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(Hypertension. 2001;37:275.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Renal Endothelin ET_A/ET_B Receptor Imbalance Differentiates Salt-Sensitive From Salt-Resistant Spontaneous Hypertension

Lars Rothermund; Susanne Luckert; Peter Koßmehl; Martin Paul; Reinhold Kreutz

From the Institut für Klinische Pharmakologie und Toxikologie (L.R., S.L., P.K., M.P., R.K.), Medizinische Klinik IV Nephrologie (R.K.), Benjamin Franklin Hospital, Freie Universität Berlin, Berlin, Germany.

Correspondence to PD Dr Reinhold Kreutz, Department of Clinical Pharmacology, Benjamin Franklin Klinikum, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail Kreutz{at}medizin.fu-berlin.de Dr Rothermund’s present address is Medizinische Klinik mit Schwerpunkt Nephrologie der Charité Campus Mitte, Humboldt Universität zu Berlin, 10117 Berlin, Germany.

	Abstract

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It is unclear why a subgroup of patients with essential hypertension develop salt-sensitive hypertension with progression of target organ damage over time. We evaluated the role of the renal endothelin (ET) system in the stroke-prone spontaneously hypertensive rat (SHRSP) model of salt-sensitive spontaneous hypertension (SS-SH) compared with the spontaneously hypertensive rat (SHR) model of salt-resistant spontaneous hypertension (SR-SH). Both strains were studied after either sham-operation on a normal diet (Sham) or after unilateral nephrectomy and high NaCl loading (NX-NaCl) with 4% NaCl in diet for 6 weeks (n=10, respectively). Systolic blood pressure (SBP) increased only in SHRSP-NX-NaCl compared with SHRSP-Sham (250±6 versus 172±5 mm Hg, P<0.0001). SBP remained unchanged in SHR-NX-NaCl compared with SHR-Sham. In SHRSP-NX-NaCl animals, urinary albumin and ET-1 excretion, renal ET-1 mRNA expression, glomerulosclerosis index, and tubulointerstitial damage index were elevated compared with SHRSP-Sham (P<0.05, respectively), whereas no significant changes were found in SHR after NX-NaCl. Urinary sodium excretion (U_Na⁺) was significantly reduced by 38% in SHRSP-NX-NaCl compared with SHR-NX-NaCl (P<0.005, respectively). SHR animals showed a similar increase in both renal ET_A and ET_B receptor densities after NX-NaCl (2.2-fold, P<0.05). In contrast, SHRSP-NX-NaCl developed a significantly more pronounced increase in ET_A compared with ET_B binding (4.7-fold versus 2.4-fold, P<0.05, compared with SHRSP-Sham, respectively), resulting in a significant 2.1-fold increase in ET_A/ET_B receptor ratio only in the SHRSP-NX-NaCl (P<0.05). Thus, activation of the renal ET system together with an increased ET_A/ET_B receptor ratio may contribute to the development and progression of SS-SH.

Key Words: sodium • hypertension, sodium-dependent • endothelin • receptors, endothelin • rats, spontaneously hypertensive • rats, stroke-prone SHR

	Introduction

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There are abundant experimental data indicating that the endothelin (ET) system plays an important role in the pathogenesis of salt-sensitive hypertension and the hypertensive target organ damage in this disease.^{1 2} This evidence has been in large part derived from experimental rat models in either deoxycorticosterone acetate (DOCA)-salt hypertension³ or the genetic Dahl⁴ and Sabra salt-sensitive⁵ hypertensive rat models. It is unclear, however, whether the activation of the renal ET system is also of significance during the progression from spontaneous hypertension to salt-sensitive spontaneous hypertension (SS-SH) with more severe target organ disease. In particular, the relative contributions of the renal ET receptor subtypes to the development and progression of spontaneous hypertension toward SS-SH are largely unknown. Most studies did not investigate the regulation of ET receptor subtypes in the kidney through the direct determination of receptor density and affinity but rather draw indirect conclusions from the application of selective or unselective ET receptor antagonists. Recently, Orth et al⁶ reported on a striking salutary effect of chronic ET_A receptor blockade with complete normalization of kidney damage in uninephrectomized stroke-prone spontaneously hypertensive rats (SHRSP) after high-salt diet. Interestingly, this finding was independent of an antihypertensive effect of the compound. However, this study lacks any further analysis of the renal ET system, including ET_A and ET_B receptor regulation in the SHRSP model studied.

In the present study, we set out to investigate the renal regulation of the ET system and the specific contribution of renal ET receptor subtype density and affinity in our SHRSP model of SS-SH compared with a model of salt-resistant spontaneous hypertension (SR-SH) represented by the spontaneously hypertensive rat (SHR). We studied the SHR and SHRSP strains after either sham operation on a normal diet or after unilateral nephrectomy on a high-NaCl diet, respectively.

	Methods

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Animals and Experimental Design
Male SHR/Fub and SHRSP/Fub rats were obtained from our colony at the Freie Universität Berlin (Fub), Benjamin Franklin Hospital. Animals were housed with constant room temperature (21°C) and humidity (75%) under a controlled light-dark cycle. At the age of 6 weeks, animals were randomly assigned to 1 of 4 groups (n=10 each): SHR and SHRSP rats were fed a normal diet (0.2% NaCl) and underwent a sham-operation (Sham) or were fed a high-salt diet (4% NaCl, ssniff Spezialdiäten GmbH) and underwent uninephrectomy (NX-NaCl). Normal tap water was available ad libitum. For sham operation or NX, each animal was anesthetized with ether inhalation, and a left nephrectomy was performed via a retroperitoneal incision. Blood samples as well as 24-hour urine samples were taken in week 6 after surgery. Thereafter, animals were killed during ether anesthesia, and the kidney was rapidly excised, rinsed in a 0.9% NaCl solution, blotted dry, and weighed. A midcoronal section of the right kidney was immersed in Dubosq-Brasil solution and embedded in paraffin for histological studies. The remaining renal tissue was immediately frozen in liquid nitrogen and stored at -80°C until further analysis.

Blood Pressure Measurement
Systolic blood pressure (SBP) was determined in awake rats at the age of 12 weeks using a tail cuff and pressure transducer in conjunction with a computerized pressure delivery and chart recording system (TSE Biosystems GmbH).

Urine and Biochemical Analysis
After completion of the blood pressure measurements, animals were placed in metabolic cages for 1 day for adaptation. The next day, 24-hour urine samples were collected for determination of urinary protein excretion (U_p), albumin excretion (U_alb), and sodium excretion (U_Na⁺). U_P was measured according to Bradford’s method, and U_alb was determined by ELISA with a rat specific antibody (ICN Biomedicals). Creatinine and sodium concentrations were measured with standard techniques.

Determination of Urine ET-1 Concentration
A commercially available enzyme immunoassay for ET-1, suitable for direct measurement of ET-1 in urine samples, was carried out according to the instructions of the manufacturer (Immundiagnostik GmbH).

Binding Assays for ET_A and ET_B Receptors
To analyze the renal expression of both known ET receptor subtypes (ET_A and ET_B), binding assays were performed in the presence or absence of the subtype-specific ET receptor ligands as described in detail previously.⁷

Northern Blotting
The mRNA expression level of ET-1 and ET-converting enzyme-1 (ECE-1) was determined by Northern blot analysis as described in detail elsewhere.⁸ A cDNA fragment for ECE-1 was amplified by RT-PCR from a 3' portion of the rat cDNA between nucleotides 949 and 1678 (GenBank accession No. D2963); all known isoforms of ECE-1 were detected by Northern blot analysis.

Morphological Investigation of the Kidney
After the samples were embedded in paraffin, they were cut into 3-µm sections and stained with periodic acid–Schiff’s, followed by hematoxylin counterstaining. Glomerulosclerosis index (GSI) was assessed with a semiquantitative scoring method as described previously⁹ at a magnification of x200. Tubulointerstitial changes such as tubular atrophy, dilation, casts, interstitial inflammation, and fibrosis were determined as a tubulointerstitial damage index (TDI) with a semiquantitative scoring system previously reported¹⁰ on periodic acid–Schiff’s–stained sections at a magnification of x100. Twenty fields per kidney were examined, and the above-mentioned lesions were graded as grade 0, no changes; grade 1, lesion involving <25%; grade 2, lesion affecting 25% to 50%; and grade 3, lesion involving >50% of the field. The resulting index in each animal was expressed as the mean value of all scores obtained. All parameters were assessed independently by 2 investigators in a blinded manner.

Statistical Analysis
All data are expressed as mean±SEM. Statistical analysis was performed using 2-way ANOVA followed by Bonferroni’s adjustment and by Mann-Whitney U test. Differences were considered significant at the level of P<0.05.

