Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models

Abstract

Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to crosslink actin microfilaments into higher order structures have been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and of CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the significant regenerative potential of injured glomeruli and that targeting the oligomerization cycle of dynamin represents an attractive potential therapeutic target to treat CKD.

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.…”

Optimal management of primary focal segmental glomerulosclerosis in adults

“…The slit diaphragm is composed of cell adhesion molecules that are connected to the actin cytoskeleton and its associated proteins (including synaptopodin, vinculin, and dynamin). These changes in podocyte phenotype are closely correlated with a loss of function in glomerular permeability and the characteristic clinical hallmark of proteinuria that occurs in FSGS; for example, the large GTPase dynamin, which plays a key role in the maintenance of kidney barrier filtration, is implicated in regulating the actin cytoskeleton via direct dynamin-actin interactions 8,9 and regulates focal adhesion maturation in podocytes via a parallel signaling pathway to RhoA. 10 Moreover, Notch signaling, which is implicated in the development of glomerular disease, 11 promotes dynamin-dependent, raftindependent endocytosis of nephrin.…”

Podocytes and the actin cytoskeleton as a feasible therapeutic target

“…It has been suggested that an assembly mode that involves many low-affinity interactions sites facilitates the reversibility of interactions and allows for the regulation of dynamin oligomerization, for example through nucleotide binding, hydrolysis or phosphorylation. Our recent study suggests that dynamin assembly presents an ideal pharmacological target as a proxy to target actin cytoskeleton dynamics (39). Another characteristic that distinguishes dynamin from canonical small GTPases is that dynamin directly binds actin filaments (10,40).…”