(Hypertension. 1995;25:1196-1201.)
© 1995 American Heart Association, Inc.
Articles |
Endothelin Production in Cultured Mesangial Cells of Spontaneously Hypertensive Rats
From the First Department of Internal Medicine, Osaka City (Japan) University Medical School.
Correspondence to Miwako Ikeda, MD, Division of Hypertension and Atherosclerosis, First Department of Internal Medicine, Osaka City University Medical School, 1-5-7 Asahi-machi, Abeno-ku, Osaka 545, Japan.
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Abstract |
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Abstract Cultured glomerular mesangial cells are shown to produce a potent vasoconstrictive peptide, endothelin-1 (ET-1). We examined whether basal or stimulated ET-1 production by angiotensin II (Ang II) and arginine vasopressin (AVP) is enhanced in cultured mesangial cells of spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). In addition, we examined which receptor subtypes of Ang II and AVP mediate ET-1 production in these cells. Basal ET-1 production in SHR mesangial cells was not different from that in WKY cells, although a trend toward increased ET-1 production was observed in the SHR cells. Ang II and AVP stimulated ET-1 production in a concentration-dependent manner in mesangial cells of both rat strains, but Ang II– and AVP-induced stimulation of ET-1 production was clearly greater in SHR than WKY cells. The protein kinase C (PKC)–activating phorbol ester phorbol myristate acetate stimulated ET-1 production in a concentration-dependent manner in cells of both rat strains, but this stimulation was significantly greater in SHR than WKY cells. Neither Ang II nor AVP stimulated ET-1 production in PKC-depleted cells of both strains. Ang II– and AVP-induced stimulation was completely abolished by selective angiotensin subtype 1 (AT1) and vasopressin subtype 1 (V1) receptor antagonists, respectively, in cells of both rat strains. These results suggest that AT1 and V1-receptor–mediated mesangial cell production of ET-1 is clearly enhanced in SHR compared with WKYs. Increased response of ET-1 production to PKC activation appears to contribute in part to the observed enhancement of ET-1 production in SHR mesangial cells.
Key Words: angiotensin II • arginine vasopressin • endothelin • mesangial cells • rats, inbred SHR • protein kinase C • rats, inbred WKY
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Introduction |
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Glomerular mesangial cells are directly related to glomerular function through their contractility and proliferation. These cells have receptors specific to various vasoactive peptides such as angiotensin II (Ang II),1 2 arginine vasopressin (AVP),3 4 5 and endothelin-1 (ET-1).6 7
ET-1 exerts a potent vasoconstrictive effect on a variety of blood vessels, including renal artery.8 9 10 This peptide is also shown to bind to its specific receptors and induce the contraction and proliferation of glomerular mesangial cells.6 7 11 12 ET-1 has been reported to play a role in a variety of diseases that affect the kidney, including severe hypertension,13 14 15 acute renal failure,16 17 18 and cyclosporine nephrotoxicity.19 20 In fact, we have previously shown that plasma ET-1 levels are significantly increased in hypertensive patients with impaired renal function and in severely hypertensive rats with renal damage.13 14 Furthermore, previous studies demonstrated constitutive expression of ET-1 transcripts and peptide secretion in cultured glomerular mesangial cells.21 22 23 This ET-1 production by mesangial cells is found to be stimulated by Ang II and AVP.24 25 These observations have led to the possibility that endogenous ET-1 of mesangial origin may play a role as a modulator of glomerular function and hemodynamics in certain pathological states. Therefore, if mesangial cell production of ET-1 is enhanced in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY), increased endogenous ET-1 in these cells may contribute to the pathophysiology of renal involvement associated with the progression of hypertension in SHR. Accordingly, we designed the present study to test whether basal mesangial cell production of ET-1 is enhanced in SHR compared with WKY and whether Ang II– and AVP-induced mesangial cell production of ET-1 is enhanced in SHR compared with WKY. In addition, we examined which receptor subtypes of Ang II and AVP mediate ET-1 production in these cells.
