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The endothelin (ET) system comprises a family of three isopeptides (ET-1, ET-2, and ET-3)involved in diverse physiological and pathophysiological events. ET-1 is the major renal peptide that exerts its biological activity by binding to ETA and ETB receptors. Both ETA and ETB receptors are expressed by renal microvascular smooth muscle cells, where activation causes vasoconstriction. ETB receptors are also expressed by microvascular endothelial cells, where activation leads to vasodilator responses. ET-1 influences preglomerular and postglomerular microvascular tone and thus can significantly influence renal hemodynamics. Alteration of renal ET-1 synthesis and receptor expression has been reported in cardiovascular diseases, and could contribute to renal injury by altering renal microvascular reactivity. In this brief review, we will try to summarize what is known about ET control of renal microvascular function.

Since endothelin (ET) was discovered in 1988 [1], three distinct ET isopeptides have been classified: ET-1, ET-2, and ET-3 [2]. Initially, ET was considered to be of endothelial origin. It is now clear that ET is synthesized and released from many vascular and nonvascular cell types, including renal epithelial cells [3-5]. ET-1 is the predominant isoform produced by the vasculature and is constitutively secreted from the endothelium, where it acts in a paracrine/autocrine manner on adjacent endothelial or vascular smooth muscle cells (VSMC). ET-1 is produced from big ET-1 catalyzed by ET-converting enzymes present in endothelial cells and is reportedly the most potent and long-lasting vasoconstrictor [1]. Approximately 80% of secreted ET-1 is released into the basolateral compartment, whereas only a limited amount of ET-1 enters the circulation [6]. Generally, plasma ET-1 concentrations range between 0.5 and 5 pm in healthy human subjects [4, 7]. Interestingly, levels of immunoreactive ET are higher in the kidney inner medulla than any other organ or tissue [8], implying an important physiological role for ET-1 in regulating renal function.

ET influences diverse physiological and pathophysiological mechanisms by activation of distinct ETA and ETB receptor subtypes [3-5]. In the vasculature, ETA and ETB receptors are expressed by VSMC, while endothelial cells mainly express ETB receptors. Activation of ETA and ETB receptors on VSMC increases intracellular Ca2+ concentration ([Ca2+]i), leading to increased vascular tone [4, 5]. Activation of endothelial ETB receptors stimulates release of nitric oxide (NO) and prostacyclin leading to vasodilatation [9]. Additionally, ETB receptors also serve as ‘clearance receptors’ to sequester ET-1 from the plasma [10, 11]. Accordingly, blockade or deletion of ETB receptors tends to elevate ET-1 levels. Competition-binding studies reveal that ETA and ETB receptors have different binding affinities for the three ET isoforms. ETA receptors have a higher affinity for ET-1 and ET-2, and a weaker affinity for ET-3. ETB receptors, on the other hand, display similar affinities for all three ET isopeptides [3]. These receptorbinding characteristics have been widely used to identify tissue distribution of receptors.

In the kidney, evidence indicates that ET-1 is produced locally and regulates renal hemodynamics by acting on preglomerular and postglomerular microvascular reactivity. ET-1 is also involved in sodium and water transport, and cell proliferation [4, 5]. Alteration of renal ET-1 levels and receptor expression are implicated in cardiovascular disease development. This review will focus on the role of ET peptides in the renal microcirculation.

Early studies using receptor-binding, immunocytochemical, and pharmacological tools revealed that almost every renal vascular and tubular cell type expresses ETA and/or ETB receptors, but the expression levels vary greatly between different regions of the kidney and across species [4, 5]. In the canine kidney, ETA and ETB receptor ratios average 22:78, 40:60, and 50:50 in cortical, medullary, and papillary membranes, respectively [12], while in rat kidneys, the regional ETA/ ETB receptor ratios were 50:50, 30:70, and 90:10, respectively [13]. ET receptors are expressed in high levels in the renal medulla, particularly in the inner medulla [14, 15]. Positron emission tomography makes it possible to quantify receptor concentration by measuring receptor-bound radioligands in vivo. This approach revealed that medullary ETB receptor expression is double that of the cortex in rabbit kidney [15]. Similarly, ETB receptor expression is nearly four times greater in the human renal medulla than in the cortex (33:9) [15], but the ETA/ETB receptor distribution is similar between the cortex and medulla (30:70) [16].

