertrophy and glycogen accumulation with no electrical conductance defects. The hearts also showed signs of pathological cardiac hypertrophy, and it was established that global AMPKγ1 activation mice had elevated blood pressure. The PKD phenotype and elevated blood pressure were also observed in a kidney-specific model of AMPKγ1 activation, implicating a role for renal AMPKγ1 activation in negatively impacting CV function. Characterisation of the kidney phenotype showed the global AMPKγ1 activation model presented with polyuria, altered electrolyte homeostasis and impaired renal function. Renal cysts appeared to form exclusively in the collecting ducts, and kidneys harvested from gain-of-function AMPKγ1 mice featured increased cAMP accumulation, activation of the MAPK pathway, altered expression of lysosomal-associated proteins and glycogen accumulation. Overall, this work highlights a potential role for AMPK activation in the pathogenesis of renal cyst formation, which may negatively impact the cardio-renal axis.