5.1. Interstitial and Tubular Angiotensin II
Intrarenal Ang II is not distributed in a homogenous fashion but is compartmentalized in both regional and segmental manners (121). Earlier studies indicated that medullary Ang II-levels are higher than the cortical levels in normal rats and increase further in Ang II infused hypertensive rats (81). The combination of high Ang II levels in the medulla coupled with the high density of Ang II receptors suggest that Ang II exerts a major role in regulating hemodynamics and tubular function in the medulla (2,114). The higher Ang II levels in the medulla suggest that there may be specialized Ang II forming pathways or accumulation mechanisms in medullary tissues that are subject to local regulation. However, Ingert et al. (26,122) failed to confirm that medullary Ang II contents are higher than cortical Ang II contents. These authors found that Ang I and Ang II
levels in cortex and medulla are equivalent and respond in a similar manner to alterations in dietary salt intake.
Within the cortex, there is a distribution of Ang II in the interstitial fluid, tubular fluid and the intracellular compartments. The interstitial as well as the intratubular compartments contribute to the disproportionately high total Ang II (Fig. 3) levels. Studies using microdialysis probes implanted in the renal cortex demonstrated that Ang II concentrations in interstitial fluid are much higher than the plasma concentrations with recent results suggesting values in the range of 3-5 pmol/mL (117,123-125). Interestingly, Nishiyama et al. (124,125) demonstrated that ACE inhibitors administered either directly into the renal artery or via the microdialysis probe were not able to substantially suppress the renal interstitial fluid Ang II levels. These studies suggest that much of the Ang II in the renal interstitial compartment is formed through non-ACE-dependent pathways or by ACE that is not easily accessed by the exogenously administered ACE inhibitors. Increases in renal interstitial fluid Ang II levels have been reported for two models of hypertension. Siragy et al. (117) found that renal interstitial Ang II is increased in the wrapped kidney of rats with Grollman hypertension. Nishiyama et al. (126) reported that renal interstitial fluid Ang II concentrations are also increased in rats infused with Ang II for 2 wk. Because the renal interstitial values are much higher than can be explained on the basis of equilibration with the plasma concentrations, the data suggest local regulation of Ang II formation in the renal interstitial compartment and an enhancement of interstitial Ang II production in Ang II-dependent hypertension.
As shown in Fig. 3, micropuncture studies have shown that proximal tubule fluid concentrations of Ang I and Ang II are also much greater than the plasma concentrations (27). The finding that tubular fluid samples collected from perfused segments had Ang II concentrations similar to those measured in nonperfused tubules indicates that the proximal tubule secretes Ang II or a precursor into the proximal tubule fluid (127).
In addition to AGT, proximal tubule cells also have renin mRNA that is stimulated by a low sodium diet, which may thus act on AGT to generate Ang I (47). Evidence for the presence of distal nephron renin mRNA and protein (49,51,53) also provides a pathway for Ang I generation from proximally delivered AGT. Furthermore, distal nephron renin regulation by Ang II differs from that in JGA cells because chronic Ang II infusion in rats enhances renin protein in principal cells but suppresses renin in JGA cells (49). Ang II stimulatory effects on collecting duct renin could help explain the marked impairment of sodium excretion and suppression of the pressure-natriuresis relationship observed in Ang II-infused hypertensive rats (128). Because renal AGT mRNA and protein levels are upregulated by increases in circulating Ang II levels (129,130), we postulate that renin in connecting tubule and collecting duct cells may be secreted into the tubular fluid and it acts on proximally delivered AGT to form Ang I in the luminal fluid. In turn, the presence of ACE in the distal nephron would lead to maintained renal Ang II-generating capacity that occurs in Ang II-dependent hypertension leading to high intrarenal Ang II levels and the maintenance of high blood pressure.
Measurements of proximal tubular fluid Ang II concentrations in anesthetized rats have not revealed significant differences among control rats and in several hypertensive models (131-133). Considering that kidneys of the hypertensive rats have marked depletion of JGA renin and are exposed to elevated arterial pressures, the maintenance of high proximal tubular Ang II concentrations reflects an inappropriate maintenance of intrarenal Ang II formation levels. Nevertheless, the results so far have not demonstrated further elevations in proximal tubule Ang II concentrations above the levels found in normal anesthetized rats. In normal rats, volume expansion failed to suppress proximal tubule Ang II concentrations, but increased levels were documented following reductions in renal perfusion pressure (134).
The Ang II concentrations in tubular fluid from the other segments of the nephron remain unknown. Several studies support an important role for Ang II in regulating reabsorptive function in distal nephron and collecting duct segments, as well as in proximal tubule segments, which activate the Ang II receptors on the luminal borders (27,135). Recently, a direct action of Ang II on the luminal amiloride-sensitive sodium channel (ENaC) was reported (136). These data indicate that when luminal distal nephron Ang II concentrations are augmented, they could contribute directly to the regulation of distal tubule and collecting duct sodium reabsorption.
As indicated earlier, some of the Ang II that binds to receptors is internalized via ATj receptor-mediated endocytosis (26,137,138). Zhuo et al. (139) reported direct evidence for accumulation of Ang II in intermicrovillar clefts and endosomes of Ang II-infused hypertensive rats. It was also shown that ATj receptor blockade with candesartan prevented the ensodomal accumulation even though plasma Ang II increased further, demonstrating the importance of ATj receptor-mediated uptake. The presence of Ang II in renal endosomes indicates that some of the internalized Ang II remains intact and contributes to the total Ang II content measured in tissue homogenates (25,127,138-141). As shown for proximal tubule cells, endocytosis of the Ang II-ATj receptor complex seems to be required for the full expression of functional responses coupled to the activation of signal transduction pathways (142,143). In Ang II-dependent hypertension, a higher fraction of the total kidney Ang II is internalized into intracellular endosomes (light endosomes as well as intramicrovillar clefts) via an ATj receptor-mediated process (139). The demonstration that ATj receptor blockade prevents the augmentation of intrarenal Ang II that occurs during chronic infusions of Ang II suggests ATj receptor-mediated accumulation of Ang II into an intracellular compartment, and that some of the internalized Ang II is protected from degradation (26,139). Van Kats (138) infused labeled Ang II and showed six- to sevenfold increase in intrarenal Ang II, which was prevented by an ATj receptor antagonist.
There are several possible functions of the internalized Ang II. Ang II could be recycled and secreted in order to exert further actions by binding to Ang II receptors on the cell membranes. Ang II may also act on cytosolic receptors to stimulate IP3 as has been described for vascular smooth muscle cells (144). A particularly intriguing hypothesis is that Ang II migrates to the nucleus to exert genomic effects (141). Nuclear binding sites for Ang II in renal cells have been reported by Licea-Vargas et al. (145). The nuclear receptors were primarily of the ATj subtype because they were displaced by losartan as well as by saralasin. Nuclear Ang II receptor density was not altered in Ang II-infused hypertension. Chen et al. (141) transfected Chinese hamster ovary cells with an ATla receptor fused with green fluorescent protein (GFP), which allowed the visualization of trafficking of the internalized ligand-receptor complex. Ang II increased colocalization of GFP fluorescence with nuclear markers suggesting the migration of the receptor complex to the nucleus (141). Because Ang II exerts a positive stimulation on AGT mRNA and protein production, it is possible that the intracellular Ang II may have genomic actions to regulate AGT or renin mRNA expression in proximal tubule cells (127).
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