A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease

Dagorn PG, Buchholz B, Kraus A, Batchuluun B, Bange H, Blockken L, Steinberg GR, Moller DE, Hallakou-Bozec S (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Kidney International Nature Publishing Group: Open Access Hybrid Model Option A

Book Volume: 103

Pages Range: 917-929

Journal Issue: 5

DOI: 10.1016/j.kint.2023.01.026

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) mainly results from mutations in the PKD1 gene, which encodes polycystin 1. It is the most common inherited kidney disease and is characterized by a progressive bilateral increase in cyst number and size, often leading to kidney failure. The cellular energy sensor and regulator adenosine monophosphate stimulated protein kinase (AMPK) has been implicated as a promising new therapeutic target. To address this hypothesis, we determined the effects of a potent and selective clinical stage direct allosteric AMPK activator, PXL770, in canine and patient-derived 3D cyst models and an orthologous mouse model of ADPKD. PXL770 induced AMPK activation and dose-dependently reduced cyst growth in principal-like Madin-Darby Canine Kidney cells stimulated with forskolin and kidney epithelial cells derived from patients with ADPKD stimulated with desmopressin. In an inducible, kidney epithelium-specific Pkd1 knockout mouse model, PXL770 produced kidney AMPK pathway engagement, prevented the onset of kidney failure (reducing blood urea by 47%), decreased cystic index by 26% and lowered the kidney weight to body weight ratio by 35% compared to untreated control Pkd1 knockout mice. These effects were accompanied by a reduction of markers of cell proliferation (-48%), macrophage infiltration (-53%) and tissue fibrosis (-37%). Thus, our results show the potential of direct allosteric AMPK activation in the treatment of ADPKD and support the further development of PXL770 for this indication.

Authors with CRIS profile

Björn Buchholz Medizinische Fakultät Andre Kraus Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

McMaster University CA Canada (CA) InnoSer België BE Belgium (BE) Poxel SA FR France (FR) Crown Bioscience NL Netherlands (NL)

How to cite

APA:

Dagorn, P.G., Buchholz, B., Kraus, A., Batchuluun, B., Bange, H., Blockken, L.,... Hallakou-Bozec, S. (2023). A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease. Kidney International, 103(5), 917-929. https://dx.doi.org/10.1016/j.kint.2023.01.026

MLA:

Dagorn, Pascale Gluais, et al. "A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease." Kidney International 103.5 (2023): 917-929.

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