Angiotensin converting enzyme inhibitor but not angiotensin receptor blockade or statin ameliorates murine adriamycin nephropathy.

Tang SC, Leung JC, Chan LY, Eddy AA, Lai KN
Kidney Int. 2008 73 (3): 288-99

PMID: 18033243 · DOI:10.1038/sj.ki.5002674

Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins have renoprotective effects. We studied the cellular mechanisms for this effect in adriamycin-treated mice receiving captopril, losartan, simvastatin, or their combinations. The mice developed albuminuria, renal insufficiency, and parenchymal inflammation/fibrosis accompanied by overexpression of intrarenal converting enzyme and angiotensin II. Only captopril consistently improved these abnormalities and reduced the cortical expression of several proinflammatory and profibrotic factors including transforming growth factor-beta (TGF-beta). These effects were independent of blood pressure, accompanied by increased urine N-acetylseryl-aspartyl-lysyl-proline (Ac-SDKP) levels, and the restoration of renal angiotensin-converting enzyme and angiotensin II to baseline levels. Losartan or simvastatin alone or together had no effect, and their addition to captopril did not enhance protection. In vitro, angiotensin II stimulated TGF-beta in renal tubular cells via mitogen-activated protein kinase (MAPK) signaling. Captopril or Ac-SDKP suppressed angiotensin II-induced MAPK activation and TGF-beta secretion. Angiotensin-converting enzyme inhibition confers renoprotection in adriamycin nephropathy by reducing intrarenal angiotensin II and augmenting Ac-SDKP expression that together attenuate MAPK signaling and its downstream proinflammatory and fibrogenic properties. The addition of receptor blocker and/or statin failed to potentiate such effects.

MeSH Terms (24)

Angiotensin-Converting Enzyme Inhibitors Angiotensin II Angiotensin II Type 1 Receptor Blockers Animals Cell Proliferation Cells, Cultured Chemokine CCL2 Collagen Type I Doxorubicin Drug Therapy, Combination Epithelial Cells Glomerulosclerosis, Focal Segmental Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors Kidney Macrophages Mice Mice, Inbred BALB C Peptidyl-Dipeptidase A Phenotype Placenta Growth Factor Pregnancy Proteins Signal Transduction Transforming Growth Factor beta

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