Little is known regarding how ETA and ETB receptors differentially influence renal vascular reactivity to ET-1. Most studies have employed pharmacological tools to determine the contribution of specific ET receptors in modulating renal microvascular function. Several studies conducted to localize ET receptor expression in renal vessels indicate that both ETA and ETB receptors are present in preglomerular and postglomerular microvessels [17-21]. ETA receptors are present in VSMC, while ETB receptors are mainly expressed in vascular and glomerular endothelial cells and are barely detectable in VSMC [17]. Radioligand-binding studies show that the proportion of ETA and ETB receptors in membranes of preglomerular vessels is 40:60 in rabbits [18] and 50:50 in rats [19]. In human kidneys, ETA receptors are present in the vasculature throughout the cortex and medulla, with low binding densities in vasa recta and glomeruli [20]. Renal and arcuate arteries express a high density of ETA receptors at 90-95% of total ET receptors [21]. Additionally, both ETA and ETB receptors are detected in rat vasa recta but they are located in pericytes and endothelial cells, respectively [17], implying that they might play different roles in regulating medullary perfusion.

The renal microcirculatory system is a unique portal circulation characterized by two independently regulated resistance vessels (afferent and efferent arterioles) in series straddling the glomerular capillaries. The endothelial cells release a variety of vasodilators and vasoconstrictors in response to physical and chemical stimuli, shear stress, or stretch. These vasoactive substances modulate the glomerular microcirculation through autocrine and/or paracrine mechanisms to influence afferent and efferent arteriolar resistance and hence renal hemodynamics. Thus, the balance of vascular resistance conferred by afferent and efferent arterioles is a crucial factor in determining overall glomerular hemodynamics.

A role for ET in regulating the renal microcirculation has been substantiated by numerous in vivo and in vitro studies in different animal models. The kidney is highly sensitive to exogenous ET-1 compared to other organs [22]. Almost all in vivo studies show that infusion of exogenous ET-1 produces a marked and prolonged renal vasoconstriction marked by profound reductions in renal blood flow (RBF) and glomerular filtration rate (GFR) reflecting increased renal vascular resistance [12, 23-31]. However, the relative contribution of ET receptors to the ET-1-mediated vasoconstriction is variable among species and results are controversial. In canine kidneys, ET-1-induced reduction of RBF and GFR was abolished by ETA receptor blockade [12], implicating ETA receptors in regulating renal vascular reactivity. Furthermore, infusion of a highly selective ETB receptor agonist, sarafotoxin 6c (S6c), markedly increased urine flow and sodium excretion, but had little effect on RBF and GFR [12], indicating that ETB receptors primarily regulate tubular transport compared to vascular function in dog kidneys. ET-1 is also a powerful vasoconstrictor in rabbit kidneys [25, 26]. Interestingly, however, ET-1-mediated decreases in rabbit RBF reflect cortical vasoconstriction because medullary perfusion reportedly either increased [26] or did not change [32] during ET-1 infusion. ET-1-induced reduction of cortical perfusion was attenuated by ETA receptor blockade, but enhanced by ETB receptor blockade [26]. These studies indicate that ET-1-induced renal vasoconstriction in dogs and rabbits is primarily mediated by ETA receptors.

