Cisplatin is a highly effective chemotherapeutic agent. However, its use is limited by nephrotoxicity.
Enalapril is an
angiotensin I-converting enzyme inhibitor used for the treatment of
hypertension, mainly through the reduction of
angiotensin II formation, but also through the increase of
kinins half-life.
Kinin B1 receptor is associated with
inflammation and migration of immune cells into the injured tissue. We have previously shown that the deletion or blockage of
kinin B1 and B2 receptors can attenuate
cisplatin nephrotoxicity. In this study, we tested
enalapril treatment as a tool to prevent
cisplatin nephrotoxicity. Male C57Bl/6 mice were divided into 3 groups: control group;
cisplatin (20 mg/kg i.p) group; and
enalapril (1.5 mg;kg i.p) +
cisplatin group. The animals were treated with a single dose of
cisplatin and euthanized after 96 h.
Enalapril was able to attenuate
cisplatin-induced increase in
creatinine and
urea, and to reduce tubular injury and upregulation of apoptosis-related genes, as well as inflammatory
cytokines in circulation and kidney. The upregulation of B1 receptor was blocked in
enalapril +
cisplatin group.
Carboxypeptidase M expression, which generates B1 receptor agonists, is blunted by
cisplatin +
enalapril treatment. The activity of
aminopeptidase P, a secondary key
enzyme able to degrade
kinins, is restored by
enalapril treatment. These findings were confirmed in mouse renal epithelial tubular cells, in which
enalaprilat (5 μM) was capable of decreasing tubular injury and inflammatory markers. We treated mouse renal epithelial tubular cells with
cisplatin (100 μM), cisplatin+enalaprilat and
cisplatin+
enalaprilat+
apstatin (10 μM). The results showed that
cisplatin alone decreases cell viability,
cisplatin plus
enalaprilat is able to restore cell viability, and
cisplatin plus
enalaprilat and
apstatin decreases cell viability. In the present study, we demonstrated that
enalapril prevents
cisplatin nephrotoxicity mainly by preventing the upregulation of B1 receptor and
carboxypeptidase M and the increased concentrations of
kinin peptides through
aminopeptidase activity restoration.