Nicotinic acetylcholine receptor α1 promotes calpain-1 activation and macrophage inflammation in hypercholesterolemic nephropathy

Guoqiang Zhang, Alison L. Thomas, Amanda L. Marshall, Kelly A. Kernan, Yanyuan Su, Yi Zheng, Jiro Takano, Takaomi C. Saido, Allison A. Eddy

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The nicotinic acetylcholine receptor α1 (nAChRα1) was investigated as a potential proinflammatory molecule in the kidney, given a recent report that it is an alternative urokinase plasminogen activator (uPA) receptor, in addition to the classical receptor uPAR. Two animal models and in vitro monocyte studies were involved: (1) In an ApoE -/- mouse model of chronic kidney disease, glomerular-resident cells and monocytes/macrophages were identified as the primary cell types that express nAChRα1 during hypercholesterolemia/uninephrectomy-induced nephropathy. Silencing of the nAChRα1 gene for 4 months (6 months on Western diet) prevented the increases in renal monocyte chemoattractant protein-1 and osteopontin expression levels and F4/80 macrophage infiltration compared with the nonsilenced mice. These changes were associated with significantly reduced transforming growth factor-Β1 mRNA (50% decrease) and α smooth muscle actin-positive (αSMA) myofibroblasts (90% decrease), better glomerular and tubular basement membranes (GBM/TBM) preservation (threefold less disintegration), and better renal function preservation (serum creatinine 40% lower) in the nAChRα1-silenced mice. The nAChRα1 silencing was also associated with significantly reduced renal tissue calcium deposition (78% decrease) and calpain-1 (but not calpain-2) activation (70% decrease). (2) The nAChRα1 was expressed in vitro by mouse monocyte cell line WEHI-274.1. The silencing of nAChRα1 significantly reduced both calpain-1 and-2 activities, and reduced the degradation of the calpain substrate talin. (3) To further explore the role of calpain-1 activity in hypercholesterolemic nephropathy, disease severities were compared in CAST -/- ApoE -/- (calpain overactive) mice and ApoE -/- mice fed with Western diet for 10 months (n12). Macrophages were the main cell type of renal calpain-1 production in the model. The number of renal F4/80 macrophages was 10-fold higher in the CAST -/- ApoE -/- mice (P<0.05), and was associated with a significantly higher level of αSMA cells, increased GBM/TBM destruction, and higher serum creatinine levels. Our studies suggest that the receptor nAChRα1 is an important regulator of calpain-1 activation and inflammation in the chronic hypercholesterolemic nephropathy. This new proinflammatory pathway may also be relevant to other disorders beyond hyperlipidemic nephropathy.

Original languageEnglish (US)
Pages (from-to)106-123
Number of pages18
JournalLaboratory Investigation
Volume91
Issue number1
DOIs
StatePublished - Jan 2011

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Calpain
Macrophage Activation
Nicotinic Receptors
Inflammation
Apolipoproteins E
Kidney
Macrophages
Monocytes
Smooth Muscle
Actins
Creatinine
Talin
Urokinase Plasminogen Activator Receptors
Glomerular Basement Membrane
Osteopontin
Myofibroblasts
Chemokine CCL2
Transforming Growth Factors
Hypercholesterolemia
Serum

Keywords

  • calpain-1
  • gene therapy
  • hypercholesterolemia
  • monocyte/macrophage
  • nephropathy
  • nicotinic receptor α1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Cite this

Nicotinic acetylcholine receptor α1 promotes calpain-1 activation and macrophage inflammation in hypercholesterolemic nephropathy. / Zhang, Guoqiang; Thomas, Alison L.; Marshall, Amanda L.; Kernan, Kelly A.; Su, Yanyuan; Zheng, Yi; Takano, Jiro; Saido, Takaomi C.; Eddy, Allison A.

In: Laboratory Investigation, Vol. 91, No. 1, 01.2011, p. 106-123.

Research output: Contribution to journalArticle

Zhang, Guoqiang ; Thomas, Alison L. ; Marshall, Amanda L. ; Kernan, Kelly A. ; Su, Yanyuan ; Zheng, Yi ; Takano, Jiro ; Saido, Takaomi C. ; Eddy, Allison A. / Nicotinic acetylcholine receptor α1 promotes calpain-1 activation and macrophage inflammation in hypercholesterolemic nephropathy. In: Laboratory Investigation. 2011 ; Vol. 91, No. 1. pp. 106-123.
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