In contrast to dogs and rabbits, many in vivo studies in rats indicate that both ETA and ETB receptors mediate renal vasoconstriction induced by ET-1, but ETB receptors may play a more prominent role [27-31]. Intravenous infusion of ET-1 in anesthetized rats usually decreases RBF and GFR. This is accompanied by a transient reduction in blood pressure followed by a sustained pressor response. ETA receptor antagonists abrogated the pressor effects of ET-1, but had little effect on the renal hemodynamic response [27, 31]. Others have shown that ET-1 and the ETB receptor ligand or agonist (ET-3 or S6c) elicited a similar reduction in RBF [28, 30, 31]. The ET-1-induced reduction of RBF was partially blocked by ETA receptor antagonists and completely abolished by combined ETA/B receptor blockade [30, 31]. Similar to observations in rabbits, ET-1-mediated reduction of RBF results from cortical vasoconstriction because medullary blood flow remained unchanged [33] or increased [34, 35]. Collectively, these findings indicate that both ETA and ETB receptors are involved in the renal microvascular response to ET-1, but ETB receptors play a predominant role in rats. Moreover, the ability of ET-1 to decrease RBF was exaggerated by selective ETB receptor blockade with BQ-788 [30], suggesting that ET-1 elicits both vasoconstrictor and vasodilator effects. The vasodilator component could reflect ETB receptordependent release of vasodilators or reduced ET-1 clearance due to ETB receptor blockade.

While the whole kidney studies provide in vivo evidence supporting ET-1 as a regulator of renal vascular reactivity, the data are often confounded by concomitant changes in mean arterial pressure and released circulating factors. Furthermore, the distribution of ETA and ETB receptors in different microvascular segments compromises interpretation of which ET receptors are responsible for ET-1's overall effect and to what degree they contribute to ET-1-induced alteration of renal hemodynamics. Accordingly, many in vitro models have been used to provide site-specific information. Studies have frequently utilized partially resected kidney models, with or without hydronephrosis, or isolated renal microvessels to directly visualize ET's effects on afferent and efferent arteriolar diameters.

The in vitro blood-perfused juxtamedullary nephron preparation is frequently used for direct assessment of renal microvascular reactivity while maintaining an intact association between the vascular and tubular elements [36]. ET-1, ET-2, and ET-3 all evoke concentration-dependent vasoconstriction of afferent and efferent arterioles (fig. 1) [37-40]. ET-1 vasoconstricts afferent and efferent arterioles at concentrations of 1 and 10 pM, respectively [38]. ET-1 vasoconstricted afferent arterioles more effectively than efferent arterioles such that the afferent diameter declined by 83% of the control compared to 67% for efferent arterioles at a concentration of 10 nM. Similar to ET-1, ET-3 also yielded a greater vasoconstrictor response in afferent than efferent arterioles. ET-2, however, elicited similar degrees of vasoconstriction for afferent and efferent arterioles. The ET-1 concentration curve in afferent arterioles was significantly shifted to the right by pretreatment with ETA or ETB receptor blockers and was completely abolished by combined ETA/B blockers, indicating the vasoconstrictor property of both ET receptors at preglomerular microvessels. In contrast, ETA receptor blockade in efferent arterioles converted ET-1-induced vasoconstriction to vasodilation at low concentrations (0.01-0.1 nm) while vasoconstriction was retained at higher concentrations (1-10 nm), suggesting that ETB receptors can elicit vasodilation and vasoconstriction of efferent arterioles. The dual effect of ETB receptors in efferent arterioles was confirmed using S6c, which yielded efferent arteriolar vasodilation under control conditions but vasoconstriction during ETB receptor blockade with A-192621 [38]. These observations suggest that during ETA receptor blockade, low ET-1 concentrations mainly stimulate endothelial ETB receptors, probably by releasing NO or prostacyclin, while higher concentrations of ET-1 shift to activating ETB receptors on VSMC in efferent arterioles.