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Methods |
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Mesangial Cell Culture
Glomeruli from SHR and WKY (50 to 100 g) were isolated by sieving with stainless steel and nylon meshes under sterile conditions as previously reported.5 24 The isolated glomeruli were then cultured in RPMI 1640 medium containing 20% fetal calf serum and antibiotics. The identity of the mesangial cells was confirmed by (1) morphology; (2) typical microfilaments seen by transmission electron microscopy; (3) survival in a medium containing D-valine substituted for L-valine, indicating the existence of D-amino acid oxidase; (4) resistance to puromycin aminonucleoside (10 µg/mL) but susceptibility to mitomycin C (10 µg/mL); (5) presence of receptors specific to Ang II and contraction in response to Ang II; and (6) absence of immunofluorescence with factor VIII antibody. The cultures were maintained at 37°C with atmospheric air and 5% CO2, and subculture was carried out after treatment with Versene followed by trypsin. Cells after passages 4 to 8 were used for this experiment.
Materials
Ang II, AVP, [1-(ß-mercapto-ß,ß-cyclopentamethylene
propion acid), 2-(O-methyl)tyrosine]arginine vasopressin
(PMP), phorbol myristate acetate (PMA), and
4
-phorbol-12,13-didecanoate (4-PDD) were purchased from Sigma
Chemical Co. RPMI 1640, trypsin, Versene, and fetal calf serum were
purchased from GIBCO Laboratories. Flasks were purchased from Becton
Dickinson and Co. ET-1, ET-2, ET-3, and big ET-1 [porcine (1-39)]
were purchased from Peptide Institute, Inc. ET-1 antiserum was
purchased from Peninsula Laboratories Inc. 125I–ET-1 was
purchased from Amersham Japan Inc. The selective angiotensin subtype 1
(AT1) receptor antagonist losartan was donated by DuPont
Merck Pharmaceutical Co. The AT2 receptor antagonist PD
123319 was donated by Parke-Davis.
Pharmacological Treatment
The culture medium was removed, and the cell monolayers were
washed twice with serum-free RPMI 1640. SHR and WKY mesangial cells
were exposed to different concentrations (10-7,
10-8, and 10-9 mol/L) of Ang II and
AVP for 24 and 48 hours. In separate experiments, losartan and PD
123319 were added to the well 5 minutes before addition of Ang II, and
the cells were incubated for 24 hours. The V1 receptor
antagonist PMP was added to the well 5 minutes before addition of AVP,
and the cells were incubated for 24 hours.
To examine the effect of the PKC-activating phorbol ester PMA on ET-1 production in cells of both rat strains, we exposed cells to different PMA concentrations (10-7, 10-8, and 10-9 mol/L) for 24 hours. In addition, to confirm the importance of PKC-dependent mechanisms in the stimulation of ET-1 production, we examined the effect of PKC depletion. PKC was depleted by preincubation with a high dose of PMA (10-7 mol/L) for 24 hours in cells of both rat strains.
All experiments were performed with 2 mL RPMI 1640 under quiescent (0.5% fetal calf serum) conditions. After incubation, the medium was aspirated and centrifuged at 3000g for 10 minutes and the supernatant collected and stored at 80°C until radioimmunoassay.
Measurement of ET-1 Concentration
ET-1 was extracted as previously described.25
Briefly, 1.5 mL of each sample was diluted with 4 mL of 4% acetic
acid. After centrifugation, the solution was pumped at the rate of 1
mL/min through a Sep-Pak C18 cartridge (Millipore Corp). After
evaporation of the eluate with 86% ethanol in 4% acetic acid by a
centrifugal evaporator (model RD-31, Yamato Scientific Co), the dry
residue was dissolved in the assay buffer described below. The recovery
rate was found by addition of three different quantities of cold ET-1
(10, 50, and 100 pg/mL) to serum-free RPMI 1640. Recovery was
69±2%.
The ET-1 concentration was assayed using ET-1 antiserum and 125I–ET-1 as a tracer. This antibody reacts 100% with ET-1 and cross-reacts 7% with ET-2, 7% with ET-3, and 35% with big ET-1 [porcine (1-39)]. The antiserum did not cross-react with somatostatin, ß-endorphin, human secretin, Ang II, or AVP.
Radioimmunoassay was performed in an assay buffer of 0.01 mol/L sodium phosphate, pH 7.4, containing 0.05 mol/L NaCl, 0.1% bovine serum albumin, 0.1% Nonidet P-40, and 0.01% NaN3, as previously described.26 In brief, rehydrated antiserum (100 µL) was added to 100 µL of the sample or 100 µL of standard ET-1 dissolved in the assay buffer, and the mixture was incubated for 24 hours at 4°C. Approximately 15 000 cpm of 125I–ET-1 was added to each reaction and incubated for an additional 24 hours. After this incubation, 100 µL of diluted normal rabbit serum and 100 µL of diluted goat anti-rabbit IgG were added, and the mixture was again incubated for 24 hours. After the third incubation, the precipitate was collected by centrifugation at 1700g for 30 minutes. The supernatant was removed by aspiration and the pellet counted for 125I with a gamma counter. The detection level of this assay was 0.2 pg/mL (range, 0.2 to 200 pg/mL). The interassay variation was 13%, and the intra-assay variation was 7%.
