Abstract 16703: Regulation of Cell Proliferation in Renal Injury by Dopamine D2 Receptors

Abstract

Introduction: Genetic factors contribute to the susceptibility to chronic renal disease associated with essential hypertension. The renal dopamine D2 receptor (D2R) has a significant role in blood pressure (BP) control and in negative regulation of the development of inflammation and injury. Several common single nucleotide polymorphisms of the human DRD2 gene are associated with decreased D2R expression and function. Impaired D2R function results in renal inflammation and end-organ damage. Injury to the kidney triggers a cell proliferation response that can be either adaptive, leading to repair of the tubular epithelium, or maladaptive, leading to fibrosis and chronic kidney disease. Hypothesis: We tested the role of renal D2Rs in the cell proliferation response Methods: We used models of renal injury in mice and human renal proximal tubule cells (hRPTCs) Results: 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. Renal tubule-selective rescue of D2R function in these mice by the ureteral infusion of AAV carrying D2R 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. Renal tubule 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 renal tubule-selective 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 (2.8±0.2 fold; P<0.05; n=4-5) in comparison with cells treated with vehicle while the presence of a D2R agonist, quinpirole (1μM, 24h), in the medium reduced the increase by 42% and also reduced the increase in fibronectin 1 and collagen 1a1 elicited by aristolochic acid Conclusions: 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.