Fig. 1.
Renal microvascular responses to ET peptides. Kidneys were superfused with increasing concentrations of ET-1 (a), ET-2 (b), or ET-3 (c) from 1.0 pM to 10 nM (5 min for each concentration), while perfusion pressure was maintained at 100 mm Hg. Afferent arteriolar diameters (black symbols) and efferent arteriolar diameters (gray symbols) were measured at 12-second intervals and calculated from the average of all measurements obtained during the final 2 min of each 5-min treatment period. Data are expressed as percent of the control diameter. Values are means ± SEM. *p < 0.05 vs. control diameter in same group; † p < 0.05 vs. control rats at same perfusion pressure. Adapted from Inscho et al. [38].
Fig. 1.
Renal microvascular responses to ET peptides. Kidneys were superfused with increasing concentrations of ET-1 (a), ET-2 (b), or ET-3 (c) from 1.0 pM to 10 nM (5 min for each concentration), while perfusion pressure was maintained at 100 mm Hg. Afferent arteriolar diameters (black symbols) and efferent arteriolar diameters (gray symbols) were measured at 12-second intervals and calculated from the average of all measurements obtained during the final 2 min of each 5-min treatment period. Data are expressed as percent of the control diameter. Values are means ± SEM. *p < 0.05 vs. control diameter in same group; † p < 0.05 vs. control rats at same perfusion pressure. Adapted from Inscho et al. [38].
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Preferential ET-1-mediated vasoconstriction of rat afferent arterioles has been demonstrated using different experimental approaches [24, 31, 41-43]. For example, micropuncture studies in Munich-Wistar rats showed that ET-1 reduced single nephron GFR with significant increases in afferent and efferent arteriolar resistance, but particularly in afferent arterioles [41]. This is consistent with studies in hydronephrotic rat kidneys showing that ET-1 caused substantial afferent arteriolar vasoconstriction but only modest efferent arteriolar vasoconstriction [24, 42]. Alternatively, other studies have indicated that efferent arterioles are more sensitive to ET-1 than afferent arterioles [23, 44]. Glomerular capillary pressure, as assessed by measuring stop-flow pressure, was significantly increased in response to ET, which was associated with a greater increase in efferent arteriolar resistance than in afferent arteriolar resistance [23]. Studies in isolated-perfused microvessels showed that the EC50 of ET-1 was lower in efferent arterioles (5.7 pm) compared to afferent arterioles (52 pm) [44], suggesting that ET-1 is a more potent vasoconstrictor of efferent arterioles. The explanation for the discrepancies among these studies is unclear, but may reflect differences between experimental conditions.

The aforementioned studies of ET-1 on renal microvascular reactivity mostly employed pharmacological tools to establish the contribution of ET receptors. Genetic approaches provide useful strategies to determine specific gene or protein functions. Although several ET-1 or ETB receptor knockout mouse models have been developed, only one study has been conducted to assess the distribution of ET receptors in ET-1-induced renal microvascular responsiveness in vascular ETB receptor-deficient mice and wild-type control mice [45]. The results obtained from isolated-perfused renal microvessels indicate that ET-1 more potently vasoconstricts afferent arterioles compared to efferent arterioles. Furthermore, ET-1-induced vasoconstriction involves activation of ETA receptors in afferent arterioles, but involves both ETA and ETB receptors in efferent arterioles [45]. The relative contribution of ET receptors in ET-1-induced responses in mouse renal microvessels is different from rats. Interestingly, endothelium-specific ET-1 knockout mice exhibit 10- to 12-mm Hg lower mean arterial pressure [46], suggesting a pivotal role of endogenous endothelium- derived ET receptor system in control of blood pressure and maintenance of vascular tone under physiological conditions. How these changes affect renal hemodynamics remains to be determined.

Medullary perfusion is supplied by descending vasa recta (DVR) arising from juxtamedullary efferent arterioles [47]. Given the potent vasoconstrictor effect of ET-1 in juxtamedullary nephron microvasculature and expression of ETA and ETB receptors in vasa recta [17], it is not surprising that ET is also involved in regulating medullary microcirculation. Elegant studies using isolated-perfused DVR establish ET as a potent vasoconstrictor of DVR [47]. ET-1, ET-2, and ET-3 elicit potent vasoconstriction with a rank order of potency of ET-1>ET-2>ET-3. DVR diameter started to decrease with 0.01 pmET-1 and almost completely collapsed at 100 pm. ET-1-induced vasoconstriction was attenuated by an ETA antagonist or a mixed ETA/B receptor antagonist, whereas ET-3-induced vasoconstriction was only blocked by an ETB receptor antagonist, suggesting the dual involvement of ETA and ETB receptors. These observations, however, seem to contradict rabbit studies where infusion of ET-1 increases medullary blood flow with concurrent reduction in total RBF and cortical blood flow [26]. Conflicting outcomes probably reflect species variation (rats vs. rabbits) and different experimental conditions (in vitro vs. in vivo). The intense vasoconstriction of DVR by ET-1 suggests a potentially important role of ET-1 for the development of renal injury in cases where the renal ET system is upregulated [47].