Ang II and AVP did not interfere with the radioimmunoassay.
Calculations and Statistical Analysis
The statistical significance of differences was evaluated by
ANOVA, and probability values were calculated by Scheffé's
method.27 Values are expressed as mean±SD.
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Results |
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Effects of Ang II and AVP on ET-1 Production
Confluent cultured mesangial cells of both rat strains produced ET-1 in a time-dependent manner. Under quiescent conditions (0.5% fetal calf serum), basal ET-1 production in SHR cells was not different from that in WKY cells, although a trend toward increased ET-1 production was observed in SHR cells (Figs 1 and 2).
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significant difference between SHR and WKY (P<.05).
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Ang II stimulated ET-1 production in a concentration-dependent manner between 10-7 and 10-9 mol/L in cells of both rat strains. However, the stimulation of ET-1 production was clearly greater in SHR cells than in WKY cells (Fig 1).
AVP stimulated ET-1 production in a concentration-dependent manner between 10-7 and 10-9 mol/L in cells of both strains. The stimulation by AVP of ET-1 production appeared to be greater than that by Ang II in cells of both rat strains. However, the stimulation of ET-1 production was clearly greater in SHR cells than in WKY cells (Fig 2).
Effects of Ang II Receptor Antagonists on ET-1 Production
Effects of losartan and PD 123319 on Ang II–stimulated production
of ET-1 in cultured mesangial cells of both rat strains are shown in
Fig 3. Preincubation of the cells with 10-6
mol/L losartan 5 minutes before the addition of 10-7 mol/L
Ang II abolished the Ang II–mediated increase of ET-1 production in
both strains. However, preincubation of the cells with
10-6 mol/L PD 123319 for 5 minutes before the addition of
10-7 mol/L Ang II had no effect on ET-1 production. This
suggests that the AT1 receptor is coupled to Ang
II–mediated ET-1 production in cultured mesangial cells of both rat
strains.
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Effects of V1 Receptor Antagonist on ET-1
Production
Effects of the selective V1 receptor antagonist PMP on
AVP-stimulated production of ET-1 in cultured mesangial cells of
both rat strains are shown in Fig 4. Preincubation of
the cells with 10-6 mol/L PMP for 5 minutes before the
addition of 10-7 mol/L AVP abolished the AVP-mediated
increase of ET-1 production. This effect of PMP was observed in cells
of both strains, suggesting that the V1 receptor is coupled
to AVP-mediated ET-1 production in cultured mesangial cells of both rat
strains.
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Effects of PMA on ET-1 Production
Effects of the PKC-activating phorbol ester PMA on ET-1 production
in cultured mesangial cells of both rat strains are shown in Fig 5. PMA stimulated ET-1 production in a
concentration-dependent manner between 10-9 and
10-7 mol/L in cells of both rat strains, although the
increase by 10-9 mol/L PMA in WKY cells was not
statistically significant. However, the stimulation of ET-1 production
was clearly greater in SHR cells than in WKY cells. An inactive
enantiomer of phorbol ester, 4-PDD, had no effect on the ET-1
production in these cells of both rat strains (Fig 5).
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To confirm the importance of PKC-dependent mechanisms in the stimulation of ET-1 production, we examined the effect of PKC depletion. The ET-1 production by PKC-depleted cells was not increased by addition of 10-7 mol/L Ang II or 10-7 mol/L AVP (Tables 1 and 2).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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First, we have shown that cultured mesangial cells of both SHR and WKY produce ET-1 in a time-dependent manner. Under quiescent conditions (0.5% fetal calf serum), basal ET-1 production in SHR cells was not different from that in WKY cells, although a trend toward increased ET-1 production was observed in SHR cells.
