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NDT Advance Access first published online on April 5, 2008
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Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn159
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Transforming growth factor-β1 is associated with kidney damage in patients with essential hypertension: renoprotective effect of ACE inhibitor and/or angiotensin II receptor blocker

Shiming Zhu1, Yuying Liu1, Liqi Wang1 and Qing H. Meng2

1 Division of Cardiology, Department of Medicine, Clinical Medical College of Shandong University, Jinan Central Hospital, Jinan, People's Republic of China 2 Department of Pathology and Laboratory Medicine, Royal University Hospital, University of Saskatchewan, Canada

Correspondence and offprint requests to: Qing Meng, Department of Pathology and Laboratory Medicine, Room 4917, Royal University Hospital, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada. Tel: +1-306-655-2165; Fax: +1-306-655-2193; E-mail: qing.meng{at}usask.ca



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Evidence suggests that transforming growth factor-β1 (TGF-β1) is associated with target organ damage in hypertension. This study aimed to investigate the relationship between TGF-β1 levels and kidney damage and renoprotective effects of angiotensin-converting enzyme inhibitor and/or angiotensin II type 1 receptor blocker in patients with essential hypertension (EH).

Methods. A total of 156 patients with EH were enrolled and grouped according to albumin-to-creatinine ratio (ACR). Of these, 90 patients with EH underwent a 12-week antihypertensive trial with administration of benazepril, valsartan or both. Serum TGF-β1, plasma angiotensin (Ang) II and urinary albumin were quantified by immunoassays.

Results. Serum TGF-β1, plasma Ang II and ACR were highly elevated in patients with EH (P < 0.01). There was a positive correlation between serum TGF-β1 levels and ACR (r = 0.53, P < 0.01). Significant decreases in TGF β1 and ACR were obtained in all groups at the end of 12-week antihypertensive therapy compared to the baseline values, with the combined group to a greater extent (P < 0.01). Plasma Ang II levels were significantly decreased in the benazepril group but increased in the valsartan group (P < 0.05) while no significant change was observed in the combined group.

Conclusions. TGF-β1 is highly elevated and strongly associated with urinary albumin excretion in patients with EH. Treatment with benazepril or valsartan attenuates serum TGF-β1 levels and microalbuminuria with the combined therapy receiving the greater effect. TGF-β1 could be a potential surrogate marker in monitoring the development and progression of kidney damage in EH.

Keywords: angiotensin; essential hypertension; kidney damage; microalbuminuria; transforming growth factor-β1



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Essential hypertension (EH) is a key factor that can initiate and facilitate renal damage, leading to renal insufficiency [1]. Subtle renal insufficiency such as microalbuminuria usually takes place long before evident renal failure occurs [1,2]. On the other hand, reduction in albuminuria improves prognosis in hypertension [3]. Microalbuminuria is frequently seen in patients with established EH. A number of studies have shown that microalbuminuria is an independent risk predictor for cardiovascular complications in hypertensive patients [3,4]. Microalbuminuria is also considered as an early, sensitive marker for kidney damage commonly seen in hypertensive patients [2,5–9].

Transforming growth factor-β (TGF-β) is a multifunctional cytokine and is strongly associated with the development of nephrosclerosis [10]. TGF-β1 regulates cell growth and differentiation, stimulates extracellular matrix production and inhibits matrix degradation [11,12]. Emerging evidence suggests that TGF-β1 is involved in the pathogenesis of hypertension and the development of hypertensive target organ damage [13]. A TGF-β1-induced blood pressure elevation is mediated through the stimulation of endothelin mRNA expression in the vascular endothelium, the increase of renin release from juxtaglomerular cells in the kidney and the regulation of angiotensin II expression [14,15]. A higher plasma TGF-β1 concentration is found in hypertensive patients with microalbuminuria [16]. In fact, data indicate that TGF-β1 levels are positively associated with urinary albumin excretion in hypertensive subjects [17]. August et al. demonstrated that circulating TGF-β1 levels are highly elevated in hypertensive patients compared to the normotensives and related to the progression of renal disease [18]. Taken together, emerging evidence indicates that TGF-β1 is associated with kidney damage in hypertension.