While both in vivo and in vitro studies provide compelling evidence that ET-1 regulates renal hemodynamics by influencing preglomerular and postglomerular microvascular tone, there is conflicting evidence establishing that ET-1 regulates renal vascular tone under basal conditions. Infusion of ETA receptor antagonists did not change RBF or GFR in conscious rats [9, 27, 48], implying that ETA receptors may not regulate renal hemodynamics under basal conditions. In contrast, combined ETA/B receptor blockade with bosentan markedly reduced glomerular capillary pressure with a significant increase in preglomerular resistance while postglomerular resistance remained unchanged [48]. ETB receptor blockade with RES-701-1 or BQ-788 significantly decreased RBF without affecting arterial blood pressure [9, 29]. Reduction of RBF was prevented by pretreatment with l-NAME (NO synthase inhibitor) and ibuprofen (cyclooxygenase inhibitor). These findings suggest that endogenous ET-1 contributes to basal renal vascular resistance by ETB receptor-dependent release of NO and/or prostacyclin. Overall, these studies imply that ETB receptor-mediated vasodilation may influence renal microcirculatory function under physiological conditions. For example, exogenous ET-1 or S6c normally vasoconstricts normal rat afferent arterioles [38]; however, when rats are fed a high-salt diet, ET-1 and S6c-mediated vasoconstriction is attenuated and even converted to vasodilation at low ET-1 concentrations. ETB receptor expression in preglomerular microvessels is increased during salt loading [40]. Accordingly, salt-induced upregulation of ETB receptor expression may counteract ETA and ETB receptor activation in VSMC and facilitate sodium excretion by increasing RBF. The physiological mechanisms behind salt-induced increases in ETB receptor expression need further investigation.

Autoregulation is an important mechanism protecting selected organs against injury from variations in arterial pressure. This protective mechanism is accomplished in the kidney by precise pressure-mediated adjustments of preglomerular resistance via myogenic and tubuloglomerular feedback responses [49]. Although earlier studies indicated that ET-1 was not involved in renal autoregulation [50, 51], recent studies suggest that ET-1 might interact with NO in modulating or resetting renal autoregulation [52, 53]. l-NAME augmentation of autoregulation was eliminated by the nonselective ETA/B receptor antagonist bosentan or the ETB receptor blocker BQ-788 [52]. A subsequent study by Shi et al. [53] showed that myogenic reactivity was significantly impaired by pretreatment with BQ-788, suggesting that ET-1 may be involved in resetting renal autoregulation by release of NO via ETB receptor stimulation. Interestingly, exposure of macula densa cells to ET-1 caused a rapid increase of signal-nephron GFR, a measure of tubuloglomerular feedback responsiveness, without changes in systemic and renal hemodynamics [54]. This study suggests that ET-1 may influence tubuloglomerular feedback responses, but the mechanism(s) underlying this is (are) unclear.

Both ETA and ETB receptors belong to the G protein-coupled receptor family. ET receptor activation is coupled to many second messenger pathways including phospholipase C, phospholipase D, protein kinase C, mitogen-activated protein kinases, cytosolic Ca2+, and tyrosine kinase [4, 5]. Application of ET-1 to VSMC increases [Ca2+]i via influx of extracellular Ca2+ and mobilization of Ca2+ from intracellular stores [55]. ETA receptors are coupled with activation of phospholipase C to generate diacylglycerol and inositol triphosphate, which in turn stimulates Ca2+ release from intracellular stores, ultimately causing vasoconstriction (fig. 2). In contrast, activation of ETB receptors in endothelial cells stimulates release of NO and/or prostacyclin, which increase cGMP and cAMP formation, leading to vasodilation. Downstream signaling of ETB receptor activation in VSMC still remains uncertain.

Fig. 2.
Intracellular ET pathway in renal preglomerular microvessels. ET-1 is produced from big ET-1 catalyzed by the ET-converting enzyme from endothelial cells. Activation of ETA receptors in VSMC increases intracellular calcium concentration ([Ca2+]i) via influx of extracellular Ca2+ through activating L-type voltage-dependent Ca2+ channels (L-VDCC) and mobilization of Ca2+ from sarcoplasmic reticulum (SR) through activating inositol triphosphate (IP3) pathway and cyclic adenine diphosphate ribose (cADPR) cyclase/ryanodine receptor (RyR) pathways. Activation of endothelial ETB receptors releases NO and prostaglandins (PGs), causing vasodilation. Activation of ETB receptors in vascular smooth muscle cells mediates vasoconstriction via as yet undefined intracellular mechanisms (dashed line).
Fig. 2.
Intracellular ET pathway in renal preglomerular microvessels. ET-1 is produced from big ET-1 catalyzed by the ET-converting enzyme from endothelial cells. Activation of ETA receptors in VSMC increases intracellular calcium concentration ([Ca2+]i) via influx of extracellular Ca2+ through activating L-type voltage-dependent Ca2+ channels (L-VDCC) and mobilization of Ca2+ from sarcoplasmic reticulum (SR) through activating inositol triphosphate (IP3) pathway and cyclic adenine diphosphate ribose (cADPR) cyclase/ryanodine receptor (RyR) pathways. Activation of endothelial ETB receptors releases NO and prostaglandins (PGs), causing vasodilation. Activation of ETB receptors in vascular smooth muscle cells mediates vasoconstriction via as yet undefined intracellular mechanisms (dashed line).
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In the kidney, L-type voltage-dependent Ca2+ channels (L-VDCC) are important for regulating basal vascular tone and preglomerular microvascular responses to many vasoconstrictors [49]. However, there are conflicting results whether ET-1-induced vasoconstriction involves L-VDCC signaling. Several in vivo and in vitro studies indicate that L-VDCC blockade has little effect on ET-1 or ETB receptor-mediated renal vasoconstriction [39, 55, 56], while others found that ET-1-induced renal vasoconstriction is via L-VDCC-dependent influx of extracellular Ca2+ [57-59], specifically in afferent arterioles but not in efferent arterioles [24, 60]. Studies in freshly isolated preglomerular microvascular VSMC found that ET-1 evoked a biphasic increase in [Ca2+]i, with a rapid initial increase followed by a sustained plateau [55]. The sustained plateau was eliminated by superfusion with Ca2+-free medium while the initial peak was unaltered, indicating that ET-1 increases [Ca2+]i in preglomerular microvascular VSMC by stimulating Ca2+ release from intracellular stores and Ca2+ influx from extracellular fluid. In contrast, ET-3 or S6c only evoked small and monophasic increases in [Ca2+]i [39, 55]. Subsequent studies revealed that ET-1-induced increases in [Ca2+]i were unchanged by blockade of L-VDCC with diltilazem or Ni2+. This was confirmed with both in vivo and in vitro studies. Nifedipine only slightly attenuated the reduction of RBF when ET-1 or S6c were applied at very high doses, while ET-1-induced juxtamedullary afferent arteriolar vasoconstriction was slightly inhibited by diltilazem only at very low ET-1 concentrations (1 and 10 pm) [39]. Although L-VDCC inhibition led to slightly different observations in these two experimental settings, the results suggest that L-VDCC do not play a critical role in ET-1 and ETB receptor-mediated afferent arteriolar vasoconstriction in rats. Alternatively, studies in hydronephrotic rat kidney showed that nifedipine completely eliminated ET-1-induced afferent arteriolar vasoconstriction, indicating a prominent role for L-VDCC in ET-1-mediated afferent arteriolar responses [24].

