Dexamethasone Prevents Podocyte Apoptosis Induced by Puromycin Aminonucleoside

Abstract

Nephrotic-range proteinuria is due to glomerular diseases characterized by podocyte injury. Glucocorticoids are the standard of care for most forms of nephrotic syndrome. However, the precise mechanisms underlying the beneficial effects of glucocorticoids on podocytes, beyond its general immunosuppressive and anti-inflammatory effects, are still unknown. This study tested the hypothesis that the synthetic glucocorticoid dexamethasone directly reduces podocyte apoptosis. Growthrestricted immortalized mouse podocytes in culture were exposed to puromycin aminonucleoside (PA) to induce apoptosis. Our results showed that dexamethasone significantly reduced PA-induced apoptosis by 2.81-fold. Dexamethasone also rescued podocyte viability when exposed to PA. PA-induced apoptosis was associated with increased p53 expression, which was completely blocked by dexamethasone. Furthermore, the inhibition of p53 by the p53 inhibitor pifithrin-␣ protected against PA-induced apoptosis. Dexamethasone also lowered the increase in the proapoptotic Bax, which was increased by PA, and increased expression of the antiapoptotic Bcl-xL protein. Moreover, the decrease in p53 by dexamethasone was associated with increased Bcl-xL levels. Podocyte apoptosis induced by PA was caspase-3 independent but was associated with the translocation of apoptosis-inducing factor (AIF) from the cytoplasm to nuclei. AIF translocation was inhibited by dexamethasone. These results show that PA-induced podocyte apoptosis is p53 dependent and associated with changes in Bcl-2-related proteins and AIF translocation. The protective effects of dexamethasone on PA-induced apoptosis were associated with decreasing p53, increasing Bcl-xL, and inhibition of AIF translocation. These novel findings provide new insights into the beneficial effects of corticosteroids on podocytes directly, independent of its immunosuppressive effects.

The Kidney as a Reservoir for HIV-1 after Renal Transplantation

“…Importantly, we found a very low rate of the APOL1 polymorphism in our donor cohort, suggesting that donor APOL1 may play a local role in HIVAN pathophysiology, as was also suggested by the recent report of kidney APOL1 expression in normal and pathologic conditions. 26 Besides genetic predisposition, we cannot exclude that immunosuppressive drugs, by either interacting with the immune system or directly with podocytes (calcineurin inhibitors 27 and steroids 28 ), may modify the classical pattern of kidney lesions observed with HIV-1.…”

Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome

“…Furthermore, podocyte foot processes consist of cortical actin filaments and actin-associated proteins, which ensure the dynamic maintenance and reorganization of the cytoskeleton. In vitro studies have shown the direct effects of glucocorticoids on podocytes by protection of cultured podocytes via actin filament stabilization and prevention of apoptosis [60,61]. The effect on apoptosis [61] and upregulation of nephrin [59] appeared to be dose-dependent, which might be an explanation for the observed differences in clinical response to glucocorticoids.…”

“…In vitro studies have shown the direct effects of glucocorticoids on podocytes by protection of cultured podocytes via actin filament stabilization and prevention of apoptosis [60,61]. The effect on apoptosis [61] and upregulation of nephrin [59] appeared to be dose-dependent, which might be an explanation for the observed differences in clinical response to glucocorticoids. Another in vitro study, performed by Guess et al, demonstrated functional glucocorticoid signaling by multiple glucocorticoid-induced responses, including downregulation of the GR [62].…”

Podocyte number predicts progression of proteinuria in IgA nephropathy

“…42 Moreover, recent studies have shown that corticosteroid treatment may have direct effects on podocytes. 43,44 In contrast, the clinical response to immunosuppression therapy in focal segmental glomerular sclerosis is different according to the podocyte number. 45 We, therefore, postulated that it was not the severity of the proteinuria at diagnosis but rather the dynamic change of proteinuria during treatment and follow-up that is a more important predictor for the outcome of IgAN.…”