Angiotensin II (Ang II), the primary effective molecule of the renin–angiotensin system (RAS), induces target organ damage in hypertension via its interaction with angiotensin II type 1 receptor [19]. Ang II has been implicated in renal TGF-β1 over-expression, which, in turn, contributes to renal fibrosis [15]. Recent studies have shown that treatment with angiotensin-converting enzyme inhibitors (ACEI) and/or Ang II receptor blocker (ARB) to block Ang II production and action was associated with a reduced TGF-β1 expression and urinary albumin excretion [20,21]. These findings suggest that antihypertensive drugs that block the actions of Ang II have beneficial effects in protecting kidney function in hypertension. Although the link between TGF-β1 and urinary albumin (protein) excretion was studied [20,21], the quantitative correlation between the TGF-β1 and urinary albumin excretion was not well described and the sample size used was too small. Moreover, the underlying pathogenic mechanisms of microalbuminuria in hypertension and the role of TGF-β1 in hypertensive renal damage have not been fully understood. In this study, we investigated the relationship between circulating TGF-β1 and microalbuminuria in EH using a larger sample size with various degree of albuminuria. In particular, we evaluated for the first time, the renoprotective effects and potential mechanisms of ACEI, benazepril and ARB, valsartan in patients with EH.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Study subjects
The research protocol was approved by the ethics committee of the Clinical Medical College of Shandong University. All participants gave written consent. All participants were recruited at Jinan Central Hospital Clinic during June to December 2006. A total of 156 patients with stages 1 (systolic blood pressure, SBP 140–159 mmHg and diastolic blood pressure, DBP 90–99 mmHg) and 2 (SBP 160–179 mmHg and DBP 100–109 mmHg) EH [2] and 50 normotensive controls were included. Exclusion criteria included infectious and inflammatory diseases, the presence of any form of secondary hypertension, heart failure with left ventricular hypertrophy, diabetes, metabolic disease, hepatic disease, renal disease and malignancy.

Clinical study
All patients were taken off antihypertensive and lipid-lowering medications from one week prior to entering this study. Blood pressure was taken as the mean of two to three independent measurements with at least 2-min separation obtained with a standard sphygmomanometer after 5 min of rest at clinic. Detailed history of the participants was taken, and their physical examination and routine laboratory testing were done. A 24-h ambulatory blood pressure monitoring was also applied to record SBP and DBP for those who were admitted to the antihypertensive drug trial at baseline and 12 weeks.

According to American Diabetes Association guideline [22], patients with EH were classified into three groups based on the albumin-to-creatinine ratio (ACR): group A (macroalbuminuria, ACR ≥ 300 mg/g), group B (microalbuminuria, ACR 30–299 mg/g) and group C (normal, ACR < 30 mg/g). In addition, group D was included as normotensive healthy controls (ACR < 30 mg/g).

To investigate the renoprotective effects of ACEI (benazepril) and/or ARB (valsartan) in EH, a prospective, randomized, double-blind trial was conducted. This study followed the recommendation for reporting randomized trials [23]. Ninety hypertensive patients (stages 1 and 2) further participated in the 12-week antihypertensive drug trial (Figure 1). Participants were randomly allocated into three groups: benazepril group (10 mg once daily, n = 30), valsartan group (80 mg once daily, n = 30) and the combined group (benazepril 10 mg + valsartan 80 mg once daily, n = 30). All groups were matched for sex, age, BMI, blood pressure and ACR. Blood pressure was measured 2 weeks after administration of antihypertensive drug(s). For those in whom the blood pressure was not normalized (SBP ≤ 140 mmHg and DBP ≤ 90 mmHg), the dose was doubled for each medication. If the blood pressure was still not normalized after 2-week double-dose medication, hydrochlorothiazide (12.5 mg once daily) was given to achieve the goal (benazepril group, n = 3 patients; valsartan group, n = 3 patients; the combined group, n = 2 patients). In the course of the trial, eight participants dropped out from this study. Of these, two patients dropped out due to severe cough from benazepril group, one patient due to failure of normalization of blood pressure from valsartan and four patients due to failure of follow-up. So the final participants qualified for the data collection and analyses were the benazepril group (n = 28), the valsartan group (n = 27) and the combined group (n = 27). The end-point of this study was to determine the improvement of ACR in association with TGF-β1 reduction. The sample size of 82 subjects enabled detection of a standardized difference of 0.9 at a two-sided significance value of 0.05 and a power of 0.8.


