Abstract
The melanocortin-1 receptor (MC1R) in podocytes has been suggested as the mediator of the ACTH renoprotective effect in patients with nephrotic syndrome with the mechanism of action beeing stabilization of the podocyte actin cytoskeleton. To understand how melanocortin receptors are regulated in nephrotic syndrome and how they are involved in restoration of filtration barrier function, melanocortin receptor expression was evaluated in patients and a rat model of nephrotic syndrome in combination with cell culture analysis. Phosphoproteomics was applied and identified MC1R pathways confirmed using biochemical analysis. We found that glomerular MC1R expression was increased in nephrotic syndrome, both in humans and in a rat model. A MC1R agonist protected podocytes from protamine sulfate induced stress fiber loss with the top ranked phoshoproteomic MC1R activated pathway beeing actin cytoskeleton signaling. Actin stabilization through the MC1R consisted of ERK1/2 dependent phosphorylation and inactivation of EGFR signaling with stabilization of synaptopodin and stressfibers in podocytes. These results further explain how patients with nephrotic syndrome show responsiveness to MC1R receptor activation by decreasing EGFR signaling and as a consequence restore filtration barrier function by stabilizing the podocyte actin cytoskeleton.
Highlights
The maintenance of podocyte foot process structure and glomerular barrier function greatly depend on spatial and temporal regulation of the actin cytoskeleton
The melanocortin-1 receptor (MC1R) regulated actin cytoskeleton signaling by inhibiting epidermal growth factor receptor (EGFR) and destabilizing synaptopodin, thereby restoring podocyte stressfibers
The fact that MC1R was found to be the most abundant ACTH receptor in the glomeruli, in combination with it being the only MCR that is augmented in nephrotic syndrome (Fig. 1A), confirm its role as being the receptor responsible for the beneficial effects of ACTH seen in patients with nephrotic syndrome
Summary
The maintenance of podocyte foot process structure and glomerular barrier function greatly depend on spatial and temporal regulation of the actin cytoskeleton. Proteins regulating actin dynamics in podocytes have been shown to play a major role in the development of nephrotic syndrome. Promising therapeutic targets in glomerular disease and actin cytoskeleton regulation are transmembrane proteins, such as β1-integrins[9], Nephrin[6], PLA2R10 and the transient receptor potential canonical (TRPC) ion channels TRPC511 and TRPC67. Importance of regulation of the master actin regulatory proteins, the RhoGTPases consisting of RhoA, Rac[1] and Cdc[42], in maintenance of podocyte function, has been demonstrated in studies showing that onset of proteinuria can be caused by activation of Cdc[42] and Rac[1] signaling and concomitant decrease of RhoA signaling in podocytes[11,12]. We show that MC1R is the ACTH receptor being augmented in nephrotic syndrome, thereby promoting restoration of stressfibers in podocytes by inhibition of EGFR signaling
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