Published online before print February 11, 2008, doi: 10.1161/HYPERTENSIONAHA.107.100339
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(Hypertension. 2008;51:915.)
© 2008 American Heart Association, Inc.
Original Articles |
Downregulation of Renal TRPM7 and Increased Inflammation and Fibrosis in Aldosterone-Infused Mice
Effects of Magnesium
From the Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ontario, Canada.
Correspondence to Rhian M. Touyz, MD, PhD, Kidney Research Centre, University of Ottawa/Ottawa Health Research Institute, 451 Smyth Rd, Ottawa, ON, KIH 8M5. E-mail rtouyz{at}uottawa.ca
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Abstract |
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Hyperaldosteronism is associated with hypertension, cardiovascular fibrosis, and electrolyte disturbances, including hypomagnesemia. Mechanisms underlying aldosterone-mediated Mg2+ changes are unclear, but the novel Mg2+ transporters TRPM6 and TRPM7 may be important. We examined whether aldosterone influences renal TRPM6/7 and the TRPM7 downstream target annexin-1 and tested the hypothesis that Mg2+ administration ameliorates aldosterone-induced cardiovascular and renal injury and prevents aldosterone-associated hypertension. C57B6 mice were studied (12 weeks, n=8 to 9/group); (1) control group (0.2% dietary Mg2+), (2) Mg2+ group (0.75% dietary Mg2+), (3) aldosterone group (Aldo, 400 µg/kg/min and 0.9% NaCl drinking water), and (4) Aldo+Mg2+ group. Blood pressure was unaltered by aldosterone and was similar in all groups throughout the experiment. Serum Na+ was increased and serum K+ and Mg2+ decreased in the Aldo group. Aldo mice had hypomagnesuria and proteinuria, and renal, cardiac, and aortic fibrosis, which were normalized by Mg2+ supplementation. Renal and cardiovascular expression of interleukin-6, VCAM1 and COX2 was increased in the Aldo group. Magnesium attenuated renal and cardiac interleukin-6 content and decreased renal VCAM1 and cardiac COX2 expression (P<0.05). Aldosterone decreased expression of renal TRPM7 and the downstream target annexin-1 (P<0.05) without effect on TRPM6. Whereas Mg2+ increased mRNA expression of TRPM6 and TRPM7, it had no effect on TRPM7 and annexin-1 protein content. Our data demonstrate that aldosterone mediates blood pressure–independent renal and cardiovascular fibrosis and inflammation through Mg2+-sensitive pathways. We suggest that altered Mg2+ metabolism in hyperaldosteronism may relate to TRPM7 downregulation and that Mg2+ protects against cardiovascular and renal damaging actions of aldosterone.
Key Words: TRP channels • cations • cardiovascular remodeling • blood pressure • vascular cell adhesion molecule • COX2 • annexin-1
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Introduction |
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Aldosterone, classically thought to be produced by the zona glomerulosa of the adrenal cortex and implicated in the maintenance of sodium, potassium, and acid-base balance and blood pressure regulation, is now considered a hormone with pleiotropic actions, produced by multiple tissues, including the heart, vessels, kidney, and brain.1,2 In addition to regulating renal electrolyte excretion, aldosterone contributes to vascular inflammation, oxidative stress, collagen deposition, and endothelial dysfunction.3–5 As such, aldosterone has been implicated in the development of cardiovascular and renal remodeling, fibrosis, and injury. The importance of these processes in clinical medicine is being increasingly recognized by the cardiovascular and renal protective effects of the aldosterone antagonists, spironolactone and eplerenone.6,7
The profibrotic and proinflammatory actions of aldosteronism are accompanied by disturbances in cation homeostasis including hypomagnesemia and decreased intracellular free magnesium concentration ([Mg2+]i).8,9 Recent evidence suggests that aldosterone-induced cardiovascular inflammation is induced, in part, by decreased [Mg2+]i with Ca2+ loading leading to increased H2O2 formation and cellular oxidative stress.8–10 Hyperaldosteronism-associated renal magnesium wasting and cardiovascular injury and fibrosis are ameliorated by spironolactone and eplerenone and by Mg2+ administration.6,7,11 Mechanisms whereby aldosterone causes Mg2+ depletion are unclear, but the recently identified novel magnesium transporters, transient receptor potential melastatin cation channels 6 and 7 (TRPM6 and TRPM7), may be important.12,13 Both proteins share the unique feature of an atypical kinase domain at their C terminus and are negatively regulated by intracellular Mg2+ levels.14,15 TRPM6 and TRPM7 have been described as the "gatekeepers" of human Mg2+ metabolism, but may also play a role in intracellular signaling events, because TRPM7 kinase activates downstream targets annexin-1, calpain, and myosin IIA heavy chain.12,13,16–19 TRPM7 is an important player in cellular Mg2+ homeostasis whereas TRPM6 appears to be more important in epithelial Mg2+ transport.13,16 Patients with loss-of-function mutations in TRPM6 exhibit a severe form of hereditary hypomagnesaemia (primary hypomagnesaemia with secondary hypocalcaemia [HSH]).20 We demonstrated that vasoactive agents, including angiotensin II and aldosterone, regulate vascular TRPM7 expression and activity and that TRPM7 plays a critical role in vascular smooth muscle cell (VSMC) transcellular Mg2+ transport and [Mg2+]i homeostasis.21,22 The effect of aldosterone on renal TRPM6/7 status is unknown.
