M1 Muscarinic Receptor Deficiency Attenuates Azoxymethane-Induced Chronic Liver Injury in Mice

Vikrant Rachakonda, Ravirajsinh N. Jadeja, Nathalie H. Urrunaga, Nirish Shah, Daniel Ahmad, Kunrong Cheng, William S. Twaddell, Jean Pierre Raufman, Sandeep Khurana

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Cholinergic nervous system regulates liver injury. However, the role of M1 muscarinic receptors (M1R) in modulating chronic liver injury is uncertain. To address this gap in knowledge we treated M1R-deficient and WT mice with azoxymethane (AOM) for six weeks and assessed liver injury responses 14 weeks after the last dose of AOM. Compared to AOM-treated WT mice, M1R-deficient mice had attenuated liver nodularity, fibrosis and ductular proliferation, α-SMA staining, and expression of α1 collagen, Tgfβ-R, Pdgf-R, Mmp-2, Timp-1 and Timp-2. In hepatocytes, these findings were associated with reductions of cleaved caspase-3 staining and Tnf-α expression. In response to AOM treatment, M1R-deficient mice mounted a vigorous anti-oxidant response by upregulating Gclc and Nqo1 expression, and attenuating peroxynitrite generation. M1R-deficient mouse livers had increased expression of Trail-R2, a promotor of stellate cell apoptosis; dual staining for TUNNEL and α-SMA revealed increased stellate cells apoptosis in livers from M1R-deficient mice compared to those from WT. Finally, pharmacological inhibition of M1R reduced H2O2 -induced hepatocyte apoptosis in vitro. These results indicate that following liver injury, anti-oxidant response in M1R-deficient mice attenuates hepatocyte apoptosis and reduces stellate cell activation, thereby diminishing fibrosis. Therefore, targeting M1R expression and activation in chronic liver injury may provide therapeutic benefit.

Original languageEnglish (US)
Article number14110
JournalScientific Reports
Volume5
DOIs
StatePublished - Sep 16 2015

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Muscarinic M1 Receptors
Azoxymethane
Liver
Wounds and Injuries
Apoptosis
Hepatocytes
Staining and Labeling
Oxidants
Peroxynitrous Acid
Caspase 3
Liver Cirrhosis
Cholinergic Agents
Nervous System
Fibrosis
Collagen
Pharmacology

ASJC Scopus subject areas

  • General

Cite this

Rachakonda, V., Jadeja, R. N., Urrunaga, N. H., Shah, N., Ahmad, D., Cheng, K., ... Khurana, S. (2015). M1 Muscarinic Receptor Deficiency Attenuates Azoxymethane-Induced Chronic Liver Injury in Mice. Scientific Reports, 5, [14110]. https://doi.org/10.1038/srep14110

M1 Muscarinic Receptor Deficiency Attenuates Azoxymethane-Induced Chronic Liver Injury in Mice. / Rachakonda, Vikrant; Jadeja, Ravirajsinh N.; Urrunaga, Nathalie H.; Shah, Nirish; Ahmad, Daniel; Cheng, Kunrong; Twaddell, William S.; Raufman, Jean Pierre; Khurana, Sandeep.

In: Scientific Reports, Vol. 5, 14110, 16.09.2015.

Research output: Contribution to journalArticle

Rachakonda, V, Jadeja, RN, Urrunaga, NH, Shah, N, Ahmad, D, Cheng, K, Twaddell, WS, Raufman, JP & Khurana, S 2015, 'M1 Muscarinic Receptor Deficiency Attenuates Azoxymethane-Induced Chronic Liver Injury in Mice', Scientific Reports, vol. 5, 14110. https://doi.org/10.1038/srep14110
Rachakonda, Vikrant ; Jadeja, Ravirajsinh N. ; Urrunaga, Nathalie H. ; Shah, Nirish ; Ahmad, Daniel ; Cheng, Kunrong ; Twaddell, William S. ; Raufman, Jean Pierre ; Khurana, Sandeep. / M1 Muscarinic Receptor Deficiency Attenuates Azoxymethane-Induced Chronic Liver Injury in Mice. In: Scientific Reports. 2015 ; Vol. 5.
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