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

ABSTRACT: The nicotinic acetylcholine receptor ?1 (nAChR?1) 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 nAChR?1 during hypercholesterolemia/uninephrectomy-induced nephropathy. Silencing of the nAChR?1 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-?1 mRNA (50% decrease) and ? smooth muscle actin-positive (?SMA+) 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 nAChR?1-silenced mice. The nAChR?1 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 nAChR?1 was expressed in vitro by mouse monocyte cell line WEHI-274.1. The silencing of nAChR?1 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 (n=12). 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 ?SMA+ cells, increased GBM/TBM destruction, and higher serum creatinine levels. Our studies suggest that the receptor nAChR?1 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.

SUBMITTER: Zhang G

PROVIDER: S-EPMC3188436 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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

Zhang Guoqiang G Thomas Alison L AL Marshall Amanda L AL Kernan Kelly A KA Su Yanyuan Y Zheng Yi Y Takano Jiro J Saido Takaomi C TC Eddy Allison A AA

Laboratory investigation; a journal of technical methods and pathology 20100726 1

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 d ...[more]

PMID: 20661225

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Project description:Inflammatory responses to stimuli are essential body defenses against foreign threats. However, uncontrolled inflammation may result in serious health problems, which can be life-threatening. The ?7 nicotinic acetylcholine receptor, a ligand-gated ion channel expressed in the nervous and immune systems, has an essential role in the control of inflammation. Activation of the macrophage ?7 receptor by acetylcholine, nicotine, or other agonists, selectively inhibits production of pro-inflammatory cytokines while leaving anti-inflammatory cytokines undisturbed. The neural control of this regulation pathway was discovered recently and it was named the cholinergic anti-inflammatory pathway (CAP). When afferent vagus nerve terminals are activated by cytokines or other pro-inflammatory stimuli, the message travels through the afferent vagus nerve, resulting in action potentials traveling down efferent vagus nerve fibers in a process that eventually leads to macrophage ?7 activation by acetylcholine and inhibition of pro-inflammatory cytokines production. The mechanism by which activation of ?7 in macrophages regulates pro-inflammatory responses is subject of intense research, and important insights have thus been made. The results suggest that activation of the macrophage ?7 controls inflammation by inhibiting NF-?B nuclear translocation, and activating the JAK2/STAT3 pathway among other suggested pathways. While the ?7 is well characterized as a ligand-gated ion channel in neurons, whole-cell patch clamp experiments suggest that ?7's ion channel activity, defined as the translocation of ions across the membrane in response to ligands, is absent in leukocytes, and therefore, ion channel activity is generally assumed not to be required for the operation of the CAP. In this perspective, we briefly review macrophage ?7 activation as it relates to the control of inflammation, and broaden the current view by providing single-channel currents as evidence that the ?7 expressed in macrophages retains its ion translocation activity despite the absence of whole-cell currents. Whether this ion-translocating activity is relevant for the proper operation of the CAP or other important physiological processes remains obscure.

Project description:The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ?300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by ?Y190) that behaves similarly at all sites and a coupled pair (led by ?W55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of ?(1) and one each of ?, ?, and either ? (fetal) or ? (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at ?? and either ?? or ?? subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C?O opening rate constant and C?O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly to reach a peak that corresponds to PO ?0.96.

Dataset Information

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

Publications

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

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