In the present in vivo study we sought to determine whether aldosterone influences renal TRPM6/7 expression and the TRPM7 downstream target annexin-1 and tested the hypothesis that Mg2+ administration ameliorates aldosterone-mediated cardiovascular and renal injury and prevents aldosterone-induced hypertension in mice.
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Materials and Methods |
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An expanded Methods section is available in an online data supplement at http//hyper.ahajournals.org.
Animals
This study was approved by the Animal Ethics Committee of the University of Ottawa and performed according to the recommendations of the Canadian Council for Animal Care. Four groups of 12-week-old male C57B6 mice (Jackson Laboratory, Maine, Del) were studied: Control (normal mouse chow; Harlan Teklad Global Diet:2018; 0.2% dietary Mg2+, n=8), magnesium-supplemented group (Mg2+ group; 0.75% dietary Mg2+, Harlan Teklad, n=9), aldosterone-infused group (Aldo group; 300 µg/kg/d for 2 wk then 400 µg/kg/d by Alzet osmotic mini-pumps and 0.9% NaCl drinking water, n=9) and Aldo+Mg2+ group (aldosterone infusion, 0.9% NaCl drinking water and 0.75% dietary Mg2+ n=9).
Blood Pressure Measurements and Serum and Urine Analysis
The systolic blood pressure (SBP) was measured in conscious mice every 3 days using the Visitech tail cuff system (BP 2000 Blood Pressure Analysis System, Visitech).
Blood and urine were collected at the beginning and end of the experiment. Levels of Mg2+, Ca2+, Na+, and K+ and urine protein were measured by automated methods at the hospital laboratory.
Analysis of TRPM6 and TPRM7 mRNA Levels With Real-Time Polymerase Chain Reaction
Frozen kidney samples were homogenized and RNA extracted using Trizol reagent (Invitrogen). 200 ng of each RNA sample was reverse transcribed using random hexamers and TaqMan reverse transcription (RT) reagents (Applied Biosystems). Specific primers and FAM-labeled probes for mouse TRPM6 and TRPM7 were designed using Primer Express software (Applied Biosystems) and sequences from the NCBI database (Table S1). All reactions were performed in triplicate, and a standard curve constructed on each plate using an independent control sample of kidney cDNA. The PCR conditions were: 50°C for 2 minutes, 95°C for 10 minutes, then 40 cycles of 95°C for 15 seconds and 60°C for 1 minute (Applied Biosystems 7300 Real-time PCR system). Relative expressions of TRPM6 and TRPM7 in the unknown samples were determined from a standard curve and expressed relative to 18S.
Western Blotting
Proteins from kidney (renal cortex), heart, and aorta were extracted from frozen tissue as previously described.22 Proteins were separated by SDS-PAGE, transferred to nitrocellulose membranes, and incubated with specific antibodies to VCAM1 (Santa Cruz Biotechnology), COX2 (Cayman chemical), TRPM7 (Abcam), annexin-1 (Santa Cruz Biotechnology). Signals were revealed by chemiluminescence, visualized autoradiographically, and subsequently membranes were stripped (Pierce Biotechnology) and reprobed with GAPDH or 
-actin antibodies (Chemicon International), which were used as internal controls. Optical density of bands was quantified densitometrically.
Histopathologic Analysis
Tissues were fixed in 4% formaldehyde solution for 24 hours at 4°C, dehydrated, embedded in paraffin, and sectioned transversely (4 µm). Sections were stained with hematoxylin and Sirius red and scored for vascular damage and collagen deposition.
