| First Author | Yuan J | Year | 2021 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1867 |
| Issue | 1 | Pages | 165987 |
| PubMed ID | 33039594 | Mgi Jnum | J:304600 |
| Mgi Id | MGI:6695369 | Doi | 10.1016/j.bbadis.2020.165987 |
| Citation | Yuan J, et al. (2021) Pancreas-specific deletion of protein kinase D attenuates inflammation, necrosis, and severity of acute pancreatitis. Biochim Biophys Acta Mol Basis Dis 1867(1):165987 |
| abstractText | 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 PKD3Deltapanc 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 PKD3Deltapanc and Pkd3flox/flox (control mice) littermates by intraperitoneal injections of cerulein or L-arginine. RESULTS: Compared to the control mice, PKD3Deltapanc mice displayed significant attenuation in inflammation, necrosis, and severity of pancreatitis in both experimental models. PKD3Deltapanc mice had markedly decreased NF-kappaB and trypsinogen activation, pancreatic mRNA expression of multiple inflammatory molecules, and the receptor-interacting protein kinase 1 (RIP1) activation in pancreatitis. PKD3Deltapanc mice also had less pancreatic ATP depletion, increased pro-survival Bcl-2 family protein expression, and autophagy promotion. CONCLUSION: With PKD3Deltapanc 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. |