Figure 1
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  		Fig. 1 Flow diagram of antihypertensive trial.

 
Biochemical determinations
Peripheral venous blood samples were collected into a serum separator tube from each subject after overnight fast and allowed to clot for 30 min at room temperature. Sera were isolated, aliquoted and stored at –70°C for the TGF-β1 measurement. After activation of the sera by acidification and neutralization as recommended by the manufacturer, TGF-β1 protein concentration was determined using solid-phase TGF-β1-specific sandwich ELISA (Quantikine human TGF-β1 ELISA, R&D Systems, Minneapolis, MN, USA) as described previously [24]. The detection limit for this assay was 5 pg/ml. The intra-assay and inter-assay coefficients of variations were 3% and 9%, respectively.

Blood samples for Ang II determination were collected on ice in tubes containing EDTA as anticoagulant, and angiotensinase inhibitor (Buhlmann Laboratories, Basel, Switzerland) was added to preserve the sample stability. Plasma was isolated at 4°C and stored at –20°C until assay was performed. Ang II was determined by radioimmunoassay (Nicholas Institute, San Juan Capistrano, CA, USA). The detection limit for this assay was 3.80 pg/ml. The intra-assay and inter-assay coefficients of variations were 4% and 5%, respectively.

Urinary albumin was measured by an immunonephelometric assay (Dade Behring Inc., detection limit, 0.1 mg/dl; inter-assay coefficient of variation, 3.5%). Blood urea nitrogen (BUN) and creatinine were determined spectrophotometrically on a Bayer 2400 chemistry analyser (Bayer Corporation). Plasma glucose, lipids, uric acid and electrolytes were measured by routine laboratory methods.

Statistical analysis
All data are expressed as mean ± SD. Statistical analyses were performed with SPSS14.0 software (SPSS Inc.). Differences among groups were tested using one-way ANOVA followed by a post hoc analysis (Tukey test). Differences between the means of the two groups and between the values taken at baseline and the end of the intervention period were compared with Student's t-test. The categorical variable comparison was performed by means of the {chi}2 test. Regression analysis was performed to determine the correlation. The statistical significance was defined as P < 0.05.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Clinical data of study population
There were no differences in terms of sex, age, smoking history and blood pressure among groups A, B and C. However, BMI, serum BUN and creatinine levels in group A or B were higher than those in group C (Table 1). All the above parameters were comparable between groups C and D. Serum TGF-β1, plasma Ang II and ACR were highly elevated in patients with EH. Furthermore, serum levels of TGF-β1, plasma Ang II and ACR in group A or B were higher that those in group C (P < 0.01). Levels of serum TGF-β1, plasma Ang II and ACR in group A were higher than those in group B (P < 0.01) (Table 1). There were no differences of TGF-β1, Ang II and ACR between groups C and D (Table 1).


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  		Table 1 Characteristics of study population and association of TGF β1 with Ang II and ACR

 
Correlation between TGF β1 and ACR in essential hypertension
The correlation between serum TGF-β1 levels and ACR or Ang II in EH was assessed. There was a positive correlation between serum TGF-β1 levels and ACR (r = 0.53, P < 0.01) (Figure 2). A positive correlation between serum TGF-β1 levels and Ang II was also observed (r = 0.35, P < 0.05) (Table 1).


