Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury.

Academic Article

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.
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    Keywords

  • Animals, Cytoprotection, Epithelial Cells, Genetic Predisposition to Disease, Heme Oxygenase (Decyclizing), Kidney Diseases, Kidney Tubules, Proximal, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Protein-Serine-Threonine Kinases, Proteomics, Rats, Rhabdomyolysis, Up-Regulation
  • Digital Object Identifier (doi)

    Authorlist

  • Boddu R; Hull TD; Bolisetty S; Hu X; Moehle MS; Daher JPL; Kamal AI; Joseph R; George JF; Agarwal A
  • Start Page

  • 4078
  • End Page

  • 4093
  • Volume

  • 24
  • Issue

  • 14