PMID- 10027924
OWN - NLM
STAT- MEDLINE
DCOM- 19990416
LR  - 20211203
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 55
IP  - 3
DP  - 1999 Mar
TI  - Blocking angiotensin II ameliorates proteinuria and glomerular lesions in 
      progressive mesangioproliferative glomerulonephritis.
PG  - 877-89
AB  - BACKGROUND: The renin-angiotensin system is thought to be involved in the 
      progression of glomerulonephritis (GN) into end-stage renal failure (ESRF) 
      because of the observed renoprotective effects of angiotensin-converting enzyme 
      inhibitors (ACEIs). However, ACEIs have pharmacological effects other than ACE 
      inhibition that may help lower blood pressure and preserve glomerular structure. 
      We previously reported a new animal model of progressive glomerulosclerosis 
      induced by a single intravenous injection of an anti-Thy-1 monoclonal antibody, 
      MoAb 1-22-3, in uninephrectomized rats. Using this new model of progressive GN, 
      we examined the hypothesis that ACEIs prevent the progression to ESRF by 
      modulating the effects of angiotensin II (Ang II) on the production of 
      transforming growth factor-beta (TGF-beta) and extracellular matrix components. 
      METHODS: We studied the effect of an ACEI (cilazapril) and an Ang II type 1 
      receptor antagonist (candesartan) on the clinical features and morphological 
      lesions in the rat model previously reported. After 10 weeks of treatment with 
      equihypotensive doses of cilazapril, cilazapril plus Hoe 140 (a bradykinin 
      receptor B2 antagonist), candesartan, and hydralazine, we examined systolic blood 
      pressure, urinary protein excretion, creatinine clearance, the glomerulosclerosis 
      index, and the tubulointerstitial lesion index. We performed a semiquantitative 
      evaluation of glomerular immunostaining for TGF-beta and collagen types I and III 
      by immunofluorescence study and of these cortical mRNA levels by Northern blot 
      analysis. RESULTS: Untreated rats developed massive proteinuria, renal 
      dysfunction, and severe glomerular and tubulointerstitial injury, whereas 
      uninephrectomized control rats did not. There was a significant increase in the 
      levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I 
      and III in untreated rats. Cilazapril and candesartan prevented massive 
      proteinuria, increased creatinine clearance, and ameliorated glomerular and 
      tubulointerstitial injury. These drugs also reduced levels of glomerular protein 
      and cortical mRNA for TGF-beta and collagen types I and III. Hoe 140 failed to 
      blunt the renoprotective effect of cilazapril. Hydralazine did not exhibit a 
      renoprotective effect. CONCLUSION: These results indicate that ACEIs prevent the 
      progression to ESRF by modulating the effects of Ang II via Ang II type 1 
      receptor on the production of TGF-beta and collagen types I and III, as well as 
      on intrarenal hemodynamics, but not by either increasing bradykinin activity or 
      reducing blood pressure in this rat model of mesangial proliferative GN.
FAU - Nakamura, T
AU  - Nakamura T
AD  - Division of Blood Transfusion, Department of Internal Medicine, Niigata 
      University School of Medicine, Niigata, Japan. nakamura@res.yamanashi-med.ac.jp
FAU - Obata, J
AU  - Obata J
FAU - Kimura, H
AU  - Kimura H
FAU - Ohno, S
AU  - Ohno S
FAU - Yoshida, Y
AU  - Yoshida Y
FAU - Kawachi, H
AU  - Kawachi H
FAU - Shimizu, F
AU  - Shimizu F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Angiotensin Receptor Antagonists)
RN  - 0 (Angiotensin-Converting Enzyme Inhibitors)
RN  - 0 (Antihypertensive Agents)
RN  - 0 (Benzimidazoles)
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Bradykinin Receptor Antagonists)
RN  - 0 (Tetrazoles)
RN  - 0 (Transforming Growth Factor beta)
RN  - 11128-99-7 (Angiotensin II)
RN  - 19KW7PI29F (Cilazapril)
RN  - 26NAK24LS8 (Hydralazine)
RN  - 7PG89G35Q7 (icatibant)
RN  - 9007-34-5 (Collagen)
RN  - S8Q36MD2XX (candesartan)
RN  - S8TIM42R2W (Bradykinin)
SB  - IM
MH  - Angiotensin II/*antagonists & inhibitors
MH  - Angiotensin Receptor Antagonists
MH  - Angiotensin-Converting Enzyme Inhibitors/therapeutic use
MH  - Animals
MH  - Antihypertensive Agents/therapeutic use
MH  - Benzimidazoles/therapeutic use
MH  - Biphenyl Compounds
MH  - Bradykinin/analogs & derivatives/therapeutic use
MH  - Bradykinin Receptor Antagonists
MH  - Cilazapril/therapeutic use
MH  - Collagen/biosynthesis
MH  - Disease Models, Animal
MH  - Glomerulonephritis, Membranoproliferative/*drug therapy/pathology/physiopathology
MH  - Hydralazine/therapeutic use
MH  - Kidney Failure, Chronic/prevention & control
MH  - Male
MH  - Proteinuria/*prevention & control
MH  - Rats
MH  - Rats, Wistar
MH  - Renal Circulation/drug effects
MH  - Renin-Angiotensin System/drug effects/physiology
MH  - Tetrazoles/therapeutic use
MH  - Transforming Growth Factor beta/biosynthesis
EDAT- 1999/02/23 00:00
MHDA- 1999/02/23 00:01
CRDT- 1999/02/23 00:00
PHST- 1999/02/23 00:00 [pubmed]
PHST- 1999/02/23 00:01 [medline]
PHST- 1999/02/23 00:00 [entrez]
AID - S0085-2538(15)46034-X [pii]
AID - 10.1046/j.1523-1755.1999.055003877.x [doi]
PST - ppublish
SO  - Kidney Int. 1999 Mar;55(3):877-89. doi: 10.1046/j.1523-1755.1999.055003877.x.