Abstract 052: Role of Dopamine D2 Receptors in The Regulation of Cell Proliferation in Renal Injury

Abstract

The dopamine D2 receptor (D2R) in the kidney has a direct and significant role in blood pressure (BP) control and in negatively regulating the mechanisms involved in the development of inflammation and injury. Impaired D2R function results in renal inflammation and end organ damage. Injury to the kidney triggers a cell proliferation response that can be adaptive, leading to repair of the tubular epithelium, or maladaptive, leading to fibrosis and chronic kidney disease. We investigated the role of renal D2Rs in the cell proliferation response in models of renal injury in mice and human renal proximal tubule cells (hRPTCs). Renal selective silencing of the D2R in mice resulted in an increase in the mRNA expression of the proliferation marker Ki-67 (2.8±0.8 vs 1.0±0.1 fold; qRT-PCR; P<0.05; n=4-5) along with an increase in the number of proliferating cells in renal cortical slices determined by nuclear Ki-67 staining (36±3 vs 6±1; positive cells/ field; P<0.05) in comparison with mice with no silencing. Rescue of D2R function in these mice by the ureteral infusion of AAV carrying a D2R vector reduced the expression of cortical Ki-67 mRNA (42±3 vs 100±5 %; P<0.05; n=4) and the number of positive cells/field (16±2 vs 32±5; P<0.05) in comparison with mice treated with a control AAV. In mice subjected to renal ischemia reperfusion KI-67 mRNA expression was higher (1.5±0.03 vs 1.0±0.05 fold; P<0.05; n=3-4) than in mice with sham operation. Treatment with AAV carrying D2R after ischemic injury reduced Ki-67 expression (0.65±0.05 vs 1±0.1; P<0.05) and the number of Ki-67 positive cells in kidney sections. Rescue of function or D2R overexpression reduced tissue damage, fibrosis and the increase in BP in these models. Treatment of hRPTCs with the nephrotoxic, aristolochic acid (5 μg/ml, 24h), increased mRNA Ki-67 expression (2.8±0.2 fold; P<0.05) in comparison with cells treated with vehicle while the presence in the medium of a D2R agonist, quinpirole (1μM, 24h), reduced the increase by 42%. The D2R agonist also reduced the increase in fibronectin 1 and collagen 1a1 elicited by aristolochic acid. Our data suggest that regulation of cell proliferation is one of the mechanisms involved in the protective effect of D2R function on renal inflammation and injury.