Minimal change nephropathy (MCN) is the third most common cause of primary
nephrotic syndrome in adults. Most patients with MCN respond to
corticosteroid therapy, but relapse is common. In children,
steroid-dependent patients are often given alternative agents to spare the use of
steroids and to avoid the cumulative
steroid toxicity. In this respect,
levamisole has shown promise due to its ability to effectively maintain remission in children with
steroid-sensitive or
steroid-dependent nephrotic syndrome. Despite clinical effectiveness, there is a complete lack of molecular evidence to explain its mode of action and there are no published reports on the use of this compound in adult patients. We studied the effectiveness of
levamisole in a small cohort of adult patients and also tested the hypothesis that
levamisole's mode of action is attributable to its direct effects on podocytes. In the clinic, we demonstrate that in our adult patients, cohort
levamisole is generally well tolerated and clinically useful. Using conditionally immortalized human podocytes, we show that
levamisole is able to induce expression of
glucocorticoid receptor (GR) and to activate GR signalling. Furthermore,
levamisole is able to protect against podocyte injury in a
puromycin aminonucleoside (PAN)-treated cell model. In this model the effects of
levamisole are blocked by the GR antagonist
mifepristone (
RU486), suggesting that GR signalling is a critical target of
levamisole's action. These results indicate that
levamisole is effective in
nephrotic syndrome in adults, as well as in children, and point to molecular mechanisms for this
drug's actions in podocyte diseases.