TY - JOUR

T1 - PFE-360-induced LRRK2 inhibition induces reversible, non-adverse renal changes in rats

AU - Andersen, Michael Aagaard

AU - Wegener, Karen Malene

AU - Larsen, Steen

AU - Badolo, Lassina

AU - Smith, Garrick Paul

AU - Jeggo, Ross

AU - Jensen, Poul Henning

AU - Sotty, Florence

AU - Christensen, Kenneth Vielsted

AU - Thougaard, Annemette

N1 - Copyright © 2018 H. Lundbeck A/S. Published by Elsevier B.V. All rights reserved.

PY - 2018/2/15

Y1 - 2018/2/15

N2 - Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no existing therapeutic approach to delay or stop progression. Genetic, biochemical and pre-clinical studies have provided evidence that leucine-rich-repeat-kinase-2 (LRRK2) kinase is involved in the pathogenesis of PD, and small molecule LRRK2 inhibitors represent a novel potential therapeutic approach. However, potentially adverse target-related effects have been discovered in the lung and kidneys of LRRK2 knock-out (ko) mice and rats. It is unclear if the LRRK2 ko effect in the kidneys and lung is also induced by pharmacological inhibition of the LRRK2 kinase. Here, we show that treatment with the LRRK2 inhibitor PFE-360 in rats induces a morphological kidney phenotype resembling that of the LRRK2 ko rats, whereas no effects were observed in the lung. The PFE-360 treatment induced morphological changes characterised by darkened kidneys and progressive accumulation of hyaline droplets in the renal proximal tubular epithelium. However, no histopathological evidence of renal tubular injury or changes in the blood and urine parameters that would be indicative of kidney toxicity or impaired kidney function were observed after up to 12 weeks of treatment. Morphological changes were detected in the kidney after 2 weeks of treatment and were partially reversible within a 30 day treatment-free period. Our findings suggest that pharmacological LRRK2 inhibition may not have adverse consequences for kidney function.

AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no existing therapeutic approach to delay or stop progression. Genetic, biochemical and pre-clinical studies have provided evidence that leucine-rich-repeat-kinase-2 (LRRK2) kinase is involved in the pathogenesis of PD, and small molecule LRRK2 inhibitors represent a novel potential therapeutic approach. However, potentially adverse target-related effects have been discovered in the lung and kidneys of LRRK2 knock-out (ko) mice and rats. It is unclear if the LRRK2 ko effect in the kidneys and lung is also induced by pharmacological inhibition of the LRRK2 kinase. Here, we show that treatment with the LRRK2 inhibitor PFE-360 in rats induces a morphological kidney phenotype resembling that of the LRRK2 ko rats, whereas no effects were observed in the lung. The PFE-360 treatment induced morphological changes characterised by darkened kidneys and progressive accumulation of hyaline droplets in the renal proximal tubular epithelium. However, no histopathological evidence of renal tubular injury or changes in the blood and urine parameters that would be indicative of kidney toxicity or impaired kidney function were observed after up to 12 weeks of treatment. Morphological changes were detected in the kidney after 2 weeks of treatment and were partially reversible within a 30 day treatment-free period. Our findings suggest that pharmacological LRRK2 inhibition may not have adverse consequences for kidney function.

KW - Animals

KW - Body Weight/drug effects

KW - Enzyme Inhibitors/toxicity

KW - Female

KW - Kidney/anatomy & histology

KW - Kidney Function Tests

KW - Kidney Tubules, Proximal/anatomy & histology

KW - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors

KW - Lung/anatomy & histology

KW - Morpholines/toxicity

KW - Pyrimidines/toxicity

KW - Pyrroles/toxicity

KW - Rats

KW - Rats, Sprague-Dawley

U2 - 10.1016/j.tox.2018.01.003

DO - 10.1016/j.tox.2018.01.003

M3 - Journal article

C2 - 29307545

VL - 395

SP - 15

EP - 22

JO - Toxicology

JF - Toxicology

SN - 0300-483X

ER -