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Angiotensin-Converting Enzyme Inhibition but Not Angiotensin II Receptor Blockade Regulates Matrix Metalloproteinase Activity in Patients with Glomerulonephritis

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Angiotensin-Converting Enzyme Inhibition but Not Angiotensin II Receptor Blockade Regulates Matrix Metalloproteinase Activity in Patients with Glomerulonephritis J Am Soc Nephrol 14: 2861–2872, 2003 Angiotensin-Converting Enzyme Inhibition but not Angiotensin II Receptor Blockade Regulates Matrix Metalloproteinase Activity in Patients with Glomerulonephritis NADE` GE LODS,* PAOLO FERRARI,* FELIX J. FREY,* ANDREAS KAPPELER,† CELINE BERTHIER,* BRUNO VOGT,* and HANS-PETER MARTI* *Division of Nephrology and Hypertension, Inselspital Bern, Bern, Switzerland; and †Institute of Pathology, University of Bern, Bern, Switzerland Abstract. Equivalent long-term effects on the kidney are attrib- periods of 4 wk each without therapy. Untreated patients with uted to angiotensin-converting enzyme inhibitors (ACEI) and glomerulonephritis displayed distinctively higher serum levels angiotensin II type 1 receptor blockers (ARB). Nevertheless, it of MMP-2 but much lower MMP-1/-8/-9 concentrations com- is unknown to which degree effects of these compounds on pared with healthy control subjects. Immunohistology of individual inflammatory mediators, including matrix metallo- MMP-2 and MMP-9 in kidney biopsy specimen was accord- proteinases (MMP), are comparable. On the basis of structural ingly. However, these patients excreted higher amounts of and functional differences, it was hypothesized that ACEI and MMP-2 and MMP-9 in urine than healthy control subjects, ARB differentially regulate MMP activity. In a randomized, possibly reflecting ongoing glomerular inflammation. In pa- prospective crossover trial, the effect of an ACEI (fosinopril; tients with glomerulonephritis, ACEI significantly reduced 20 mg/d) and of an ARB (irbesartan; 150 mg/d) on MMP overall MMP serum activity to 25%, whereas ARB did not activity was evaluated. Ten hypertensive patients with glomer- show any effect. Activities of MMP-1/-2/-8/-9 were also sig- ulonephritis and normal or mildly reduced creatinine clearance nificantly inhibited by fosinopril but not by irbesartan. Levels were studied. MMP activity and tissue inhibitors of metallo- of TIMP-1/-2 remained unaffected. In conclusion, ACEI and proteinase (TIMP) levels were analyzed in serum and urine: ARB differentially regulate MMP activity, which may ulti- without therapy, with ACEI, with ARB, and with both agents mately have consequences in certain types of MMP-dependent combined. Treatment periods continued for 6 wk separated by glomerulonephritis. Glomerular inflammatory diseases represent frequent and often long-term effects with regard to the kidney is not yet fully difficult-to-treat causes of end-stage kidney failure. Hyperten- resolved, and the identification of patient groups in which one sion and proteinuria are important independent determinants of these agents demonstrates potential advances over the other and risk factors for progression of these diseases (1). There- one remains of pivotal clinical interest. fore, these two conditions are prime targets for the therapy of Angiotensin II plays a key role in the pathogenesis of all types of glomerulonephritis. chronic injury to the kidneys resulting in loss of function. Pharmacologic inhibition of the renin-angiotensin system by Beyond hemodynamic effects, angiotensin II also has direct angiotensin-converting enzyme inhibitors (ACEI) and angio- effects on glomerular cells, including induction of cytokine tensin II type 1 receptor blockers (ARB) has been particularly production. Angiotensin II supports mesangial cell prolifera- well demonstrated to treat high BP and proteinuria successfully tion and induces the expression of TGF-␤, leading to extracel- (1). Moreover, the decline of kidney function occurring in lular matrix (ECM) accumulation (1,4,5). The degradation of diabetic as well as in nondiabetic glomerulopathies was greatly the ECM occurs mainly by the action of extracellularly active reduced by these agents in many investigations (2,3). Although neutral proteinases, the matrix metalloproteinases (MMP), in ARB have only recently been introduced to common clinical conjunction with other proteolytic enzymes (6–8). Impor- use, several studies reported equivalent renoprotection for both tantly, MMP seem to play an increasingly prominent role as classes of agents, ACEI and ARB (1). However, the issue of inflammatory mediators in the regulation of glomerular ECM proteins and of cell proliferation (6,7,9). Agents that are given over prolonged periods to patients with Received December 20, 2002. Accepted August 1, 2003. inflammatory diseases need to be evaluated for their effect on Correspondence to Dr. Hans-Peter Marti, Division of Nephrology/Hyperten- sion, University of Bern, Inselspital Bern, CH-3010, Bern, Switzerland. Phone: