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(Hypertension. 2000;36:517.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Transforming Growth Factor ß in Hypertensives With Cardiorenal Damage

Concepción Laviades; Nerea Varo; Javier Díez

From the Division of Nephrology, San Jorge General Hospital, Huesca (C.L.); Department of Clinical Chemistry, University Clinic, University of Navarra, Pamplona (N.V.); and Department of Cardiology, University Clinic and Vascular Pathophysiology Unit, School of Medicine, University of Navarra, Pamplona (J.D.), Spain.

Correspondence to Dr Javier Díez, Unidad de Fisiopatología Vascular, Facultad de Medicina, C/Irunlarrea s/n, 31080 Pamplona, Spain. E-mail jadimar{at}unav.es

	Abstract

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Abstract—We investigated whether a relationship exists between circulating transforming growth factor ß -1 (TGF-ß₁), collagen type I metabolism, microalbuminuria, and left ventricular hypertrophy in essential hypertension and whether the ability of the angiotensin II type 1 receptor antagonist losartan to correct microalbuminuria and regress left ventricular hypertrophy in hypertensives is related to changes in TGF-ß₁ and collagen type I metabolism. The study was performed in 30 normotensive healthy controls and 30 patients with never-treated essential hypertension classified into 2 groups: those with microalbuminuria (urinary albumin excretion >30 and <300 mg/24 h) associated with left ventricular hypertrophy (left ventricular mass index >116 g/m² for men and >104 g/m² for women) (group B; n=17) and those without microalbuminuria or left ventricular hypertrophy (group A; n=13). The measurements were repeated in all patients after 6 months of treatment with losartan (50 mg once daily). The serum concentration of TGF-ß₁ was measured by a 2-site ELISA method, and the serum concentrations of carboxy-terminal propeptide of procollagen type I (a marker of collagen type I synthesis) and carboxy-terminal telopeptide of collagen type I (a marker of collagen type I degradation) were measured by specific radioimmunoassays. The duration of hypertension and baseline values of blood pressure were similar in the 2 groups of patients. No differences in serum TGF-ß₁, carboxy-terminal propeptide of procollagen type I, and carboxy-terminal telopeptide of collagen type I were found between normotensives and group A of hypertensives. Serum TGF-ß₁, carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I were increased (P<0.05) in group B of hypertensives compared with group A of hypertensives and normotensives. No differences in carboxy-terminal telopeptide of collagen type I were found among the 3 groups of subjects. After treatment with losartan, microalbuminuria and left ventricular hypertrophy persisted in 6 patients (then considered nonresponders) and disappeared in 11 patients (then considered responders) from group B. Compared with nonresponders, responders exhibited similar control of blood pressure and higher (P<0.05) blockade of angiotensin II type 1 receptors (as assessed by a higher increase in plasma levels of angiotensin II). Whereas TGF-ß₁, carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I decreased (P<0.05) in responders, no changes in these parameters were observed in nonresponders. These findings show that an association exists between an excess of TGF-ß₁, stimulation of collagen type I synthesis, inhibition of collagen type I degradation, and cardiorenal damage in a group of patients with essential hypertension. In addition, our results suggest that the ability of losartan to blunt the synthesis of TGF-ß₁ and normalize collagen type I metabolism may contribute to protect the heart and the kidney in a fraction of patients with essential hypertension.

Key Words: collagen • hypertension, essential • hypertrophy, left ventricular • angiotensin antagonist • albuminuria • transforming growth factors

	Introduction

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Microalbuminuria and left ventricular hypertrophy (LVH) are associated with an enhanced cardiovascular risk in hypertensive patients.^{1 2} Although microalbuminuria has been attributed to various mechanisms (ie, functional and/or structural abnormalities of the glomeruli and/or the vessels and/or the tubuli),³ the origin of hypertensive microalbuminuria remains obscure. On the other hand, hemodynamic and nonhemodynamic factors (ie, vasoactive substances, cytokines, and growth factors)⁴ have been proposed to explain the origin of LVH associated with hypertension.