Immunohistochemistry
Frozen tissue (kidney, heart apex, and aorta) were cryosectioned (7 µm thickness) and fixed with cold acetone for 10 min. For direct immunohistochemistry, sections were incubated with 3% H2O2 and a Pierce solution to block endogenous peroxidase and biotin, respectively, followed by overnight incubation (humidified box, 4°C) with a biotinated antigoat IL-6 monoclonal antibody (Santa Cruz). Sections were lightly stained in hematoxylin, dehydrated with alcohol and xylene, and scored by an independent observer unaware of the groups and treatments of the mice.
Data Analysis
Values are expressed as means±SEM, with n indicating the number of mice. Two-way ANOVA was used to evaluate differences between the groups followed by Tukey Kramer post hoc testing. Data are presented as the effects of Mg2+, Aldo, and Aldo+Mg2+. P<0.05 was considered to be statistically significant. For evaluation of Western blot data, controls were normalized to 100% and experimental groups compared to controls (taken as 100%).
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Results |
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Body Weight and Cardiac and Renal Size
Mice in all groups thrived with similar body weights at the end of the experimental period (Table 1). Heart and kidney size, corrected for tibial length, were significantly greater in the aldosterone-treated groups compared with control counterparts (heart, 6.88±0.17 versus 8.38±0.46, P<0.05; kidney, 1.94±0.04 versus 2.63±0.12, P<0.001). In magnesium-supplemented aldosterone-treated mice, cardiac size was not different from the control group, but kidney size was significantly increased versus controls (P<0.01).
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Blood Pressure
Mice were treated for 3 months with aldosterone. They also received 0.9% NaCl in the drinking water. Aldosterone was infused initially at a dose of 300 µg/kg/min. Because blood pressure did not increase after 2 weeks infusion at this dose, we increased the aldosterone concentration to 400 µg/kg/min until the end of the experiment. Aldosterone failed to increase SBP, even at the higher dose of infusion (Figure S1). Magnesium supplementation did not influence blood pressure in control or aldosterone-treated mice.
Serum and Urine Biochemistry
Serum and urine biochemistry was similar in all groups at the beginning of the experiment. Table 1 demonstrates serum and urine cation and urine proteins levels in the different groups at the end of the experimental period. Serum Mg2+ was significantly increased in the magnesium-supplemented groups versus other groups (P<0.01). Serum Na+ was increased and serum K+ was decreased in the aldosterone-infused mice, without effect of magnesium supplementation. Serum Ca2+ was similar in all groups. Serum Mg2+ was reduced in the aldosterone group, but did not reach significance (P<0.06).
Urinary Mg2+ levels were significantly increased in the Mg2+-supplemented groups (Table 1). Aldosterone infusion was associated with significantly reduced Na+ and Mg2+ levels, which were normalized by Mg2+ supplementation. Aldosterone-infused mice exhibited significant proteinuria, which was ameliorated by Mg2+.
Renal Effects of Aldosterone and Magnesium Supplementation
Renal fibrillar collagen deposition was increased in aldosterone-treated animals (Table 2). This was associated with an increased inflammatory response as evidenced by increased expression of IL-6, VCAM1, and COX2 (Figures 1 through 3
). Magnesium supplementation did not influence renal fibrosis or inflammatory mediators in the control group, but significantly decreased effects in the aldosterone-treated group.
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Effects of Aldosterone and Magnesium on Renal Expression of TRPM6 and TRPM7
As shown in (Figure 4), aldosterone had no effect on mRNA expression of TRPM6, but significantly reduced TRPM7 mRNA content (P<0.05). Magnesium supplementation increased expression of TRPM6 and TRPM7 in aldosterone-infused mice (P<0.01). In control mice, TRPM7 mRNA expression was increased by Mg2+ (P<0.05, t test).
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At the protein level, we evaluated expression of TRPM7, but not of TRPM6, because only TRPM7 gene seemed to be influenced by aldosterone, confirming our previous studies.22 Moreover it is very difficult to accurately assess TRPM6 protein because of the unavailability of sensitive anti-TRPM6 antibodies. As demonstrated in (Figure 5), protein content of renal TRPM7 and its downstream substrate annexin-1 was significantly reduced in the aldosterone group. This was unaffected by Mg2+ (Figure 5).
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Cardiovascular Effects of Aldosterone and Magnesium Supplementation
As observed in the kidney, collagen deposition was significantly increased in the heart in response to aldosterone (Figure 6). This effect was attenuated in mice supplemented with Mg2+. Expression of cardiac IL-6, VCAM, and COX2 was significantly enhanced in the aldosterone group (Figures S2 and S3). Magnesium reduced IL-6 and COX2 expression, but did not influence cardiac VCAM1 expression.