	Results

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Body Weight, Kidney Weight, and Creatinine Clearance
The data for body weight (BW), normalized kidney weight (K/BW), and creatinine clearance (C_crea) are presented in Table 1. BW was significantly lower in the SHRSP-NX-NaCl compared with SHRSP-Sham and SHR-NX-NaCl. K/BW was higher in SHRSP-Sham than SHR-Sham, increased in both strains after NX-NaCl, and was higher in SHRSP-NX-NaCl than in SHR-NX-NaCl (P<0.05, respectively). C_crea was significantly decreased in SHRSP-NX-NaCl compared with SHRSP-Sham and SHR-NX-NaCl (P<0.05, respectively).

View this table: [in this window] [in a new window]   Table 1. BW, K/BW, and Ccrea

Blood Pressure
SBP is shown in Figure 1. We observed no significant difference in SBP between SHR-Sham and SHRSP-Sham. SBP was not elevated in SHR-NX-NaCl compared with SHR-Sham. In contrast, SBP was significantly increased in SHRSP-NX-NaCl compared with SHRSP-Sham or SHR-NX-NaCl (P<0.0001, respectively).

View larger version (26K): [in this window] [in a new window]   Figure 1. SBP, UV normalized to body weight, UNa+ normalized to body weight, and urinary Na+ concentration. *P<0.05 vs SHRSP-Sham. #P<0.05 vs SHR-NX-NaCl.

Sodium and Volume Excretion
The data for U_Na⁺, urinary volume excretion (U_V), and urinary Na⁺ concentration are presented in Figure 1. U_Na⁺ increased 9.1-fold in SHR-NX-NaCl compared with SHR-Sham and 6.8.-fold in SHRSP-NX-NaCl compared with SHRSP-Sham (P<0.0001, respectively). However, sodium excretion was significantly lower in SHRSP-NX-NaCl than in SHR-NX-NaCl (P<0.005). U_V increased 4.0-fold in SHR-NX-NaCl compared with SHR-Sham (P<0.01) and 7.8-fold in SHRSP-NX-NaCl compared with SHRSP-Sham (P<0.0001). Thus, urinary Na⁺ concentration was significantly elevated in SHR-NX-NaCl compared with SHR-Sham and SHRSP-NX-NaCl (P<0.001, respectively) but remained unchanged in SHRSP-NX-NaCl compared with SHRSP-Sham.

Proteinuria, Albuminuria, and Urinary ET-1 Excretion
The data for U_P, U_alb, and urinary ET-1 excretion (U_ET-1) are presented in Figure 2. U_p and U_alb did not differ between SHR-Sham and SHRSP-Sham and did not change in SHR-NX-NaCl compared with SHR-Sham. However, a significant increase in both parameters was observed in SHRSP-NX-NaCl compared with SHRSP-Sham and compared with SHR-NX-NaCl (P<0.0001, respectively).

View larger version (9K): [in this window] [in a new window]   Figure 2. UP, Ualb, and urinary ET-1 excretion. *P<0.05 vs SHRSP-Sham. #P<0.05 vs SHR-NX-NaCl.

U_ET-1 was unchanged in SHR-Sham compared with SHRSP-Sham and did not differ in SHR-NX-NaCl compared with SHR-Sham. A significant increase in U_ET-1 was observed in SHRSP-NX-NaCl compared with SHRSP-Sham and compared with SHR-NX-NaCl (P<0.0001, respectively).

Expression of PreproET-1 and ECE-1 mRNA
We observed no significant difference in kidney mRNA expression of preproET-1 between SHR-Sham and SHRSP-Sham. PreproET-1 expression did not change in SHR-NX-NaCl compared with SHR-Sham but was significantly elevated in SHRSP-NX-NaCl compared with SHRSP-Sham and with SHR-NX-NaCl (2.2±0.47 versus 0.09±0.10 and 1.03±0.13, respectively; P<0.05). Overall, no significant differences were detected for renal ECE-1 mRNA levels (data not shown).

ET_A and ET_B Receptor Binding
The data for kidney ET receptor binding are presented in Figure 3. Kidney ET_A receptor density increased in SHR-NX-NaCl and SHRSP-NX-NaCl compared with SHR-Sham and SHRSP-Sham (P<0.0001, respectively). The increase in ET_A receptor density was significantly more pronounced in SHRSP-NX-NaCl than in SHR-NX-NaCl (P=0.003). No significant difference in ET_A receptor affinity was observed between the 2 strains or in response to the treatment protocol (Table 2).

