Combination therapy with an angiotensin II receptor blocker and an HMG-CoA reductase inhibitor in experimental subtotal nephrectomy.
BACKGROUND
Angiotensin receptor 1 blockers (ARB) are standard nephroprotective drugs in chronic kidney disease. There is less evidence for a nephroprotective effect of HMG-CoA reductase inhibitors (statins) and much less is known about potential benefits of combination therapy. We evaluated the therapeutic potential of a statin alone or in combination with an ARB in experimental chronic kidney disease.


METHODS
Subtotally nephrectomized (5/6 Nx) rats were treated early with vehicle, losartan, cerivastatin or losartan/cerivastatin. Expression of messenger RNA (mRNA) was assessed by real-time reverse transcription-polymerase chain reaction. Tissue proteins were localized by immunohistochemistry. Nuclear factor-κB (NF-κB) activation was measured in whole kidneys.


RESULTS
In contrast to the sham group, at 6 weeks, vehicle-treated 5/6 Nx rats displayed renal lesions, albuminuria and increased blood pressure, serum creatinine and total kidney NF-κB p65 DNA-binding activity and preproendothelin-1, fibronectin and type I and III collagen mRNA. NF-κB activation correlated with albuminuria and histological renal injury. Losartan or combination therapy preserved renal function, abrogated albuminuria and improved glomerular and interstitial histology. Cerivastatin alone preserved renal function and improved interstitial injury but did not influence albuminuria, glomerular histology or NF-κB activation. Losartan/cerivastatin normalized kidney NF-κB activation and extracellular matrix mRNA expression pattern. The effect of losartan alone on these parameters was less intense. All treatments decreased preproendothelin-1 mRNA and preserved interstitial capillaries.


CONCLUSIONS
In a chronic kidney disease model, early treatment with either an ARB or a statin preserved renal function although the mechanisms differed. Combination therapy with an ARB and a statin did not confer clear-cut advantages on biochemical and histological parameters over ARB alone, although it further improved the kidney NF-κB and gene expression profile.
Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, and Morphology Department, Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.
Alejandro
A
Álvarez-Prats
Octavio
O
Hernández-Perera
Pilar
P
Díaz-Herrera
Álvaro C
ÁC
Ucero
Aránzazu
A
Anabitarte-Prieto
Antonio
A
Losada-Cabrera
Alberto
A
Ortiz
José C
JC
Rodríguez-Pérez
D047228:Angiotensin II Type 1 Receptor Blockers / Q000037:antagonists & inhibitors; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004359:Drug Therapy, Combination; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009392:Nephrectomy / Q000009:adverse effects*; D011725:Pyridines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D024042:Collagen Type I; D024061:Collagen Type III; D005353:Fibronectins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011725:Pyridines; D012333:RNA, Messenger; C086276:cerivastatin; D019808:Losartan