Abstract
BackgroundPodocyte apoptosis is a major mechanism that leads to proteinuria in many kidney diseases. However, the concert mechanisms that cause podocyte apoptosis in these kidney diseases are not fully understood. RhoA is one of Rho GTPases that has been well studied and plays a key role in regulating cytoskeletal architecture. Previous study showed that insufficient RhoA could result in rat aortic smooth muscle cell apoptosis. However, whether RhoA is involved in podocyte apoptosis remains unknown.MethodsCulture podocytes were treated with LPS, ADR or siRNA for 48 h before harvest. Subcellular immunoblotting, qRT-PCR, immunofluorescence and flow cytometry were used to exam the expression and function of RhoA or YAP in podocytes.ResultsWe found that the expression of RhoA and its activity were significantly decreased in LPS or ADR-injured podocytes, accompanying loss of stress fibers and increased cell apoptosis. Knocking down RhoA or its downstream effector mDia expression by siRNA also caused loss of stress fibers and podocyte apoptosis. Moreover, our results further demonstrated that RhoA deficiency could reduce the mRNA and protein expression of YAP, which had been regarded as an anti-apoptosis protein in podocyte. Silenced dendrin expression significantly abolished RhoA, mDia or YAP deficiency-induced podocyte apoptosis.ConclusionRhoA deficiency could disrupt podocyte cytoskeleton and induce podocyte apoptosis by inhibiting YAP/dendrin signal. RhoA/mDia/YAP/dendrin signal pathway may potentially play an important role in regulating podocyte apoptosis. Maintaining necessary RhoA would be one potent way to prevent proteinuria kidney diseases.
Highlights
Podocyte apoptosis is a major mechanism that leads to proteinuria in many kidney diseases
Loss of RhoA/Mammalian diaphanousrelated formin (mDia) decreased Yes-associated protein (YAP) expression in podocytes To further explore the underlying mechanism of RhoA deficiency-induced podocyte apoptosis, we investigated the expression of YAP in RhoA or its downstream effector mDia knockdown podocytes
We further demonstrated that RhoA deficiency could reduce the mRNA and protein expression of YAP, which had been regarded as an anti-apoptosis protein in podocyte
Summary
Podocyte apoptosis is a major mechanism that leads to proteinuria in many kidney diseases. RhoA is one of Rho GTPases that has been well studied and plays a key role in regulating cytoskeletal architecture. Podocytes are highly differentiated cells with complex actin cytoskeletal architecture that play a key role in maintaining the integrity of glomerular filtration barrier, which is crucial for normal glomerular function [1,2,3]. The function of cytoskeletal architecture is mainly regulated by small GTPases belonging to the Rho GTPase family [12, 13]. A baseline activity of RhoA is essential for the normal function of glomerular podoctyes, podocytes deficiency in RhoA will lead to loss of stress fibers and proteinuria [16, 17]. Accumulating evidences have showed that RhoA deficiency could result in cell apoptosis [11, 18], maybe by decreasing Yes-associated protein (YAP) expression in both A549 and HepG2 cells [19]
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