Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure.

Abstract

Dopamine D2 receptor (DRD2) deficiency increases renal inflammation and blood pressure in mice. We show here that long-term renal-selective silencing of <i>Drd2</i> using siRNA increases renal expression of proinflammatory and profibrotic factors and blood pressure in mice. To determine the effects of renal-selective rescue of <i>Drd2</i> expression in mice, the renal expression of DRD2 was first silenced using siRNA and 14 days later rescued by retrograde renal infusion of adeno-associated virus (AAV) vector with <i>DRD2</i>. Renal <i>Drd2</i> siRNA treatment decreased the renal expression of DRD2 protein by 55%, and <i>DRD2</i> AAV treatment increased the renal expression of DRD2 protein by 7.5- to 10-fold. Renal-selective <i>DRD2</i> rescue reduced the expression of proinflammatory factors and kidney injury, preserved renal function, and normalized systolic and diastolic blood pressure. These results demonstrate that the deleterious effects of renal-selective <i>Drd2</i> silencing on renal function and blood pressure were rescued by renal-selective overexpression of <i>DRD2</i>. Moreover, the deleterious effects of 45-minute bilateral ischemia/reperfusion on renal function and blood pressure in mice were ameliorated by a renal-selective increase in DRD2 expression by the retrograde ureteral infusion of <i>DRD2</i> AAV immediately after the induction of ischemia/reperfusion injury. Thus, 14 days after ischemia/reperfusion injury, the renal expression of profibrotic factors, serum creatinine, and blood pressure were lower in mice infused with <i>DRD2</i> AAV than in those infused with control AAV. These results indicate an important role of renal DRD2 in limiting renal injury and preserving normal renal function and blood pressure.