Sorting nexin 1 loss results in D5 dopamine receptor dysfunction in human renal proximal tubule cells and hypertension in mice.

The peripheral dopaminergic system plays a crucial role in blood pressure regulation through its actions on renal hemodynamics and epithelial ion transport. The dopamine D5 receptor (D(5)R) interacts with sorting nexin 1 (SNX1), a protein involved in receptor retrieval from the trans-Golgi network. In this report, we elucidated the spatial, temporal, and functional significance of this interaction in human renal proximal tubule cells and HEK293 cells stably expressing human D(5)R and in mice. Silencing of SNX1 expression via RNAi resulted in the failure of D(5)R to internalize and bind GTP, blunting of the agonist-induced increase in cAMP production and decrease in sodium transport, and up-regulation of angiotensin II receptor expression, of which expression was previously shown to be negatively regulated by D(5)R. Moreover, siRNA-mediated depletion of renal SNX1 in C57BL/6J and BALB/cJ mice resulted in increased blood pressure and blunted natriuretic response to agonist in salt-loaded BALB/cJ mice. These data demonstrate a crucial role for SNX1 in D(5)R trafficking and that SNX1 depletion results in D(5)R dysfunction and thus may represent a novel mechanism for the pathogenesis of essential hypertension.

Sorting nexin 5 and dopamine d1 receptor regulate the expression of the insulin receptor in human renal proximal tubule cells.

Sorting nexin 5 (SNX5) belongs to the SNX family, which is composed of a diverse group of proteins that mediate trafficking of plasma membrane proteins, receptors, and transporters. SNX5 is important in the resensitization of the dopamine D1-like receptor (D1R). D1R is uncoupled from its effector proteins in hypertension and diabetes, and treatment of diabetes restores D1R function and insulin receptor (IR) expression. We tested the hypothesis that the D1R and SNX5 regulate IR by studying the expression, distribution, dynamics, and functional consequences of their interaction in human renal proximal tubule cells (hRPTCs). D1R, SNX5, and IR were expressed and colocalized in the brush border of RPTs. Insulin promoted the colocalization of SNX5 and IR at the perinuclear area of hRPTCs. Unlike SNX5, the D1R colocalized and coimmunoprecipitated with IR, and this interaction was enhanced by insulin. To evaluate the role of SNX5 and D1R on IR signaling, we silenced via RNA interference the endogenous expression of SNX5 or the D1R gene DRD1 in hRPTCs. We observed a decrease in IR expression and abundance of phosphorylated IR substrate and phosphorylated protein kinase B, which are crucial components of the IR signal transduction pathway. Our data indicate that SNX5 and D1R are necessary for normal IR expression and activity. It is conceivable that D1R and SNX5 may interact to increase the sensitivity to insulin via a positive regulation of IR and insulin signaling.

Neonatal blood pressure regulation.

Hypertension is often viewed solely as a disease of the adult. However, early indicators of hypertension are frequently observed in young children and neonates. Having an adequate appreciation of the normal range of infant blood pressure is critical for the appropriate management of the conditions associated with elevated or abnormally low blood pressure. In healthy neonates, systolic blood pressure increases rapidly during the first 6 weeks of life with the most rapid rise observed during the first 5 days. A similar pattern is observed for diastolic pressures. The observed increases in blood pressure are positively correlated with birth weight and both gestational and postnatal age. The incidence of hypertension in the neonate has been reported to range from 0.2% to 2.6% and is frequently an indicator of other renal or cardiovascular abnormalities. Systemic hypotension is reported in 24% to 45% of very low birth weight infants and is frequently caused by hypovolemia. The regulation of blood pressure is complex and the mechanisms involved remain to be fully elucidated. The results of several investigations into the molecular mechanism(s) of hypertension are considered.

Mechanisms of fetal programming in hypertension.

Events that occur in the early fetal environment have been linked to long-term health and lifespan consequences in the adult. Intrauterine growth restriction (IUGR), which may occur as a result of nutrient insufficiency, exposure to hormones, or disruptions in placental structure or function, may induce the fetus to alter its developmental program in order to adapt to the new conditions. IUGR may result in a decrease in the expression of genes that are responsible for nephrogenesis as nutrients are rerouted to the development of more essential organs. Fetal survival under these conditions often results in low birth weight and a deficit in nephron endowment, which are associated with hypertension in adults. Interestingly, male IUGR offspring appear to be more severely affected than females, suggesting that sex hormones may be involved. The processes of fetal programming of hypertension are complex, and we are only beginning to understand the underlying mechanisms.

Hypertension in young children and neonates.

Hypertension is most often considered a disease of old age, but the precursors are often present in young children long before the clinically accepted definitions of hypertension in the adult are manifested. Essential hypertension is by far the most common form of the disease, comprising a complex interaction of genetic and environmental factors. Many individual genes that play a role in the maintenance of blood pressure have been identified; however, none has been shown specifically to be a component of essential hypertension. Hypertension is among the leading risk factors for coronary heart disease, stroke, and end-stage renal disease, making it critically important to identify individuals at risk early in life prior to manifestation of clinical signs and symptoms.