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(American Journal of Pathology. 2007;170:1165-1177.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060882

Rosuvastatin Treatment Prevents Progressive Kidney Inflammation and Fibrosis in Stroke-Prone Rats

Anita Gianella*, Elena Nobili*, Mauro Abbate{dagger}, Carla Zoja{dagger}, Paolo Gelosa*, Luciana Mussoni*, Stefano Bellosta*, Monica Canavesi*, Daniela Rottoli{dagger}, Uliano Guerrini*, Maura Brioschi{ddagger}, Cristina Banfi{ddagger}, Elena Tremoli*{ddagger}, Giuseppe Remuzzi{dagger} and Luigi Sironi*

From the Department of Pharmacological Sciences,* University of Milan, Milan; the Mario Negri Institute for Pharmacological Research,{dagger} Bergamo; and the Monzino Cardiologic Center, Istituto di Ricovero e Cura a Carattere Scientifico,{ddagger} Milan, Italy

Salt-loaded, spontaneously hypertensive stroke-prone rats show progressive increases in blood pressure and proteinuria and accumulate acute-phase proteins in body fluids, modeling events during renal damage. The aim of this study was to assess the pathological events occurring in the kidney of spontaneously hypertensive stroke-prone rats over time and evaluate the effects of statin treatment, which is known to improve renal and cardiovascular outcomes. Kidneys of male spontaneously hypertensive stroke-prone rats euthanized at different stages of proteinuria showed progressive inflammatory cell infiltration, the accumulation of {alpha}-smooth muscle actin-positive cells, degenerative changes in podocytes, and severe fibrosis. These were accompanied by an imbalance in the plasminogen/plasmin and metalloprotease systems characterized by the increased renal expression of plasminogen activator inhibitor-1, tissue plasminogen activator, and urokinase plasminogen activator; the net result was an increase in plasmin and matrix metalloproteinase (MMP)-2 and a reduction in MMP-9 activity. Chronic treatment with the hydrophilic rosuvastatin had renoprotective effects in terms of morphology and inflammation and prevented the changes in plasmin, MMP-2, and MMP-9 activity. These effects were independent of the changes in blood pressure and plasma lipid levels. Treatment with the lipophilic simvastatin was not renoprotective. These data suggest that rosuvastatin may have potential utility as a therapeutic option in renal diseases that are characterized by inflammation and fibrosis.




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