Figure 2
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  		Fig. 2 Correlation between serum TGF-β1 levels and ACR. Regression analysis indicates a positive correlation between serum TGF-β1 levels and ACR (r = 0.53, P < 0.01).

 
Antihypertensive effects of benazepril and/or valsartan on EH
Blood pressure (SBP and DBP) was significantly reduced after 12-week antihypertensive therapy in all the three groups compared to their baseline blood pressure values (P < 0.05). There were no significant differences in the reduction of blood pressure among the three groups although the combined group appeared to have a slight great reduction of blood pressure (Table 2). There were no significant changes in serum BUN and creatinine concentrations at the end of antihypertensive therapy (P > 0.05) (Table 2). There were no significant changes in glucose, lipids, uric acid and electrolytes compared to the baseline values (data not shown).


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  		Table 2 Effects of benazepril and/or valsartan on TGF β1 levels and ACR in essential hypertensive patients

 
Effects of benazepril and/or valsartan on ACR
Significant decreases in ACR were observed in all groups at the end of treatment, with the combined group to a greater extent compared to their baseline values (P < 0.01). There was no significant difference in ACR reduction between benazepril and valsartan groups after treatment. However, in the combined group, the reduction of ACR following treatment was greater than that of benazepril (52% versus 35%) or valsartan (52% versus 35%) alone (P < 0.05) (Table 2, Figure 3).


Figure 3
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  		Fig. 3 Effects of benazepril and/or valsartan on ACR. Significant decreases in ACR were observed in all groups at the end of treatment compared to their baseline values. In addition, the reduction of ACR in the combined group following treatment was greater than that of benazepril or valsartan alone. *P < 0.05, **P < 0.01 versus baseline; {dagger}P < 0.05 versus benazepril or valsartan group post-treatment.

 
Effects of benazepril and/or valsartan on TGF-β1
There was a significant reduction in TGF β1 levels in all the groups at the end of treatment, with the combined group to a greater extent compared to their baseline values (P < 0.01). There was no significant difference in the reduction of TGF β1 levels between benazepril and valsartan groups after treatment. However, in the combined group, the reduction of TGF β1 levels following treatment was greater than that of the benazepril (46% versus 31%) or valsartan group (46% versus 28%) (P < 0.05) (Table 2, Figure 4).


Figure 4
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  		Fig. 4 Effects of benazepril and/or valsartan on TGF-β1. Significant reduction in TGF-β1 levels was observed in all groups at the end of treatment compared to their baseline values. A greater reduction in TGF-β1 levels in the combined group was achieved following treatment compared with that of the benazepril or valsartan group alone. *P < 0.05, **P < 0.01 versus baseline; {dagger}P < 0.05 versus benazepril or valsartan group post-treatment.

 
Effects of benazepril and/or valsartan on AngII
Significant decrease in Ang II levels was only observed in the benazepril group at the end of treatment compared to the baseline values (P < 0.05). In contrast, there was a significant increase in Ang II in patients following treatment with valsartan compared to the baseline values (P < 0.05). Overall, there was no significant change in Ang II levels in the combined group following the treatment (Table 2, Figure 5).


Figure 5
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  		Fig. 5 Effects of benazepril and/or valsartan on AngII. There was a significant decrease in Ang II levels in the benazepril group at the end of treatment compared to the baseline values. In contrast, a significant increase in Ang II was observed in the valsartan group compared to the baseline values. There was no significant change in Ang II levels in the combined group following the treatment. *P < 0.05 versus baseline.