View larger version (20K): [in this window] [in a new window]   Figure 3. A, Renal ETA and ETB receptor density and ETA/ETB receptor ratio. *P<0.05 vs SHRSP-Sham. #P<0.05 vs SHR-NX-NaCl. B, Specific binding of [125I]ET-1 to kidney membranes. A representative example of [125I]ET-1–specific binding in the presence of the subtype-specific ligand BQ 3020 or BQ 123 is shown for SHRSP-NX-NaCl and SHRSP-Sham, respectively. Nonspecific binding was determined in the presence of unlabeled ET-1 and was always <10% of total binding. A, ETA receptor binding in the presence of 3 µmol/L BQ 3020, a specific ETB receptor antagonist. B, ETB receptor binding in the presence of 3 µmol/L BQ 123, a specific ETA receptor antagonist.

View this table: [in this window] [in a new window]   Table 2. ETA and ETB Receptor Affinity (Kd) in the Kidney

Kidney ET_B receptor density increased similarly in both SHR-NX-NaCl and SHRSP-NX-NaCl compared with SHR-Sham and SHRSP-Sham (P<0.05, respectively). In contrast to ET_A receptor density, no interstrain difference in ET_B receptor density was detected. However, ET_B receptor affinity was significantly reduced in SHRSP-NX-NaCl compared with SHRSP-Sham and SHR-NX-NaCl (Table 2, P<0.05). We observed no significant difference in kidney ET_A/ET_B receptor ratio between SHR-Sham and SHRSP-Sham. ET_A/ET_B receptor ratio was not elevated in SHR-NX-NaCl compared with SHR-Sham. In contrast, ET_A/ET_B receptor ratio was significantly increased in SHRSP-NX-NaCl compared with SHRSP-Sham as well as with SHR-NX-NaCl (P<0.01, respectively).

Glomerulosclerosis and Tubulointerstitial Damage Indices
The GSI and TDI data are shown in Figure 4. GSI and TDI did not differ between SHR-Sham and SHRSP-Sham and were unchanged in SHR-NX-NaCl compared with SHR-Sham. GSI as well as TDI were significantly increased in SHRSP-NX-NaCl compared with SHR-NX-NaCl (P<0.01 and P<0.0001, respectively).

View larger version (19K): [in this window] [in a new window]   Figure 4. Glomerulosclerosis and tubulointerstitial damage. *P<0.05 vs SHRSP-Sham. #P<0.05 vs SHR-NX-NaCl.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The main question of the present study was whether an activated renal ET system contributes to the development and progression of SS-SH compared with SR-SH.

We demonstrated that the renal ET system is indeed activated in our SHRSP model of SS-SH after unilateral nephrectomy and high-NaCl dietary exposure. Unlike the SHR model of SR-SH, SHRSP-NX-NaCl animals develop severe hypertension and kidney damage. We show that an important maladaptive functional change in the progression of hypertensive kidney damage in SS-SH is the manifestation of reduced U_Na⁺ in SHRSP-NX-NaCl. SS-SH and renal failure in the SHRSP-NX-NaCl model is characterized by an increased renal ET_A/ET_B receptor ratio.

Development of SS-SH and Kidney Damage
The observed development of decreased C_crea together with marked elevation of glomerulosclerosis and tubulointerstitial damage in SHRSP-NX-NaCl is in agreement with a recent study that reports similar findings in another SHRSP strain.⁶ In addition, we observed a significant elevation in U_p and U_alb, indicating manifestation of renal damage in SHRSP-NX-NaCl. In contrast, no increase in SBP or any significant changes in C_crea, GSI, TDI, U_P, or U_alb were observed in SHR-NX-NaCl. These findings clearly demonstrate that the SHRSP strain represents a model of SS-SH that is highly susceptible to progression of its spontaneous hypertension toward severe hypertension in response to dietary salt excess, unlike the SHR strain, which maintains the SR-SH phenotype even after unilateral nephrectomy.

Activation of the Renal ET System
In SHR-NX-NaCl, we observed no activation of the ET-system, whereas renal preproET-1 mRNA expression and U_ET-1 were significantly increased in SHRSP-NX-NaCl animals. Thus, the development of SS-SH and renal damage in SHRSP-NX-NaCl seems to be closely related to activation of the renal ET system. Similar findings were reported at the protein level in salt-sensitive hypertensive Dahl rats with increased vascular and renal ET-1 content¹¹ and in a rat model of progressive renal failure,¹² in which renal preproET-1 gene expression and production of ET-1 were increased and correlated with progression of renal insufficiency.¹³ Because we investigated only a single time point (6 weeks after nephrectomy and high-sodium diet), it is difficult to distinguish the effect of high blood pressure from activation of the renal ET system on development of renal damage in our experiment. Nevertheless, Orth and coworkers⁶ clearly demonstrated in their work that the nephroprotective effect of selective ET_A receptor blockade in the SHRSP-NX-NaCl model was independent of high blood pressure, which led to the conclusions that ET plays a crucial role in progressive renal injury and that the progression-promoting effects are mainly mediated via the ET_A receptor.