Recent studies indicate that cyclic adenine diphosphate ribose (cADPR) cyclase/ryanodine receptor-mediated Ca2+ signaling pathways contribute to ET-1-mediated vasoconstriction in afferent arterioles [61, 62]. Blockade of ribosyl cyclase with nicotinamide reduced ET-1-mediated [Ca2+]i signaling by 60% in rat preglomerular microvascular VSMC. This effect is largely due to stimulation of NADPH oxidase by ET-1 via ETA receptor activation because application of tempol, apocynin, or a specific cADPR cyclase inhibitor attenuated [Ca2+] i signaling induced by ET-1 but not by S6c [61]. The finding of cADPR and RyR signaling in ET-1-induced renal microvasoconstriction was further demonstrated in vivo as well as in the mice lacking the major mammalian ADPR cyclase (CD38-/-) [62]. These studies suggest that the superoxide-NADPH oxidase pathway contributes to the preglomerular microvascular response to ET-1 through cADPR.

Additionally, other studies suggest that activation of ETA and ETB receptors in the renal microvasculature are also coupled with a variety of second messenger pathways such as cytochrome P-450 metabolites [37], RhoA/Rho-kinase pathway [63], reactive oxygen species [64], and NO [65]. The role of prostacyclin in ET-1 responses is controversial. Some have reported that ET receptor activation is coupled to prostacyclin [66, 67], whereas others found that ET-1-mediated vasoconstriction was unaffected by COX inhibition [65, 68, 69] or that ET-1 stimulated a vasoconstrictor cyclooxygenase metabolite [70]. Interested readers are referred to some recent excellent reviews which provide more comprehensive discussions of the ET-1-mediated intracellular pathways in renal and nonrenal vascular beds [4, 5, 71, 72].

Since discovery of this powerful vasoconstrictor released from the endothelium, activation of the ET system has been reported in a number of models of endothelial dysfunction, including hypertension [5]. Impaired renal vasodilation has been suggested as one of the mechanisms initiating salt-sensitive hypertension [73]. Studies in Dahl salt-sensitive hypertensive rats showed increased vascular and renal ET-1 protein content and impaired endothelium-dependent renal vasodilation. Treatment with an ETA receptor antagonist not only prevented activation of tissue ET-1, but also prevented renal artery injury and endothelial dysfunction, suggesting that ETA receptor-dependent increases in renal ET-1 level contributes to renal vascular injury in Dahl salt-sensitive hypertensive rats [74]. Together, these studies indicate an important role of ET-1 in mediating endothelial injury and development of hypertensive renal injury. The precise roles of ET-1 in hypertension, however, are still under investigation.

Collectively, ET-1-mediated vasoconstriction of afferent arterioles is coupled with activation of ETA and ETB receptors with a predominant role of ETA receptors in dogs, rabbits, and mice, and a predominant role of ETB receptors in rats. ET-1-mediated vasoresponsiveness in efferent arterioles seems to be exclusively coupled to ETB receptors, except in mice. Low ET-1 concentrations activate endothelial ETB receptors leading to vasodilation, while high ET-1 concentrations activate ETB receptors expressed in VSMC evoking vasoconstriction. Additionally, endogenous ET-1 may contribute to control of basal renal vascular resistance via vasodilator influence of ETB receptors in rats. The magnitude of ET-1-mediated vasoresponsiveness depends upon the segmental distribution of ET receptor expression as well as species variation. Different responses of afferent and efferent arterioles to ET-1 may certainly have a distinct impact on glomerular capillary pressure and hence alter glomerular hemodynamics. Any changes in ET receptor expression or renal ET-1 levels may play a crucial role in renal injury under pathological conditions by impairing renal hemodynamics.

The authors would like to acknowledge grant support from National Institutes of Health (PO1 HL095499) for E.W. Inscho and the American Heart Association (10SDG3770010) for Z. Guan.

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