Transforming growth factor ß-1 (TGF-ß₁) is a multifunctional cytokine with fibrogenic and hemodynamic properties.⁵ TGF-ß₁ directly stimulates the synthesis of matrix molecules and blocks matrix degradation.⁶ In addition, TGF-ß₁ may determine blood pressure levels via endothelin⁷ and/or the renin-angiotensin system.⁸ Li et al⁹ have shown that a positive correlation exists between circulating levels of TGF-ß₁ protein and blood pressure in humans. On the other hand, upregulation of TGF-ß₁ has been reported to be associated with cardiovascular¹⁰ and renal⁸ alterations in hypertensive patients.

The procollagen type I carboxy-terminal peptide (PIP), a 100-kDa peptide cleaved from procollagen type I during the synthesis of the fibril-forming collagen type I and released into the blood stream with a stoichiometric ratio of 1:1, can be measured to assess collagen type I synthesis.¹¹ Similarly, the pyridoline cross-linked carboxy-terminal telopeptide domain of collagen type I (CITP), a 12-kDa telopeptide resulting from the cleavage of collagen type I fibers by collagenase and released into the blood stream with a stoichiometry of 1:1, may be determined to assess collagen type I degradation.¹¹ Determinations of serum PIP and CITP have been recently demonstrated to be useful markers of increased and depressed collagen type I synthesis and degradation, respectively, in spontaneously hypertensive rats^{12 13} and patients with essential hypertension.^{14 15}

In an attempt to gain insight into the potential role of TGF-ß₁ in development of microalbuminuria and LVH in hypertensives, we explored the hypothesis that TGF-ß₁ hyperexpression and altered collagen type I metabolism are associated with these 2 alterations in patients with essential hypertension. In addition, we investigated whether the ability of the angiotensin II type 1 (AT₁) receptor antagonist losartan to correct microalbuminuria¹⁶ and reverse LVH¹⁷ in patients with essential hypertension is related to downregulation of TGF-ß₁ and normalization of collagen type I metabolism.

	Methods

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Subjects
The study population consisted of 30 patients with mild to moderate essential hypertension (systolic and diastolic blood pressure >139 and 89 mm Hg, respectively) never treated in stage 1 or 2 of organ damage¹⁸ and 30 normotensive control subjects. All subjects gave informed consent, and the local committee on human research approved the study protocol. The procedures followed were in accordance with institutional guidelines.

Subjects with conditions associated with alterations in serum levels of PIP and/or CITP (liver cirrhosis, osteoporosis, hyperthyroidism, multiple myeloma, osteolytic metastases, systemic glucocorticoid treatment, and renal insufficiency) were excluded after complete medical examinations.

All patients received losartan as treatment (50 mg once daily as a fixed dose) for 6 months. The therapeutic goal was to achieve systolic blood pressure and diastolic blood pressure of <140 and 90 mm Hg, respectively. After 3 and 6 months of treatment, each patient underwent another complete medical examination.

Clinical Studies
Mean arterial pressure was calculated from the equation (SBP+2DBP)/3, where SBP and DBP represent systolic and diastolic blood pressure, respectively. Pulse pressure was the arithmetic difference between averaged systolic blood pressure and diastolic blood pressure values.

The general analytical parameters were measured by routine laboratory methods. Urinary albumin excretion (UAE) rate for 24-hour urine collection was measured by an immunonephelometric assay (Behring Institute; limit of detection, 0.1 mg/dL; interassay variation coefficient, 3.5%) on samples collected from 8 AM to 8 AM during 3 consecutive days. Microalbuminuria was defined as a UAE >30 and <300 mg/24 h. Renal clearance of creatinine was calculated as the product of urine flow rate and the urine creatinine concentration divided by the serum creatinine concentration.

Left ventricular mass was calculated from 2-dimensional, targeted M-mode recordings obtained in each patient, as previously described.^{14 15} Left ventricular mass index (LVMI) was obtained by dividing left ventricular mass by body surface area. The presence of LVH was established when LVMI was >116 g/m² for men and >104 g/m² for women.¹⁹

Biochemical Determinations
Peripheral venous blood was obtained from each subject, and the sera were isolated and stored at -70°C until assayed for TGF-ß₁. After activation of the sera by acidification, the biologically active TGF-ß₁ protein concentration was determined with the use of a solid-phase TGF-ß₁–specific sandwich ELISA (R&D Systems) according to Khanna et al.²⁰ The interassay and intra-assay variations for determining TGF-ß₁ were 8% and 6%, respectively. The sensitivity (minimum level of detection of TGF-ß₁) was 5 pg/mL.

