Time-Dependent Regulation of Cystogenesis and Disease Severity by AMPK in Polycystic Kidney Disease Cells and Mice

Autosomal dominant polycystic kidney disease (ADPKD), the most common potentially lethal genetic kidney disease, has limited treatment options and is caused by mutations in the PKD1 or PKD2 genes encoding the polycystin proteins PC1 and PC2. ADPKD presents with progressive development of renal cysts, kidney enlargement, and eventual end-stage kidney disease in ~50% of patients by the 6 th decade of life. Although many cellular signaling pathways are dysregulated in ADPKD, cells with loss of PC function are hyper-proliferative with major metabolic derangements that may contribute to formation/expansion of kidney epithelial cysts, including increased glycolysis and impaired fatty acid oxidation. In addition, reduced cellular activity of the metabolic sensor AMP-activated protein kinase (AMPK) has been implicated as a key feature of ADPKD and other chronic kidney diseases. We and others have shown that AMPK activators like metformin may reduce disease severity in mouse and other animal ADPKD models, yet other studies have failed to show benefits of metformin in other animal models with treatment at different phases of the disease. Moreover, a recent study using a transgenic mouse model expressing a constitutive activating AMPK mutation led to the development of a PKD-like cystic kidney phenotype. Thus, the significance of AMPK activity in ADPKD is unclear with the possibility that AMPK could have distinct roles during different stages of the disease. To directly test the role of AMPK in ADPKD, we performed in vivo studies using the hypomorphic, slowly progressive Pkd1 RC/RC mouse model for human ADPKD, which contains a human disease-causing missense mutation in the mouse Pkd1 gene. We compared various ADPKD disease features at 10 and 12 months of age in male and female Pkd1 RC/RC mice with or without additional constitutive knockout (KO) of the AMPK-β1 subunit, which effectively reduces AMPK activity in kidney by >80%. Based on the prevailing view that AMPK activation should be beneficial in reducing disease severity, we hypothesized that the double transgenic AMPK-β1 −/− ;Pkd1 RC/RC mice would manifest more severe disease features. Surprisingly, however, we found that AMPK KO in the Pkd1 RC/RC mice had beneficial effects in ameliorating a variety of ADPKD disease features. Specifically, morphometric analyses revealed that AMPK KO lowered % cystic index in female mouse kidneys at 12 months of age relative to controls (14.2 ± 2.9% vs. 32.5 ± 4.0%; P60% at 10 days relative to both no Dox induction and late Dox induction ( P<0.0001). In addition, late Dox induction increased cyst size by ~15% relative to no Dox ( P<0.01), suggesting that AMPK inhibition enhanced cellular proliferation and cyst growth once cysts have started to form. In conclusion, together with prior published studies, our findings here suggest that AMPK inhibition early in disease may be beneficial through inhibition of cystogenesis, whereas reduced AMPK activity in later stages of ADPKD could worsen disease manifestations, and thus the use of AMPK activators during advanced disease may be of therapeutic benefit. Supported by UKRO and U.S. Department of Defense. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.