Abstract 450: Dopamine D2 receptors regulate Wnt signaling in the kidney.
We have already reported that dopamine D2 receptors (D2R) are involved in the regulation of blood pressure and renal inflammation. In mice selective renal Drd2 silencing by subcapsular infusion of D2R siRNA for 7 days does not affect blood pressure but results in increased expression of inflammatory factors in the renal cortex, glomerulosclerosis, tubular epithelial degeneration, tubular dilation and cast formation, as well as increased expression of pro-apoptotic caspase-1 (1.34±0.02 fold; qRT-PCR n=5/ group, P<0.05) and decreased expression of the anti-apoptotic factors, Bcl2a (0.71±0.02 fold; P<0.05) and survivin (0.57±0.02 fold; P<0.03) in the D2R siRNA infused kidneys compared to those infused with non-silencing siRNA (NS siRNA). We hypothesized that some of this alterations are mediated by the Wnt pathway that is involved in cell survival and the development of fibrosis in the kidney. The expression of Wnt 3 (4.8±0.1 fold; n=3; P<0.05), and Wnt 5 (1.5±0.03 fold; P<0.05) was increased in the infused kidney, as well as that of the downstream targets Dkk1 (Dickkopf 1 homolog; 1.7±0.05 fold; P<0.05), Wisp1 (WNT1 induced secreted protein 1, 2.3±0.05 fold; P<0.05), Sfrp2 (secreted frizzled-related protein 2;1.9±0.10 fold; P<0.05), Fn1 (fibronectin 1; 1.3±0.03 fold; P<0.05), and TGFβ (1.6±0.04 fold; P<0.05). Silencing of Drd2 (siRNA, 30 nM, 72 h) in mouse renal proximal tubule cells (mPTCs) also increased significantly the expression of Wnt3, Wnt5, Wisp1, Dkk1, and Sfrp2. In contrast D2R stimulationin mPTCs (quinpirole, 1μM,24 h) decreased the expression of Wnt3, Wnt 5 and their targets. Our results indicate that D2R function is important in the regulation of the Wnt pathway and that the alterations in D2R function result in profound modifications in the pathway potentially leading to cell death and fibrosis and hypertension.
- © 2012 by American Heart Association, Inc.