The ADF/Cofilin-Pathway and Actin Dynamics in Podocyte Injury

Abstract

ADF/cofilins are the major regulators of actin dynamics in mammalian cells. The activation of ADF/cofilins is controlled by a variety of regulatory mechanisms. Dysregulation of ADF/cofilin may result in loss of a precisely organized actin cytoskeletal architecture and can reduce podocyte migration and motility. Recent studies suggest that cofilin-1 can be regulated through several extracellular signals and slit diaphragm proteins. Cofilin knockdown and knockout animal models show dysfunction of glomerular barrier and filtration with foot process effacement and loss of secondary foot processes. This indicates that cofilin-1 is necessary for modulating actin dynamics in podocytes. Podocyte alterations in actin architecture may initiate or aid the progression of a large variety of glomerular diseases, and cofilin activity is required for reorganization of an intact filtration barrier. Since almost all proteinuric diseases result from a similar phenotype with effacement of the foot processes, we propose that cofilin-1 is at the centre stage of the development of proteinuria and thus may be an attractive drug target for antiproteinuric treatment strategies.

Figure 1

Regulatory pathways modulating cofilin phosphorylation and dephosphorylation Rho-GTPases are the predominant regulator of cofilin kinases and phosphatases. Cofilin phosphorylation is mainly regulated by LIMK and TESK. SSH family is the most important phosphatase that dephosphorylates cofilin directly or via LIMK inactivation. Phosphorylated cofilin can no longer bind and regulate the F-actin dynamics via treadmilling, severing, or nucleation.

Figure 2

Central role of cofilin in podocyte effacement TGF-β or high-glucose stimulation triggers cofilin-1 phosphorylation. Phosphorylated/inactivated cofilin-1 undergoes translocation from cytoplasma to nucleus and is therefore not able to bind and promote F-actin rearrangement. Nephrin and integrin cluster or PKC activate the cofilin-1 via SSH1L activation. A rapid turnover of cofilin-1 is essential for the actin cytoskeleton dynamics in podocyte to perpetuate podocyte integrity. Secondary foot processes of podocyte are not shown here. Secondary foot processes are fine actin-rich processes that sprout out of primary processes and interdigitate with foot processes of neighbouring podocytes.