MMP activity. Taking into account the diverse effects of the 031-632-31-44; Fax: 031-632-94-44; E-mail: [email protected] renin-angiotensin system on glomerular cells and on ECM 1046-6673/1411-2861 regulating cytokines or growth factors, it is conceivable that Journal of the American Society of Nephrology ACEI and ARB influence MMP activity in patients with glo- Copyright © 2003 by the American Society of Nephrology merulonephritis. ACEI, such as captopril or ramiprilat, have DOI: 10.1097/01.ASN.0000092789.67966.5C already been demonstrated by us and others to inhibit directly 2862 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 2861–2872, 2003 MMP activity in vitro by chelating the zinc ion in the active Ten age- and gender-matched volunteers (aged 49 Ϯ 3 yr, mean Ϯ center of these proteases (10–12). Moreover, the ACEI cilaza- SEM; eight men and two women) without any health problems, pril was shown to decrease microalbuminuria and MMP-9 including the absence of abnormalities with respect to kidney function Ͼ plasma concentrations in eight patients with non–insulin-de- (creatinine clearance 80 ml/min) or to urinalysis, were investigated pendent diabetes (13). It is interesting that angiotensin II treat- as healthy control subjects. A second group of untreated patients with documented noninflammatory kidney disease (autosomal dominant ment of C57B1/6 female mice did not affect MMP-2 and polycystic kidney disease [ADPKD]) in the absence of concomitant MMP-9 activity (14). Conclusive data on the effect of ARB on illness (aged 43 Ϯ 4 yr, mean Ϯ SEM; seven men and three women) MMP and TIMP are still missing. were used as an additional control group. These patients had a similar MMP expression and activity can be analyzed in tissue degree of renal failure (creatinine, 147 Ϯ 29 ␮mol/L; creatinine sections and in serum or plasma. To our knowledge, there exist clearance, 72 Ϯ 10 ml/min, mean Ϯ SD; Ͼ30 ml/min in all cases) as no studies conclusively assessing the relationship between the study group. circulating and tissue MMP levels, especially in patients with glomerulonephritis. However, to show effects of pharmaco- Study Design logic agents on MMP activity per se, the use of serum seems The clinical study was performed in a prospective, randomized, to be appropriate and the most practicable solution, as in the triple-crossover manner, as reported previously (15). After an initial case of the present study. 6-wk run-in control period without antihypertensive agents, our 10 It is still unknown whether ACEI and ARB show identical patients with glomerulonephritis were observed during three treatment effects on these ECM regulating proteases. However, on the periods of 6 wk each. During these treatment periods, they received basis of structural and functional differences of ACEI and randomly once daily at 8:00 a.m. fosinopril 20 mg, irbesartan 150 mg, ARB, we hypothesized that these agents may well regulate or fosinopril 20 mg plus irbesartan 150 mg, in a prospective, random- MMP activity in a different manner. Thus, it was the prime aim ized, open, blinded end point (PROBE) study. Each of the three active of our investigation to analyze the effect of an ACEI, fosino- treatment phases was separated by a washout period lasting 4 wk. At the end of the control run-in phase and of each active treatment pril, and an ARB, irbesartan, alone or in combination, on MMP phase (weeks 6, 12, 22, and 32), MMP activities were analyzed activity in serum of patients with chronic glomerulonephritis. separately in serum and in morning spot urine samples. Similar The secondary aim of our study was to compare MMP activity analyses of healthy control subjects and of control patients with in serum and urine of our untreated patient group with age- and ADPKD, both groups without therapy, were performed on one gender-matched healthy control subjects and with a second occasion. control group consisting of subjects with noninflammatory renal failure. Blood and Urine Samples Samples containing 5 ml of blood were collected and centrifuged at 3000 rpm for 10 min. Thereafter, serum was stored in aliquots at Materials and Methods Ϫ Patients and Healthy Control Subjects 20°C before analyses. Urine spot samples (5 ml) were centrifuged in an identical manner to remove any suspended particles and stored in Ten consecutive patients (aged 49 Ϯ 4 yr, mean Ϯ SEM; eight men aliquots at Ϫ20°C. All creatinine measurements as well as analyses of and two women) who had biopsy-proven glomerulonephritis from our serum proteins were performed in the central chemical laboratory of renal clinic and met the entry criteria participated in the study (15). our institution. Urinary protein concentrations were measured using Relevant biochemical data are given in Table 1; creatinine clearance the BCA protein assay reagent kit (Pierce, Lausanne, Switzerland) was Ͼ30 ml/min in all patients. Renal histology was membranous (16). glomerulonephritis
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