Dynamin Autonomously Regulates Podocyte Focal Adhesion Maturation

Abstract

Rho family GTPases, the prototypical members of which are Cdc42, Rac1, and RhoA, are molecular switches best known for regulating the actin cytoskeleton. In addition to the canonical small GTPases, the large GTPase dynamin has been implicated in regulating the actin cytoskeleton via direct dynamin-actin interactions. The physiologic role of dynamin in regulating the actin cytoskeleton has been linked to the maintenance of the kidney filtration barrier. Additionally, the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus, increases actin polymerization, improved renal health in diverse models of CKD, implicating dynamin as a potential therapeutic target for the treatment of CKD. Here, we show that treating cultured mouse podocytes with Bis-T-23 promoted stress fiber formation and focal adhesion maturation in a dynamin-dependent manner. Furthermore, Bis-T-23 induced the formation of focal adhesions and stress fibers in cells in which the RhoA signaling pathway was downregulated by multiple experimental approaches. Our study suggests that dynamin regulates focal adhesion maturation by a mechanism parallel to and synergistic with the RhoA signaling pathway. Identification of dynamin as one of the essential and autonomous regulators of focal adhesion maturation suggests a molecular mechanism that underlies the beneficial effect of Bis-T-23 on podocyte physiology.

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

“…A very recent study could demonstrate that stabilization of the actin cytoskeleton via application of a small molecule affecting the DYNAMIN structure resulted in prevention of progressive proteinuria in a series of genetic and toxic podocyte stress models. These observations underlined the importance of the actin cytoskeleton as a common final pathway of podocyte injury (44,45). Our data now extend these observations and identify with EPB41L5, a podocyte-specific upstream link from the adhesion machinery to the regulation of the cytoskeleton.…”

Drugs targeting dynamin can restore cytoskeleton and focal contact alterations of urinary podocytes derived from patients with nephrotic syndrome

“…Treating cultured mouse podocytes with Bis-T-23 promotes stress fiber formation and focal adhesion maturation in a dynamin-dependent manner (20,23).…”

The Evolving Complexity of the Podocyte Cytoskeleton

“…The value of this approach was demonstrated by the successful prevention or at least amelioration of proteinuria in toxic as well as genetic models of podocyte damage. 108 Nevertheless, the time of treatment in this preclinical study was of course limited and long-term toxicity effects, as well as side effects, on the organism have to be addressed in future studies.…”