Blood samples to determine serum PIP and CITP were taken at the time of medical examination and stored at -40°C until manipulation. The 2 peptides were determined by specific radioimmunoassays with the use of specific antisera (Orion Diagnostica), as previously described.^{14 15} The interassay and intra-assay variations for determining PIP were 7% and 3%, respectively. The sensitivity was 0.5 µg PIP per liter. The interassay and intra-assay variations for measuring CITP were 8% and 6%, respectively. The sensitivity was 0.5 µg CITP per liter.

Blood samples for determination of angiotensin II were collected on ice in tubes containing EDTA and angiotensinase inhibitor (Buhlman Laboratories) and centrifuged at 4°C; plasma samples were frozen at -40°C until the assay was performed. Angiotensin II was determined by radioimmunoassay (Nichols Institute). The interassay and intra-assay variations for measuring angiotensin II were 5% and 4%, respectively. The sensitivity was 3.80 pg angiotensin II per milliliter.

Statistical Analysis
Results are presented as mean±SD. Differences among normotensive subjects and hypertensives from groups A and B were tested by a 1-way ANOVA once normality was demonstrated (Shapiro-Wilks test); otherwise, a nonparametric test (Kruskal-Wallis) was used. If significant differences (P<0.05) were obtained by ANOVA, subsequent multiple comparison Scheffé’s test, or contrast coefficient matrix test when variances were not homogeneous (Levene test), was applied. In the same way, after the Kruskal-Wallis test we used the Mann-Whitney U test to check differences between 2 groups. Student’s t tests for paired and unpaired data were used to examine the significance of differences in hypertensives from group B after treatment. The correlation between continuously distributed variables was tested by univariate regression analysis.

	Results

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Baseline Findings
Clinical Data
The clinical characteristics of normotensive subjects and hypertensive patients are presented in Table 1. After complete clinical examinations, hypertensive patients were classified into 2 groups: those with microalbuminuria associated with LVH (group B; n=17) and those without microalbuminuria or LVH (group A; n=13). The frequency of men was higher (P<0.05) in group B of hypertensives than in group A of hypertensives and normotensives. As expected, the values of mean arterial pressure and pulse pressure were higher (P<0.05) in the 2 groups of hypertensives than in the group of normotensives. The values of UAE and LVMI were increased (P<0.05) in the 2 groups of hypertensives compared with the group of normotensives. These 2 parameters were increased (P<0.05) in group B of hypertensives compared with group A of hypertensives. The creatinine clearance was normal in all patients.

View this table: [in this window] [in a new window]   Table 1. Clinical Parameters Determined in Normotensive Subjects and Hypertensive Patients

Biochemical Data
Serum concentration of TGF-ß₁ was increased (P<0.05) in group B of hypertensives (84±8 ng/mL) compared with group A of hypertensives (53±10 ng/mL) and normotensives (48±12 ng/mL) (Figure 1). No differences in serum TGF-ß₁ were observed between group A of hypertensives and normotensives (Figure 1). Ten patients from group B exhibited values of TGF-ß₁ above the upper normal limit measured in normotensives (71 ng/mL).

View larger version (20K): [in this window] [in a new window]   Figure 1. Baseline serum concentrations of TGF-ß1 (left), PIP (middle), and CITP (right) in normotensive controls (open bar), hypertensives without microalbuminuria or LVH (group A, shaded bar), and hypertensives with microalbuminuria and LVH (group B, solid bar). *P<0.05 compared with the other 2 groups of subjects.

As shown in Figure 1, serum PIP concentration was higher (P<0.05) in group B of hypertensives (160±16 ng/mL) than in group A of hypertensives (117±20 ng/mL) and normotensives (107±29 ng/mL). No significant changes in serum CITP were observed among the 3 groups of studied subjects (Figure 1). Therefore, the ratio between PIP and CITP, an index of the degree of coupling between the synthesis and degradation of collagen type I,¹² was increased (P<0.05) in group B of hypertensives (90±8) compared with group A of hypertensives (55±7) and normotensives (53±7).