Second, we have confirmed previous observations reported by Bakris et al4 28 and us24 25 that Ang II and AVP stimulate mesangial cell production of ET-1. Under the current experimental conditions, the stimulatory effect of AVP appeared to be greater than that of Ang II. This stimulation by Ang II and AVP of ET-1 production was observed in mesangial cells of both SHR and WKY. However, Ang II– and AVP-induced stimulation of ET-1 production was clearly greater in SHR cells than in WKY cells. The amount of Ang II– and AVP-stimulated ET-1 production is much lower even in mesangial cells of SHR compared with that in cultured vascular endothelial cells. Nevertheless, the ET-1 concentration in the culture media of Ang II– and AVP-stimulated mesangial cells of SHR appears to attain levels that are within the biologically effective range for this peptide.8 Furthermore, it is important to note that a low concentration of exogenous ET-1 potentiates the vasoconstrictive or mitogenic action of other vasoconstrictors or growth factors such as norepinephrine,29 30 serotonin,31 or platelet-derived growth factor.32 Therefore, ET-1 produced by Ang II and AVP may act, together with Ang II, AVP, or other endogenous substances, to stimulate the contraction or proliferation even at a low concentration. Recently, Bakris and Re28 have shown that Ang II acts as a mitogen under certain culture conditions in cultured human mesangial cells and that this mitogenic effect of Ang II is mediated through mesangial cell ET-1 production. Bakris et al4 have also shown that AVP acts as a mitogen in part by increasing mesangial cell production of ET-1. Furthermore, the local renin-angiotensin system within the kidney is found to play an important role in the maintenance or development of the high blood pressure in SHR, although plasma Ang II in SHR is not higher than levels in WKY.33 34 On the other hand, plasma AVP concentrations are found to be high in SHR35 and markedly increased in the malignant or severe stage of hypertension.36 37 Taken together with our data, these observations raise the possibility that the excess ET-1 production caused by Ang II or AVP in glomerular mesangial cells of SHR induces the contraction and proliferation of these cells probably in concert with Ang II and AVP, thereby contributing to the alteration of glomerular hemodynamics and function associated with the progression of hypertension in SHR. However, it remains to be clarified whether Ang II and AVP have physiological roles as modulators of ET-1 production in glomerular mesangial cells in vivo, because not only high concentrations of Ang II and AVP are required to stimulate ET-1 production, but also high concentrations of ET-1 are required to induce the contraction and proliferation of these cells.
Next, we showed in the current experiment that Ang II–induced mesangial cell ET-1 production was abolished by the selective AT1 receptor antagonist losartan. On the other hand, this stimulation by Ang II was not affected by the selective AT2 receptor antagonist PD 123319. These results indicate that Ang II stimulates ET-1 production via AT1 receptors in mesangial cells of both rat strains. Furthermore, we showed that AVP-induced mesangial cell ET-1 production was abolished by the selective V1 receptor antagonist PMP, and therefore, AVP stimulates ET-1 production via V1 receptors in these cells.
Finally, we showed that Ang II– and AVP-stimulated mesangial cell
production of ET-1 is PKC dependent in both SHR and WKY. In fact, the
PKC-activating phorbol ester PMA stimulated ET-1 production in
mesangial cells of both rat strains, and neither Ang II nor AVP
stimulated ET-1 production in PKC-depleted mesangial cells.
Furthermore, an inactive enantiomer of phorbol ester, 4-PDD, had no
effect on mesangial cell production of ET-1, indicating that the effect
of PMA was not a nonspecific action of phorbol ester. We also showed
that the stimulation by PMA of ET-1 production was significantly
greater in SHR mesangial cells than in WKY cells. This suggests that an
increased response of ET-1 production to PKC activation contributes in
part to the observed enhancement of ET-1 production in SHR mesangial
cells. However, further studies will be necessary to elucidate the
exact cellular mechanism of the above-mentioned difference in cells of
both rat strains.
Overall, our results suggest that AT1 and V1 receptor–mediated mesangial cell production of ET-1 is clearly enhanced in SHR compared with WKY. This difference appeared to be partly due to the different response of ET-1 production to PKC activation in mesangial cells of both rat strains. It is well established that Ang II and AVP stimulate ET-1 production in vascular endothelial cells.26 38 39 Therefore, in the glomerulus Ang II and AVP appear to stimulate both mesangial and endothelial cell production of ET-1. The excess ET-1 production in the glomerulus may contribute to the renal involvement associated with the progression of hypertension in SHR.
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Acknowledgments |
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This work was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture, Japan, and by a grant from the Osaka Heart Club. We gratefully acknowledge the technical assistance of Machiko Johchi, Atsumi Ohnishi, and Tomoko Okuno.
Received June 6, 1994; first decision August 29, 1994; accepted November 7, 1994.
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