The G protein-coupled P2Y<sub>2</sub> nucleotide receptor (P2Y<sub>2</sub>R) is upregulated in response to stress and tissue injury and has been postulated to play a role in chronic inflammation seen in atherosclerosis, Alzheimer’s disease and Sjögren’s syndrome. The role of P2Y<sub>2</sub>R upregulation in vivo is poorly understood, in part due to the lack of a P2Y<sub>2</sub>R overexpressing animal model. The P2Y<sub>2</sub>R overexpressing transgenic rat was generated using a lentiviral vector. Rats overexpressing P2Y<sub>2</sub>R showed a significant increase in P2Y<sub>2</sub>R mRNA levels in all tissues screened as compared to nontransgenic rats. Fura 2 imaging of smooth muscle cells (SMCs) isolated from aorta indicated that the percentage of cells exhibiting increases in the intracellular free calcium concentration in response to P2Y<sub>2</sub>R agonists was significantly greater in freshly isolated SMCs from transgenic rats than wild-type controls. Histopathological examination of tissues revealed that P2Y<sub>2</sub>R overexpressing rats develop lymphocytic infiltration in lacrimal glands and kidneys as early as at 3 months of age. These rats show similarities to patients with Sjögren’s syndrome who display lymphocyte-mediated tissue damage. This transgenic rat model of P2Y<sub>2</sub>R overexpression may prove useful for linking P2Y<sub>2</sub>R upregulation with chronic inflammatory diseases, neurodegenerative diseases and Sjögren’s syndrome.