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

Publication ,  Journal Article
Boddu, R; Hull, TD; Bolisetty, S; Hu, X; Moehle, MS; Daher, JPL; Kamal, AI; Joseph, R; George, JF; Agarwal, A; Curtis, LM; West, AB
Published in: Hum Mol Genet
July 15, 2015

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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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

July 15, 2015

Volume

24

Issue

14

Start / End Page

4078 / 4093

Location

England

Related Subject Headings

  • Up-Regulation
  • Rhabdomyolysis
  • Rats
  • Proteomics
  • Protein Serine-Threonine Kinases
  • Male
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Kidney Tubules, Proximal
  • Kidney Diseases
  • Heme Oxygenase (Decyclizing)
 

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Boddu, R., Hull, T. D., Bolisetty, S., Hu, X., Moehle, M. S., Daher, J. P. L., … West, A. B. (2015). Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury. Hum Mol Genet, 24(14), 4078–4093. https://doi.org/10.1093/hmg/ddv147
Boddu, Ravindra, Travis D. Hull, Subhashini Bolisetty, Xianzhen Hu, Mark S. Moehle, João Paulo Lima Daher, Ahmed Ibrahim Kamal, et al. “Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury.Hum Mol Genet 24, no. 14 (July 15, 2015): 4078–93. https://doi.org/10.1093/hmg/ddv147.
Boddu R, Hull TD, Bolisetty S, Hu X, Moehle MS, Daher JPL, et al. Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury. Hum Mol Genet. 2015 Jul 15;24(14):4078–93.
Boddu, Ravindra, et al. “Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury.Hum Mol Genet, vol. 24, no. 14, July 2015, pp. 4078–93. Pubmed, doi:10.1093/hmg/ddv147.
Boddu R, Hull TD, Bolisetty S, Hu X, Moehle MS, Daher JPL, Kamal AI, Joseph R, George JF, Agarwal A, Curtis LM, West AB. Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury. Hum Mol Genet. 2015 Jul 15;24(14):4078–4093.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

July 15, 2015

Volume

24

Issue

14

Start / End Page

4078 / 4093

Location

England

Related Subject Headings

  • Up-Regulation
  • Rhabdomyolysis
  • Rats
  • Proteomics
  • Protein Serine-Threonine Kinases
  • Male
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Kidney Tubules, Proximal
  • Kidney Diseases
  • Heme Oxygenase (Decyclizing)