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Angiotensin converting enzyme inhibitor modulates glomerular function and structure by distinct mechanisms
1Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Abstract:
Rats with puromycin aminonucleoside (PAN) nephrosis were given either angiotensin I converting enzyme inhibitor (ACEI), angiotensin II type 1 receptor antagonist (Ang IIRA), or no treatment for four weeks and were then monitored for an additional 12 weeks. In untreated PAN rats, proteinuria reached a maximum at two weeks (271 +/- 38 mg/day). Proteinuria in this early phase was markedly attenuated by ACEI (96 +/- 35 mg/day, P < 0.01), but unaffected by Ang IIRA (306 +/- 34 mg/day). Acute administration of a bradykinin antagonist substantially dampened the antiproteinuric effect of ACEI in PAN rats, resulting in an average increase in proteinuria of 41 +/- 14% in ACEI-treated rats (P < 0.05, ACEI vs. ACEI+bradykinin antagonist). Acute phase therapy for four weeks with ACEI or Ang IIRA did not attenuate subsequent glomerulosclerosis. Separate groups of PAN rats with similar degree of glomerulosclerosis, assessed at 16 weeks after PAN by renal biopsy, were then treated as follows: ACEI [50 mg/liter drinking water (DW), or 200 mg/liter DW], Ang IIRA (20 mg/liter DW, or 80 mg/liter DW) or no treatment, starting after renal biopsy. Whereas glomerulosclerosis increased from biopsy to autopsy at 28 weeks with emergence of low grade proteinuria in untreated PAN rats, proteinuria was absent and glomerulosclerosis was ameliorated or reversed in ACEI and Ang IIRA groups. The results indicate that the early phase proteinuria of PAN nephropathy is independent of Ang II, and that the antiproteinuric effect of ACEI is, at least in part, channeled through activation of bradykinin, whereas the subsequent progression of glomerulosclerosis is caused by a mechanism involving endogenous Ang II actions.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Early-phase proteinuria in puromycin aminonucleoside (PAN) nephrosis is reduced by angiotensin I converting enzyme inhibitors (ACEI) via bradykinin, not angiotensin II (Ang II). Later glomerulosclerosis progression involves Ang II.
Area of Science:
- Nephrology
- Pharmacology
- Physiology
Background:
- Puromycin aminonucleoside (PAN) nephrosis is a model for glomerular disease.
- Understanding the roles of the renin-angiotensin system (RAS) and bradykinin in nephrotic syndrome is crucial.
Purpose of the Study:
- To investigate the mechanisms underlying early-phase proteinuria and later glomerulosclerosis progression in PAN nephrosis.
- To differentiate the roles of angiotensin II (Ang II) and bradykinin in the therapeutic effects of ACE inhibitors (ACEI).
Main Methods:
- Rats with PAN nephrosis were treated with ACEI or Angiotensin II Type 1 Receptor Antagonist (Ang II RA) during the early phase or later stages.
- Bradykinin antagonist was used to assess the role of bradykinin in ACEI's effect.
- Renal biopsies were performed to assess glomerulosclerosis progression.
Main Results:
- Early-phase proteinuria in PAN rats was significantly attenuated by ACEI but not Ang II RA.
- ACEI's antiproteinuric effect was partially mediated by bradykinin.
- Neither ACEI nor Ang II RA prevented glomerulosclerosis during the acute phase.
- Later treatment with ACEI or Ang II RA ameliorated or reversed glomerulosclerosis and prevented proteinuria.
Conclusions:
- Early proteinuria in PAN nephropathy is independent of Ang II.
- The antiproteinuric effect of ACEI in early PAN nephrosis involves bradykinin activation.
- Later glomerulosclerosis progression in PAN nephrosis is driven by endogenous Ang II actions.