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Aortic collagen content and media thickness were significantly increased in the aldosterone-infused mice versus controls (53.91±1.8 versus 116±13.61, P<0.01) (Table 2, Figure 7). Magnesium significantly reduced the media thickness of the aorta (116±13.61 versus 68.04±2.09, Aldo versus Aldo+Mg; P<0.05). Vascular expression of VCAM1 and COX2 was significantly increased in the aldosterone-treated mice (P<0.05) (Figure S4). Magnesium supplementation did not influence expression of proinflammatory mediators in the aorta.
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Discussion |
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Major findings from the present study demonstrate that in C57B6 mice (1) aldosterone induces significant renal and cardiovascular hypertrophy, fibrosis, and inflammation independently of blood pressure elevation, (2) Mg2+ supplementation attenuates aldosterone-mediated cardiovascular and renal remodeling, (3) aldosterone decreases renal expression of the novel Mg2+ transporter TRPM7, but not TRPM6, and the TRPM7 downstream target annexin-1, and (4) Mg2+ administration prevents aldosterone-induced renal dysfunction (proteinuria) and electrolyte disturbances. Our findings highlight the potent profibrotic and proinflammatory actions of aldosterone in the heart, vasculature, and kidneys and suggest that Mg2+ plays a role in these processes. We also provide the first evidence that aldosterone modulates renal TRPM7 expression, which could be important in altered Mg2+ homeostasis associated with hyperaldosteronism.8,9,23
An unexpected finding in our study was the failure of aldosterone to induce hypertension. This may relate to the fact that the mice investigated here were not uninephrectomized as in many other studies. Moreover, we studied C57B6 mice, which seem to be resistant to hypertensive-inducing stimuli.24–26 Other studies have also reported variable blood pressure actions of aldosterone, with some studies reporting a significant hypertensive effect and others showing no change in blood pressure.24–26 To ensure that the methodology used to measure blood pressure in our study was reliable, we performed a second set of experiments where mice were infused with Ang II (400 ng/mg/min). These mice developed hypertension within 3 days (SBP
160 mm Hg), similar to our previous studies indicating that the tail cuff technique used was functional.
The fact that aldosterone did not cause hypertension yet induced marked cardiac, vascular, and renal remodeling as well as renal dysfunction (proteinuria) suggests that it has direct cardiovascular/renal effects independently of changes in blood pressure. This is supported by extensive experimental data indicating that aldosterone directly stimulates cell proliferation, hypertrophy, collagen deposition, and inflammation.27–29 Molecular mechanisms underlying these processes involve activation of MAP kinases, tyrosine kinases, NADPH oxidase-derived reactive oxygen species, and proinflammatory transcription factors, mediated through genomic and nongenomic pathways.1,30,31 Many of these signaling molecules are influenced by Mg2+. We and others reported that MAP kinases, c-Src, cell cycle proteins, and NADPH oxidase are regulated by Mg2+ and that small changes in [Mg2+]i have significant effects on signal transduction and cellular functional responses.32–34 These processes may contribute, at least in part, to the protective effects of Mg2+ observed in the magnesium-supplemented group.
Considering that our experiment was a long-term study, we cannot exclude the possibility that some of the observed cardiovascular and renal changes may be secondary to aldosterone-induced electrolyte alterations. Nevertheless, the initiating stimulus was aldosterone, indicating that this hormone does play a role in the process. Hence, in chronic in vivo studies, aldosterone effects may be both direct and indirect.
Magnesium has important antiinflammatory and antioxidant properties. Mg2+-deficient mice exhibit severe cardiovascular inflammation and oxidative injury, which are normalized by Mg2+ supplementation.34,35 In our study, dietary Mg2+ ameliorated aldosterone-induced damaging actions and reduced fibrosis in the kidney, heart, and aorta, similar to effects previously reported.10 We examined expression of IL-6, a secondary cytokine, VCAM1, a proinflammatory adhesion molecule and COX2, a key enzyme involved in the inflammatory response. Although aldosterone significantly increased expression of all of these mediators, the antiinflammatory response of Mg2+ was variable, with major effects in kidney and heart and little effect in the aorta. Reasons for this regional heterogeneity are unclear but may relate to differences in [Mg2+]i in the different tissues. In support of our findings, Kramer et al also reported variable effects of dietary Mg2+ on circulating proinflammatory mediators in cardiac disease.36 It is also possible that Mg2+ actions are tissue-specific. For example in the aorta of Mg2+ supplemented mice, remodeling was markedly improved, whereas inflammatory responses were not, suggesting that in the vasculature effects on fibrosis and growth by Mg2+ may be more important than effects on inflammation.
