Angiotensin-converting enzyme inhibition but not angiotensin II receptor blockade regulates matrix metalloproteinase activity in patients with glomerulonephritis.
Equivalent long-term effects on the kidney are attributed to angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB). Nevertheless, it is unknown to which degree effects of these compounds on individual inflammatory mediators, including matrix metalloproteinases (MMP), are comparable. On the basis of structural and functional differences, it was hypothesized that ACEI and ARB differentially regulate MMP activity. In a randomized, prospective crossover trial, the effect of an ACEI (fosinopril; 20 mg/d) and of an ARB (irbesartan; 150 mg/d) on MMP activity was evaluated. Ten hypertensive patients with glomerulonephritis and normal or mildly reduced creatinine clearance were studied. MMP activity and tissue inhibitors of metalloproteinase (TIMP) levels were analyzed in serum and urine: without therapy, with ACEI, with ARB, and with both agents combined. Treatment periods continued for 6 wk separated by periods of 4 wk each without therapy. Untreated patients with glomerulonephritis displayed distinctively higher serum levels of MMP-2 but much lower MMP-1/-8/-9 concentrations compared with healthy control subjects. Immunohistology of MMP-2 and MMP-9 in kidney biopsy specimen was accordingly. However, these patients excreted higher amounts of MMP-2 and MMP-9 in urine than healthy control subjects, possibly reflecting ongoing glomerular inflammation. In patients with glomerulonephritis, ACEI significantly reduced overall MMP serum activity to 25%, whereas ARB did not show any effect. Activities of MMP-1/-2/-8/-9 were also significantly inhibited by fosinopril but not by irbesartan. Levels of TIMP-1/-2 remained unaffected. In conclusion, ACEI and ARB differentially regulate MMP activity, which may ultimately have consequences in certain types of MMP-dependent glomerulonephritis.
Lods
Nadège
N
Division of Nephrology and Hypertension, Inselspital Bern, Bern, Switzerland.
Ferrari
Paolo
P
Frey
Felix J
FJ
Kappeler
Andreas
A
Berthier
Celine
C
Vogt
Bruno
B
Marti
Hans-Peter
HP
D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D016022:Case-Control Studies; D002908:Chronic Disease; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D005260:Female; D017328:Fosinopril / Q000008:administration & dosage*; D005921:Glomerulonephritis / Q000378:metabolism*; D006801:Humans; D000077405:Irbesartan; D008297:Male; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism; D011446:Prospective Studies; D013777:Tetrazoles / Q000008:administration & dosage*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D013777:Tetrazoles; D020782:Matrix Metalloproteinases; D000077405:Irbesartan; D017328:Fosinopril