ECE-1 gene expression was not altered by NX-NaCl in SHR or SHRSP, suggesting that the regulation of ECE-1, at least at the mRNA level, is not relevant for the development of SS-SH and renal damage in the SHRSP-NX-NaCl model. ET_A and ET_B receptor densities were higher in both SHR and SHRSP after NX-NaCl compared with untreated controls. This indicates that ET receptor expression is not a secondary effect due to organ damage but rather an indicator for counterregulatory processes in response to NX-NaCl treatment.

Specific Role of ET_A/ET_B Receptor Balance
In the DOCA-salt hypertensive rat model, some experimental evidence indicates that the ET_B receptor may serve to maintain lower arterial pressure,¹⁴ a finding that was confirmed with enhanced blood pressure sensitivity to DOCA-salt treatment in ET_B receptor–deficient rats.¹⁵ More recently, data obtained from ET_B receptor–deficient mice and rats unambiguously demonstrated a hypertensive phenotype only after salt loading in ET_B receptor–deficient animals.^{16 17} This form of hypertension was completely ameliorated by amiloride, a highly selective inhibitor of the epithelial sodium channel (ENaC) in the distal nephron.^{16 17} The most likely explanation for these findings is derived from previous elegant in vitro studies in distal nephron cells showing that ET-1 is capable of either inhibiting ENaC via the ET_B receptor or stimulating ENaC via the ET_A receptor.¹⁸

In the present study, the SHR model of SR-SH showed a similar increase in both renal ET_A and ET_B receptor densities after NX-NaCl treatment and thereby maintains its ET_A/ET_B receptor ratio constant. In contrast, SHRSP-NX-NaCl animals exhibited a significantly more pronounced increase in ET_A compared with ET_B binding, which resulted in a significant increase of ET_A/ET_B receptor ratio in this model of SS-SH. The relevance of this finding may be further amplified by a reduced ET_B receptor affinity observed only in SHRSP-NX-NaCl animals. Our data therefore suggest a role for the increased ET_A/ET_B receptor ratio in combination with the reduced ET_B receptor affinity in the pathogenesis of SS-SH and renal damage. Moreover, these data could, at least in part, explain the strong nephroprotective effect of selective ET_A receptor blockade in another SHRSP-NX-NaCl model reported previously.⁶ Finally, increased renal ET-1 levels, as indicated by higher renal ET-1 mRNA expression and urinary ET-1 excretion in our SHRSP-NX-NaCl model, may therefore stimulate sodium reabsorption by ENaC via the increased renal ET_A/ET_B receptor ratio. Although it is well established that the nephron represents a major site for intrarenal ET-1 production and ET-1 binding,¹⁹ we cannot deduce from the current set of experiments where the induction of renal ET-1 and ET_A receptor occurred in the SHRSP-NX-NaCl model. However, the observation that both renal Na⁺ excretion and urinary Na⁺ concentration were significantly reduced in SHRSP-NX-NaCl compared with SHR-NX-NaCl favors the potential relevance of the increased ET-1 expression and ET_A/ET_B receptor imbalance for the impairment of renal Na⁺ handling in SHRSP-NX-NaCl.

We therefore conclude that activation of the renal ET system in conjunction with an increased ET_A/ET_B receptor ratio contributes to decreased U_Na⁺ and to higher susceptibility to the development of SS-SH and kidney damage in SHRSP-NX-NaCl compared with SR-SS in the SHR-NX-NaCl model. A possible mechanism is impairment of U_Na⁺ via the stimulation of ENaC. Whether this unfavorable imbalance of renal ET_A/ET_B receptor ratio may also be involved in the progression of salt-sensitive hypertension in other experimental models and ultimately in patients with salt-sensitive hypertension remains to be investigated. The evaluation of this question appears of major clinical interest in face of the currently high prevalence of salt-sensitive hypertension and its impact on the development of end-stage renal disease. In this regard, ET_A receptor antagonism may become a promising new approach in the pharmacological treatment of salt-sensitive hypertension.

	Acknowledgments

 
This study was supported by the Forschungsschwerpunkt Kardiovaskuläre Medizin (Dr Kreutz) of the Benjamin Franklin Hospital and the Verbund Klinische Pharmakologie Berlin-Brandenburg.

Received May 15, 2000; first decision June 26, 2000; accepted August 14, 2000.

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