Extensive clinical and experimental evidence indicates that hyperaldosteronism causes electrolyte changes, specifically hypokalemia, hypernatremia, and hypomagnesemia.8,9 In the aldosterone-infused mice, serum Na+ was increased and serum K+ was decreased confirming efficient absorption of the administered aldosterone. Reasons for these electrolytes changes are attributable to renal actions of aldosterone, which promote K+ excretion and Na+ reabsorption through activation of the Na+/H+ exchanger, ENaC, and Na+/K+ ATPase transporters.1 In our study, serum Mg2+ tended to be lower in the aldosterone group. Urine Mg2+ was significantly reduced. These findings are in contrast to those reported by Runyan et al8 and Chhokar et al,37 where aldosterone infusion induced hypermagnesuria. However, in those studies,8,37 rats, not mice, were investigated, uninephrectomy was performed, and animals were infused for 4 to 6 wk. Hence the experimental protocol was different from our study. Reasons for hypomagnesuria and relative hypomagnesemia in our aldosterone-infused mice may relate to downregulation of renal TRPM7 and to redistributon of Mg2+ in muscle, bone, and the gastrointestinal tract. Although we did not measure activity of TRPM7 directly, we assessed annexin-1 status, which paralleled TRPM7 changes. Annexin-1 is a TRPM7 kinase-sensitive substrate12 that has been implicated in inflammation, cell proliferation, and apoptosis.38 Another mechanism whereby aldosterone may influence urinary Mg2+ excretion is through the Na+/Mg2+ exchanger, which we demonstrated to be upregulated in hypertension.39 Hence altered Mg2+ metabolism in hyperaldosteronism may be related to direct stimulation of the Na+/Mg2+ exchanger on the one hand and to downregulation of TRPM7 on the other.
Cellular models demonstrate that TRPM6 and TRPM7 are regulated by Mg2+.14,15 We speculated that Mg2+ supplementation would normalize TRPM7 in aldosterone-treated mice. This was confirmed at the gene level, where mRNA expression of TRPM6 and TRPM7 was significantly increased in aldosterone-infused mice receiving Mg2+. However, this was not evident at the protein level, because TRPM7 and annexin-1 content were not normalized in Mg2+ supplemented mice. Reasons for these differences between gene and protein status might relate to mRNA instability, transcriptional changes, or to changes at the posttranslational levels. It may also be possible that tissue [Mg2+]i was not high enough to influence TRPM7 protein expression.
In conclusion, data from the present study demonstrate that aldosterone mediates blood pressure-independent renal and cardiovascular fibrosis and inflammation and electrolyte disturbances through Mg2+-sensitive pathways. We also report the novel findings that aldosterone induces downregulation of renal TRPM7 and annexin-1. These findings suggest that altered Mg2+ metabolism in hyperaldosteronism may relate to TRPM7 dysregulation and that Mg2+ protects against cardiovascular and renal damaging actions of aldosterone.
Perspectives
Hyperaldosteronism, the incidence of which is increasing in clinical medicine, is associated with hypomagnesemia, hypertension, and cardiovascular remodeling. Mechanisms contributing to these processes, and particularly to aldosterone-associated Mg2+ changes, are unclear. Experimental evidence suggests that impaired transmembrane Mg2+ transport through TRPM6/7 channels may be important. Our data demonstrate that aldosterone mediates blood pressure-independent renal and cardiovascular fibrosis and inflammation and renal dysfunction, which are ameliorated by dietary Mg2+-supplementation. We also show that aldosterone induces downregulation of renal TRPM7 and its target annexin-1. Hence altered Mg2+ metabolism in aldosteronism may relate to TRPM7 dysregulation. Magnesium has cardiovascular protective effects and prevents renal damage and dysfunction in aldosteronism. Such findings have important clinical implications in the understanding of mechanisms underlying hyperaldosteronism-associated hypomagnesemia and associated target-organ damage and suggest that Mg2+ supplementation may have potential therapeutic benefit in this condition.
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Acknowledgments |
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Sources of Funding
This study was supported by grants from the Canadian Institutes of Health Research (CIHR) and the Heart and Stroke Foundation of Canada. R.M.T. is supported through a Canada Research Chair/Canadian Foundation for Innovation award. A.C.I.M. received a fellowship from Amgen.
Disclosures
None.
Received August 22, 2007; first decision September 15, 2007; accepted January 14, 2008.
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