Renal dopamine receptors and hypertension

The spontaneously hypertensive rat (SHR) is a widely used genetic animal model of chronic hypertension, and is created by selective inbreeding of Wistar–Kyoto (WKY) rats. It is normotensive at birth and gradually develops hypertension in the first 2–4 months of life. It also develops end-organ damage which displays some similarities to human hypertension. Because of these characteristics, it is widely studied as a model (albeit very approximate) of human essential hypertension, and may give insights into the pathophysiology of this, with the caveat that such insights require further study and confirmation in humans. Renal transplantation experiments have demonstrated that if an SHR kidney is placed in a WKY rat, the WKY rat becomes hypertensive; by contrast, if a WKY rat kidney is transplanted into an SHR, the blood pressure of the SHR decreases [1,2]. Such experiments demonstrate the important pathogenetic role of the kidney in the development of hypertension in this rat model. In young SHR, there is an increase in salt and water retention, which is attributable to a decrease in glomerular filtration rate and to a reduction in both total and fractional urinary sodium excretion [3]. Isolated, perfused proximal tubules of young SHR reabsorb more sodium than do those from WKY rats, even before the development of hypertension [4–6]. The possible reasons for this have been the subject of much research, and it is clear that changes in dopaminergic signalling may play an important role in the observed abnormalities in renal sodium handling. Dopamine has long been known to be a key regulator of renal sodium excretion. As long ago as 1964, dopamine was observed to cause natriuresis and diuresis in humans [7]. Five genetically distinct dopamine receptors have been identified to date, and more may yet be discovered. They are classified into two major families, termed D1-like (D1 and D5, whose rat homologues are D1A and D1B) and D2-like (D2, D3 and D4); these families mediate the stimulation and inhibition, respectively, of adenylyl cyclase [8]. In the kidney, D1-like receptors are well represented, and D1-like agonists increase renal blood flow and glomerular filtration rate, as well as urinary excretion of sodium and water [9,10]. In the proximal tubule of the kidney, stimulation of these receptors inhibits the activity of the Na+/K+-ATPase and the Na+/H+ exchanger; additionally, there is recent evidence that their stimulation can also inhibit the Na+/HCO3– cotransporter in renal proximal tubules [11]. These effects of dopamine, mediated through D1-like receptors, are all blunted in the SHR, and this may be related to defective coupling between the receptors and Gsα protein [12–14]. The role of D2-like receptors in the kidney, both in health and in hypertension, is much less well defined. They are known to be present in normal rat kidney [15–17], and interactions between D1-like and D2-like receptors are impaired in the SHR [18,19], which may contribute to the observed increase in sodium retention. However, precise data on the localization of different D2-like receptor subtypes in the rat kidney, as well as alterations in D2-like receptor distribution in the SHR, have been lacking. In this issue of the journal, Shin et al. [20] investigated the expression and distribution of D2-like receptors in both SHR and WKY rats, using a combination of Western blot analysis and confocal immunocytochemistry. They report no change in D2 receptors between SHR and WKY rats, whereas there is reduced expression of D3 receptors coupled with increased expression of D4 receptors in the renal cortex of the SHR compared to WKY rats. Their data are interesting and, in the future, it will be useful to determine whether these changes in receptor distribution and expression correlate with identifiable functional changes in D3 and/or D4 receptor function in the SHR kidney. What remains unclear from this and other studies is whether the abnormalities seen in the SHR in dopamine receptor expression, distribution and function are causative to the hypertension, or are the result of it. Are similar changes seen in other models of hypertension (e.g. the Dahl salt-sensitive rat and the deoxycorticosterone acetate-salt rat?). In the case of the SHR, does treatment with anti-hypertensive agents from an early age prevent these changes occurring? The answers to these questions will help to clarify the role of dopamine and its receptors in the causation of hypertension, at least in the rat. It also remains to be seen whether the findings in this and other studies concerning dopamine receptors in rat hypertensive kidneys can be replicated in humans. Data concerning renal dopamine receptors in human hypertension are scarce. One study has described an upregulation in D1-like receptor function in the distal tubules (but not proximal tubules) of hypertensive humans [21]. A defect in the coupling of D1-like receptors to adenylyl cyclase has also been reported in primary cultured cells of proximal tubules of patients with hypertension, which may be explained by serine phosphorylation of these receptors in hypertensives [22]. Genetic studies have found associations between hypertension and the non-coding region of the D1 receptor gene [23], the D5 receptor locus [24] and a polymorphism of the D2 receptor [25]. The expression and function of D2-like receptors in the kidney of humans with essential hypertension remains unknown. The findings presented by Shin et al. [20] should prompt their further study.