title: Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury.
abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known genetic cause of Parkinson's disease, and LRRK2 is also linked to Crohn's and Hansen's disease. LRRK2 is expressed in many organs in mammals but is particularly abundant in the kidney. We find that LRRK2 protein is predominantly localized to collecting duct cells in the rat kidney, with much lower expression in other kidney cells. While genetic knockout (KO) of LRRK2 expression is well-tolerated in mice and rats, a unique age-dependent pathology develops in the kidney. The cortex and medulla of LRRK2 KO rat kidneys become darkly pigmented in early adulthood, yet aged animals display no overt signs of kidney failure. Accompanying the dark pigment we find substantial macrophage infiltration in LRRK2 KO kidneys, suggesting the presence of chronic inflammation that may predispose to kidney disease. Unexpectedly, the dark kidneys of the LRRK2 KO rats are highly resistant to rhabdomyolysis-induced acute kidney injury compared with wild-type rats. Biochemical profiling of the LRRK2 KO kidneys using immunohistochemistry, proteomic and lipidomic analyses show a massive accumulation of hemoglobin and lipofuscin in renal tubules that account for the pigmentation. The proximal tubules demonstrate a corresponding up-regulation of the cytoprotective protein heme oxygenase-1 (HO-1) which is capable of mitigating acute kidney injury. The unusual kidney pathology of LRRK2 KO rats highlights several novel physiological roles for LRRK2 and provides indirect evidence for HO-1 expression as a protective mechanism in acute kidney injury in LRRK2 deficiency.
authors.affiliation: Department of Medicine.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Boddu
authors.affiliation: Department of Surgery.
authors.forename: Travis D
authors.initials: TD
authors.lastname: Hull
authors.affiliation: Department of Medicine.
authors.forename: Subhashini
authors.initials: S
authors.lastname: Bolisetty
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham 35294, USA and.
authors.forename: Xianzhen
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham 35294, USA and.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Moehle
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham 35294, USA and.
authors.forename: João Paulo Lima
authors.initials: JP
authors.lastname: Daher
authors.affiliation: Department of Medicine.
authors.forename: Ahmed Ibrahim
authors.initials: AI
authors.lastname: Kamal
authors.affiliation: Department of Medicine.
authors.forename: Reny
authors.initials: R
authors.lastname: Joseph
authors.affiliation: Department of Surgery.
authors.forename: James F
authors.initials: JF
authors.lastname: George
authors.affiliation: Department of Medicine, Birmingham Veterans Administration Medical Center, Birmingham, Birmingham 35294, USA.
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Department of Medicine, Birmingham Veterans Administration Medical Center, Birmingham, Birmingham 35294, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Curtis
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham 35294, USA and abwest@uab.edu.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: West
mesh_terms: D000818:Animals; D019610:Cytoprotection; D004847:Epithelial Cells / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics*; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D051381:Rats; D012206:Rhabdomyolysis / Q000150:complications / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases