Chronic cathepsin inhibition by E-64 in Dahl salt-sensitive rats

Cysteine cathepsins are lysosomal enzymes expressed in the kidneys and other tissues, and are involved in the maturation and breakdown of cellular proteins. They have been shown to be integrally involved in the progression of many cardiovascular and renal diseases. The goal of this study was to determine the involvement of cysteine cathepsins in the development of salt-sensitive hypertension and associated kidney damage. In our experiments, Dahl salt-sensitive (SS) rats were fed an 8% high salt NaCl diet and intravenously infused with the irreversible cysteine cathepsin inhibitor E-64 (1 mg/day) or the vehicle (control). Both the control and E-64 infused groups developed significant hypertension and kidney damage, and no difference of the mean arterial pressure and the hypertension-associated albuminuria was observed between the groups. We next tested basal calcium levels in the podocytes of both control and infused groups using confocal calcium imaging. Basal calcium did not differ between the groups, indicative of the lack of a protective or aggravating influence by the cathepsin inhibition. The efficacy of E-64 was tested in Western blotting. Our findings corresponded to the previously reported, E-64 induced increase in cathepsin B and L abundance. We conclude that the inhibition of cysteine cathepsins by E-64 does not have any effects on the blood pressure development and kidney damage, at least under the studied conditions of this model of SS hypertension.