Findings During Treatment
Clinical Data
The time course effects of treatment with losartan on hemodynamic and clinical and hormonal parameters are presented in Tables 2 and 3, respectively. None of the hypertensives from group A developed microalbuminuria or LVH during the treatment with losartan (Table 3). At the end of the treatment period, 2 subgroups of hypertensives from group B were identified according to the evolution of UAE and LVMI: those in which microalbuminuria and LVH were corrected (responders; n=11) and those in which these 2 alterations persisted (nonresponders; n=6). Whereas a similar control of blood pressure was attained in the 2 subgroups (Table 2), the intensity of AT₁ blockade, as assessed by the increase in circulating angiotensin II, was higher (P<0.05) in responders than in nonresponders (Table 3). Whereas UAE and LVMI diminished to normal values (P<0.05) in the subgroup of responders, they remained unchanged in the subgroup of nonresponders (Table 3).

View this table: [in this window] [in a new window]   Table 2. Time Course Effects of Treatment on Hemodynamic Parameters in Hypertensive Patients

View this table: [in this window] [in a new window]   Table 3. Time Course Effects of Treatment on Clinical and Hormonal Parameters in Hypertensive Patients

Biochemical Data
Figure 2 shows the time course of changes induced by treatment with losartan in several biochemical parameters in the 2 subgroups of hypertensives. Whereas TGF-ß₁ was unchanged in nonresponders, it decreased progressively to reach normal values (P<0.05) in responders. Similarly, PIP levels did not change in nonresponders, but they diminished to reach normal values (P<0.05) in responders. No significant changes in CITP were observed with treatment in the 2 subgroups of patients. The PIP:CITP ratio measured at the end of the treatment period was normal in responders (58±6) but remained abnormally increased in nonresponders (87±9).

View larger version (14K): [in this window] [in a new window]   Figure 2. Time course of changes in serum concentrations of TGF-ß1 (left), PIP (middle), and CITP (right) in group B hypertensives in whom microalbuminuria and LVH were corrected (responders, open circles) or persisted (nonresponders, solid circles) with losartan treatment. *P<0.05 compared with values measured at baseline; **P<0.05 compared with values measured at baseline and after 3 months of treatment.

A direct correlation was found after treatment between percent changes in serum TGF-ß₁ and percent changes in serum PIP (r=0.67, P<0.05) in responder patients from group B. No correlations between these 2 parameters were found in the other 2 groups of patients after treatment. No correlations were found among other parameters in this study.

	Discussion

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One finding of this study is that there is a group of hypertensives with high cardiovascular risk, as assessed by the association of microalbuminuria with LVH, who exhibit abnormally high serum levels of TGF-ß₁ and alterations in the circulating markers of collagen type I metabolism.

Overproduction of TGF-ß₁ has been experimentally linked to the sequela of chronic hypertension, including LVH,²¹ vascular remodeling,²² and progressive renal disease.²³ Although many of the biological actions of TGF-ß₁ are mediated in an autocrine or paracrine fashion, data from transgenic mice have demonstrated that high circulating levels can mediate organ and tissue damage.²⁴ Thus, our finding that an excess of circulating TGF-ß₁ is associated with microalbuminuria and LVH in patients with essential hypertension adds clinical support to the notion that this cytokine can play a role in the pathophysiology of end-organ damage in a group (57%) of patients with essential hypertension.

Experimental^{7 8} and clinical⁹ evidence suggested a role for TGF-ß₁ in the elevation of blood pressure. However, no differences in either mean arterial pressure or pulse pressure were found in this study between group A of hypertensives with normal TGF-ß₁ levels and group B of hypertensives with exaggerated TGF-ß₁ levels. Thus, a nonhemodynamic mechanism may be involved in the potential contribution of this growth factor to microalbuminuria and LVH in hypertension.

