Mechanisms underlying renoprotection during renin-angiotensin system blockade.
Potential determinants of chronic renal disease (CRD) progression were studied in male Munich-Wistar rats subjected to 5/6 nephrectomy and treated with candesartan (Csn; n = 30) or enalapril (Ena; n = 27) from 5 wk postsurgery. Despite control of systolic blood pressure (SBP; 24 wk: Csn = 143 +/- 9; Ena = 148 +/- 8 mmHg), urinary protein excretion rates (U(pr)V) increased over 24 wk (Csn = 92 +/- 10; Ena = 99 +/- 8mg/day). Glomerulosclerosis scores (GS) at 24 wk were similar for Csn (42 +/- 7%) vs. Ena (42 +/- 4%), values close to those of untreated controls at 12 wk (43 +/- 4%). At 24 wk, SBP and UprV correlated strongly with GS, together accounting for 72% of the variance in GS. Renal cortex mRNA levels (determined by competitive RT-PCR) for transforming growth factor (TGF)-beta1 and monocyte chemoattractant protein (MCP)-1 were elevated in Csn and Ena at 12 wk and remained higher at 24 wk vs. sham. Strong correlations were evident among TGF-beta1, MCP-1, and interleukin-1beta and renal injury at 24 wk. Cns and Ena are thus equally effective renoprotective agents in this model. During renin-angiotensin system inhibition, renoprotection is dependent on control of both SBP and UprV. Incomplete suppression of renal cytokine gene expression may also contribute to CRD progression.
Taal
M W
MW
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. mtaal@rics.bwh.harvard.edu
Chertow
G M
GM
Rennke
H G
HG
Gurnani
A
A
Jiang
T
T
Shahsafaei
A
A
Troy
J L
JL
Brenner
B M
BM
Mackenzie
H S
HS
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D018932:Chemokine CCL2 / Q000378:metabolism; D004656:Enalapril / Q000494:pharmacology*; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D009392:Nephrectomy; D011507:Proteinuria / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018932:Chemokine CCL2; D019332:Endothelin-1; D007375:Interleukin-1; D012333:RNA, Messenger; D013777:Tetrazoles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004656:Enalapril; C081643:candesartan