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Substantial evidence has demonstrated that TGF-β1 levels are highly elevated in EH [13,16]. High levels of TGF-β1 are associated with hypertensive target organ damage, especially renal damage indicated as increased urinary albumin excretion [13,17]. In this study, we have found that serum TGF-β1 levels were significantly increased in patients with EH with increased urinary albumin excretion, i.e. in groups A and B. The TGF-β1 levels did not differ significantly between groups C and D although patients of group C had high blood pressure similar to groups A and B, but ACR < 30 mg/g. In addition, our study shows that there is a positive correlation between serum TGF-β1 levels and ACR values. These data indicate that TGF-β1 is associated with urinary albumin excretion and the progression of hypertensive kidney damage. Therefore, TGF-β1 overproduction in hypertension could be a pathogenic mechanism for hypertensive renal damage [25]. TGF-β1 has been shown to play a critical role in hypertensive nephropathy [26]. The underlying mechanism by which circulating TGF-β1 induced hypertensive renal damage has been investigated. Studies have demonstrated that TGF-β1 promotes the epithelial-to-mesenchymal transition [27], potentiates renal tubular epithelial cell death [28] and induces mesangial cell apoptosis [29]. In addition, a great number of studies have demonstrated that TGF-β1 enhances extracellular matrix synthesis and accumulation and inhibits matrix degradation [30], leading to nephrosclerosis. The TGF-β1-induced inhibition of the lysosomal activity could also contribute to albumin excretion in hypertension [31].

Recent studies have demonstrated that Ang II increases the expression and synthesis of TGF-β1 [15,32,33], which could be responsible for the development of proteinuria. It has been reported that antihypertensive drugs, ACEI, decrease TGF-β1 levels and reduce urinary albumin excretion [34]. Another study has also shown that ACEI inhibits TGF-β1 expression in the kidney and reduce proteinnuria [35]. Other studies have shown that ARB significantly decreases the plasma levels of TGF-β1 and proteinuria [24,36,37]. Treatment with the combination of ACEI and ARB attenuates the production of TGF-β1 and protects renal function to a greater extent [20]. We have demonstrated that ACEI or ARB reduces the circulating TGF-β1 levels and ACR in patients with EH. The combination of ACEI and ARB results in a greater reduction of TGF-β1 levels and ACR than either drug alone, suggesting the beneficial effect of the combined antihypertensive therapy though the blood pressure is not further reduced. The finding that the reduction of ACR is related to the decrease in TGF-β1 levels following ACEI and/or ARB therapy further suggests that TGF-β1 is responsible for hypertensive renal damage. In theory, the combination of ACEI and ARB could provide a better blockade of Ang II than either of ACEI or ARB alone in the RAS. Therefore, the combined therapy could provide a better renoprotection as well as reduce some side effects such as dry cough and neurovascular oedema caused by ACEI. A recent study reveals that the inhibition of ACEI on TGF-β1 is mediated through inhibition of the hydrolysis of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) [38]. Our findings and those of others suggest that inhibition of TGF-β1 expression and signalling could be employed as new renoprotective treatments [39]. Compared to the studies published [13,16,20], this study provides a more comprehensive and quantitative analysis describing the correlation between TGF-β1 and microalbuminuria using a larger sample size. Moreover, the effects of benazepril and valsartan on serum TGF-β1 levels and subsequent renoprotection were investigated for the first time although other types of ACEI and ARB have been assessed in patients with EH. Further analysis of the correlation, particularly in the groups of ACR ≥300 mg/g and ACR 30–299 mg/g, could provide more valuable information and stronger prediction for the pathological role of TGF-β1 in urinary albumin excretion. The causative correlation, particularly the time course between TGF-β1 elevation and urinary albumin excretion, should be determined in the future so that early intervention or preventive measures can be initiated.

In conclusions, serum TGF-β1 levels are highly elevated and positively correlated with urinary albumin excretion in patients with EH. Treatment with the combined ACEI and ARB provides a better renoprotective effects than a single therapy alone. TGF-β1 could be a potential surrogate marker in monitoring the development and progression of kidney damage in patients with EH.



   Acknowledgments
 
This work was supported by Jinan Science and Technology Research Foundation, Jinan, China.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 23. 1.08
Accepted in revised form: 29. 2.08


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