Our finding that the excess of TGF-ß₁ is associated with an imbalance between increased PIP and normal CITP suggests that synthesis of collagen type I fibers is stimulated and its degradation inhibited in hypertensives from group B. Recently, we demonstrated in rats with spontaneous hypertension¹² and in patients with essential hypertension²⁵ that these biochemical alterations in collagen-derived serum peptides reflect closely the presence of myocardial fibrosis. It thus can be proposed that hypertensives from group B may present renal and cardiac fibrosis. Several arguments may support this proposal. First, TGF-ß₁ has been found to increase mRNA levels for most of the extracellular matrix proteins, including preprocollagen type I, and to result in increased secretion of the protein (ie, procollagen type I).⁶ These effects are complemented by the ability of TGF-ß₁ to interfere with proteolytic degradation of collagen fibers via reduction in synthesis and secretion of matrix metalloproteinases and increased synthesis of tissue inhibitors of metalloproteinases.⁶ Second, the presence of microalbuminuria in essential hypertensive patients has been interpreted as a marker of the early development of nephrosclerosis.^{26 27 28 29} Third, fibrous tissue accumulation is an integral feature of the adverse structural remodeling of cardiac tissue seen in hypertensive patients with LVH.^{30 31}

A second finding of the present study is that losartan corrected microalbuminuria and LVH only in those hypertensives in whom the circulating levels of TGF-ß₁ were progressively normalized during the treatment period. In contrast, both alterations persisted in those hypertensives in which TGF-ß₁ levels remained unchanged during treatment with losartan. Because the antihypertensive efficacy of losartan was similar in the 2 subgroups of patients, it is tempting to speculate that the ability of the drug to diminish TGF-ß₁ may be involved in its beneficial effects at the cardiac and renal levels. This is further supported by the observation that markers of collagen type I metabolism were normalized in those hypertensives in whom TGF-ß₁ was normalized with treatment but remained altered in the remaining hypertensives. Furthermore, changes observed in TGF-ß₁ with treatment correlated with changes in PIP only in responder patients.

Recent experimental⁸ and clinical³² studies have demonstrated that angiotensin-converting enzyme inhibitors or AT₁ antagonists may interfere with the synthesis and secretion of TGF-ß₁. For instance, Campistol et al³² have reported that the circulating levels of TGF-ß₁ decreased progressively and significantly in 14 transplant patients with chronic allograft nephropathy treated with losartan (50 mg) for 8 weeks. Since data exist that angiotensin II regulates the production of TGF-ß₁ at different levels,^{8 33} it is likely that the mechanism by which losartan decreases serum levels of this factor is through interrupting the interaction of the octapeptide with AT₁ receptors. In support of this possibility is our observation that the normalization of TGF-ß₁ levels was attained in those hypertensives who exhibited the highest response to AT₁ blockade (as assessed by the highest elevation in plasma angiotensin II) under treatment with losartan.

Some questions arise regarding the mechanisms responsible for the existence of 2 patterns of response to losartan, in terms of AT₁ blockade and TGF-ß₁ inhibition, in group B hypertensives. On one hand, the possibility exists that, independently of the effect on blood pressure, nonresponder patients may require doses of losartan >50 mg/d or a follow-up >6 months to observe some impact on plasma angiotensin II and TGF-ß₁ concentrations. On the other hand, a polymorphism of the AT₁ receptor gene has been described in which there is either an adenine (A) or cytosine (C) base at position 1166 in the 3' untranslated region of the gene.³⁴ Recently, it has been reported that there is a relationship between the AT₁A¹¹⁶⁶C polymorphism and the humoral and renal responses to losartan.³⁵ Losartan decreased mean arterial pressure and increased the glomerular filtration rate in the AC/CC group but did not influence these parameters in the AA group. Further studies are required to determine whether the 2 patterns of responses to losartan here reported are determined by the polymorphism of the AT₁ receptor gene.

In summary, we found an association between increased TGF-ß₁, predominance of the synthesis over the degradation of collagen type I molecules, LVH, and microalbuminuria in approximately half of patients with essential hypertension. Further studies are required to evaluate whether the excess of TGF-ß₁ may facilitate the development of cardiac and renal fibrosis in these patients. In addition, we reported that the efficient blockade of AT₁ receptors with losartan is associated with inhibition of TGF-ß₁, normalization of collagen type I metabolism, and reversal of LVH and microalbuminuria in a small fraction of hypertensive patients. The possibility that the ability of losartan to inhibit TGF-ß₁ plays a role in its cardioreparative properties in some hypertensives deserves further investigation.

Received February 21, 2000; first decision March 9, 2000; accepted April 17, 2000.

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