Jingzhen Yuan1, Chintan Chheda2, Honit Piplani2, Meng Geng3, Grace Tan4, Reetu Thakur2, Stephen J Pandol5. 1. Cedars-Sinai Medical Center, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, South California Research Center for Alcoholic Liver and Pancreatic Diseases, California, USA. Electronic address: Jingzhen.Yuan@cshs.org. 2. Cedars-Sinai Medical Center, Los Angeles, CA, USA. 3. Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, South California Research Center for Alcoholic Liver and Pancreatic Diseases, California, USA; Frank Netter H. School of Medicine at Quinnipiac University, CT, USA. 4. Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, South California Research Center for Alcoholic Liver and Pancreatic Diseases, California, USA; Loma Linda Medical School, Los Angeles, CA, United States of America. 5. Cedars-Sinai Medical Center, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, South California Research Center for Alcoholic Liver and Pancreatic Diseases, California, USA.
Abstract
BACKGROUND: Protein kinase D (PKD) family, which includes PKD/PKD1, PKD2, and PKD3, has been increasingly implicated in the regulation of multiple cellular functions and human diseases. We recently reported that pharmacologic inhibition of PKD ameliorated the pathologic responses and severity of pancreatitis. However, to further investigate the importance of PKD family members in pancreatitis, it is necessary to explore the effects of pancreas-specific genetic inhibition of PKD isoform on pathology of pancreatitis. METHODS: We generated a mouse model (referred as PKD3Δpanc mice) with pancreas-specific deletion of PKD3, the predominant PKD isoform in mouse pancreatic acinar cells, by crossing Pkd3flox/flox mice with Pdx1-Cre transgenic mice which express Cre recombinase under the control of the mouse Pdx1 promoter. Pancreas-specific deletion of the PKD3 gene and PKD3 protein was confirmed by PCR and Western blot analysis. Experimental pancreatitis was induced in PKD3Δpanc and Pkd3flox/flox (control mice) littermates by intraperitoneal injections of cerulein or L-arginine. RESULTS: Compared to the control mice, PKD3Δpanc mice displayed significant attenuation in inflammation, necrosis, and severity of pancreatitis in both experimental models. PKD3Δpanc mice had markedly decreased NF-κB and trypsinogen activation, pancreatic mRNA expression of multiple inflammatory molecules, and the receptor-interacting protein kinase 1 (RIP1) activation in pancreatitis. PKD3Δpanc mice also had less pancreatic ATP depletion, increased pro-survival Bcl-2 family protein expression, and autophagy promotion. CONCLUSION: With PKD3Δpanc mouse model, we further demonstrated that PKD plays a critical role in pathobiological process of pancreatitis and PKD constitutes a novel therapeutic target to treat this disorder.
BACKGROUND: Protein kinase D (PKD) family, which includes PKD/PKD1, PKD2, and PKD3, has been increasingly implicated in the regulation of multiple cellular functions and human diseases. We recently reported that pharmacologic inhibition of PKD ameliorated the pathologic responses and severity of pancreatitis. However, to further investigate the importance of PKD family members in pancreatitis, it is necessary to explore the effects of pancreas-specific genetic inhibition of PKD isoform on pathology of pancreatitis. METHODS: We generated a mouse model (referred as PKD3Δpanc mice) with pancreas-specific deletion of PKD3, the predominant PKD isoform in mouse pancreatic acinar cells, by crossing Pkd3flox/flox mice with Pdx1-Cre transgenic mice which express Cre recombinase under the control of the mouse Pdx1 promoter. Pancreas-specific deletion of the PKD3 gene and PKD3 protein was confirmed by PCR and Western blot analysis. Experimental pancreatitis was induced in PKD3Δpanc and Pkd3flox/flox (control mice) littermates by intraperitoneal injections of cerulein or L-arginine. RESULTS: Compared to the control mice, PKD3Δpanc mice displayed significant attenuation in inflammation, necrosis, and severity of pancreatitis in both experimental models. PKD3Δpanc mice had markedly decreased NF-κB and trypsinogen activation, pancreatic mRNA expression of multiple inflammatory molecules, and the receptor-interacting protein kinase 1 (RIP1) activation in pancreatitis. PKD3Δpanc mice also had less pancreatic ATP depletion, increased pro-survival Bcl-2 family protein expression, and autophagy promotion. CONCLUSION: With PKD3Δpanc mouse model, we further demonstrated that PKD plays a critical role in pathobiological process of pancreatitis and PKD constitutes a novel therapeutic target to treat this disorder.
Authors: Vikesh K Singh; Thomas L Bollen; Bechien U Wu; Kathryn Repas; Rie Maurer; Song Yu; Koenraad J Mortele; Darwin L Conwell; Peter A Banks Journal: Clin Gastroenterol Hepatol Date: 2011-09-03 Impact factor: 11.382
Authors: Honit Piplani; Stefanie Marek-Iannucci; Jon Sin; Jean Hou; Toshimasa Takahashi; Ankush Sharma; Juliana de Freitas Germano; Richard T Waldron; Hannaneh Saadaeijahromi; Yang Song; Aiste Gulla; Bechien Wu; Aurelia Lugea; Allen M Andres; Herbert Y Gaisano; Roberta A Gottlieb; Stephen J Pandol Journal: Biochim Biophys Acta Mol Basis Dis Date: 2019-08-06 Impact factor: 6.633
Authors: Andrea Párniczky; Balázs Kui; Andrea Szentesi; Anita Balázs; Ákos Szűcs; Dóra Mosztbacher; József Czimmer; Patrícia Sarlós; Judit Bajor; Szilárd Gódi; Áron Vincze; Anita Illés; Imre Szabó; Gabriella Pár; Tamás Takács; László Czakó; Zoltán Szepes; Zoltán Rakonczay; Ferenc Izbéki; Judit Gervain; Adrienn Halász; János Novák; Stefan Crai; István Hritz; Csaba Góg; János Sümegi; Petra Golovics; Márta Varga; Barnabás Bod; József Hamvas; Mónika Varga-Müller; Zsuzsanna Papp; Miklós Sahin-Tóth; Péter Hegyi Journal: PLoS One Date: 2016-10-31 Impact factor: 3.240