4.6 Review

Shared pathobiology identifies AMPK as a therapeutic target for obesity and autosomal dominant polycystic kidney disease

Journal

FRONTIERS IN MOLECULAR BIOSCIENCES
Volume 9, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fmolb.2022.962933

Keywords

autosomal dominant polycystic kidney disease; energy metabolism; obesity; metabolic dysregulation; AMPK

Funding

  1. Kidney Foundation of Canada
  2. 2021-2022 Queen Elizabeth II/Dr. Arnie Aberman Graduate Scholarship in Science and Technology (University of Toronto) [KRES170001]

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian kidney disease, and overweight/obesity is an independent risk factor for disease progression. Studies have found shared pathobiology between ADPKD and overweight/obesity, and pharmacological activation of AMPK provides a promising approach for ADPKD treatment.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian kidney disease, affecting approximately one in 1,000 births and accounting for 5% of end-stage kidney disease in developed countries. The pathophysiology of ADPKD is strongly linked to metabolic dysregulation, which may be secondary to defective polycystin function. Overweight and obesity are highly prevalent in patients with ADPKD and constitute an independent risk factor for progression. Recent studies have highlighted reduced AMP-activated protein kinase (AMPK) activity, increased mammalian target of rapamycin (mTOR) signaling, and mitochondrial dysfunction as shared pathobiology between ADPKD and overweight/obesity. Notably, mTOR and AMPK are two diametrically opposed sensors of energy metabolism that regulate cell growth and proliferation. However, treatment with the current generation of mTOR inhibitors is poorly tolerated due to their toxicity, making clinical translation difficult. By contrast, multiple preclinical and clinical studies have shown that pharmacological activation of AMPK provides a promising approach to treat ADPKD. In this narrative review, we summarize the pleiotropic functions of AMPK as a regulator of cellular proliferation, macromolecule metabolism, and mitochondrial biogenesis, and discuss the potential for pharmacological activation of AMPK to treat ADPKD and obesity-related kidney disease.

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