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Podocytes are postmitotic renal glomerular cells with multiple ramifications that extend from the cell body. Processes departing from a podocyte interdigitate with corresponding projections from neighboring cells and form an intricate web that enwraps the glomerular capillary completely. Podocyte processes are interconnected by the slit diaphragm, an adhesion junction mostly formed by Ig-like molecules, cadherins/protocadherins, ephrin/eph, and neurexin molecules organized in an assembly that resembles synaptic junctions. Podocyte failure is primarily or secondarily implicated in all forms of proteinuric glomerular diseases, as confirmed by the morphological changes of their elaborate cell architecture detectable by electron microscopy. Importantly, mutations of podocyte proteins are responsible for the most severe forms of congenital nephrotic syndrome. In the last 15 years, progressive technological advances have aided the study of podocyte biology and pathology, confirming the relevance of podocyte molecules and signaling pathways for the function of the glomerular filter. This review will examine the most important and newest discoveries in the field, which is rapidly evolving, hopefully leading to a detailed knowledge of this fascinating cell and to the development of specific therapeutic options for proteinuric diseases.

Podocytes have a complex cellular architecture with interdigitating processes maintained by a precise organization of actin filaments. The actin-based foot processes of podocytes and the interposed slit diaphragm form the final barrier to proteinuria. The function of podocytes is largely based on the maintenance of the normal foot process structure with actin cytoskeleton. Cytoskeletal dynamics play important roles during normal podocyte development, in maintenance of the healthy glomerular filtration barrier, and in the pathogenesis of glomerular diseases. In this review, we focused on recent findings on the mechanisms of organization and reorganization of these actin-related molecules in the pathogenesis of podocyte injury and potential therapeutics targeting the regulation of actin cytoskeleton in podocytopathies.

Podocytes, glomerular visceral cells of epithelial origin, are the direct target of both immune and non-immune forms of injury in many diverse glomerular diseases. They do not typically proliferate in the mature kidney, which means that damaged cells are not replaced by new ones. It is now generally accepted that dysfunction or loss of these cells underlies progression of almost all glomerulopathies. Progressing glomerular diseases, of which diabetic nephropathy (DN) is the most common, are the most frequent cause of end-stage renal disease. Therefore, identification of the pathways that lead to podocyte injury is essential for developing more effective, targeted therapies. The articles presented in this research topic give a comprehensive overview of recent discoveries into the mechanisms of podocyte impairment and discuss the possibilities of podocyte-targeted therapies. Each podocyte contacts its neighboring cells via a slit diaphragm (SD) connecting their interdigitating foot processes (FPs). Via transmembrane adhesion receptors in the basolateral domain of the FP, the podocytes interact with the glomerular basement membrane (GBM). Both these forms of adhesions are crucial for maintaining podocyte structure, which in turn determines the integrity and permeability of the glomerular filtration barrier. As highlighted by Lennon et al. (1), the cell–cell and cell–matrix junctions drive the coordinated response of podocytes to environmental cues in order to regulate glomerular filtration. Recent findings indicate that there are two distinct FP types, anchoring FPs (AFPs) and ordinary FPs (OFPs), both of which are involved in the regulation of fluid outflow from the subpodocyte space (2). The components of SD and adhesion complexes in FPs transduce signals from outside of the podocyte to the actin cytoskeleton inside the cell. Up to now, almost 100 actin associated proteins have been discovered in mammalian podocytes, with distribution specific for apical, SD, and basal domains of the FP membrane (2). Dysregulation of signaling is likely to lead to actin reorganization and podocyte foot process effacement, which is typically observed in proteinuric diseases. In contrast to traditional interpretations of this loss of shape as a pathological derangement, Kriz et al. (3) indicate that adhesions are reinforced in effaced FPs and therefore it seems to be a protective mechanism against detachment. Alterations in podocyte phenotype and structure are particularly prominent when proteinuria reaches nephrotic range. It is accepted that loss of the specialized podocyte morphology is associated with transition from epithelial to a more mesenchymal phenotype irrespective of the underlying causes that include both genetic defects and mediators from the microenvironment. However, May et al. (4) note that podocytes display partial features of both mesenchymal and epithelial cells. Therefore, dependent on the clinical conditions, dedifferentiation in disease could result in regression to either of these states. Upon treatment, these changes are reversible only if the insult is not very severe, as for example in minimal change disease (MCD). In focal segmental glomerulosclerosis (FSGS), phenotypic dedifferentiation of podocytes is not only irreversible but progressive. Using a rat model, Kriz et al. (3) have performed a detailed structural study demonstrating how podocytes reinforce attachment to the GBM and how they detach. It appears that if the protective mechanisms fail, viable podocytes, mostly in clusters, detach from the GBM. Some of them may reach the renal pelvis as living cells, while other may develop contacts to the parietal epithelium, forming crescents that connect glomerular capillaries with the Bowman’s capsule. Podocyte depletion represents one of the earliest cellular lesions affecting the diabetic kidney, and decreased number of podocytes in glomeruli is the strongest predictor of progression of both type 1 and 2 DN. Activation of protein kinase C (PKC) seems to play a critical role in pathogenesis of DN. Teng et al. (5) point out that conventional as well as atypical forms of PKC, which play a pivotal role in the regulation of podocyte physiology, may be a destructive factor when hyperactivated in disease conditions. PKC activation results in downregulation of podocyte and SD structural proteins such as P-cadherin or β-catenin, which may contribute to the disruption of podocyte integrity. In DN, the PKC isoforms may also mediate the high glucose-induced overproduction of VEGF and increased TGFβ signaling in podocytes, with subsequent impairment of the glomerular filtration barrier. Recent findings reveal that abnormal intracellular accumulation of sphingolipids modulates podocyte functions in glomerular disorders of both genetic and non-genetic origin. Based on their experimental results, Merscher and Fornoni (6) report that in FSGS, suPAR-dependent αVβ3 integrin activation decreased expression of sphingomyelin-like phosphodiesterase 3b (SMPDL3b) resulting in increased accumulation of sphingomyelin, which is associated with remodeling of the podocyte actin cytoskeleton, loss of stress fibers, and a shift from a migratory to an apoptotic phenotype. In contrast, in the diabetic kidney SMPDL3b expression was elevated, nonetheless rendering podocytes more susceptible to apoptosis. These observations indicate that podocyte responses to sphingolipids are complex and require additional research. Hereditary, but also sporadic, nephrotic syndrome (NS) is frequently associated with mutations in podocyte genes encoding functional and structural proteins. However, currently known mutations explain

Patients with nail-patella syndrome, which among other symptoms also includes podocyte-associated renal failure, suffer from mutations in the LMX1B gene. The disease severity among patients is quite variable and has given rise to speculations on the presence of modifier genes. Promising candidates for modifier proteins are the proteins interacting with LMX1B, such as LDB1 and E47. Since human kidney samples from patients are difficult to obtain, conventional Lmx1b knock-out mice have been extremely valuable to study the role of Lmx1b in podocyte differentiation. In contrast to findings in these mice, however, in which a downregulation of the Col4a3, Col4a4 and Nphs2 genes has been described, no such changes have been detected in kidney biopsies from patients. We now report on our results on the characterization of constitutive podocyte-specific Lmx1b, Ldb1 and E2a knock-out mice. Constitutive podocyte-specific Lmx1b knock-out mice survive for approximately 2 weeks after birth and do not present with a downregulation of the Col4a3, Col4a4 and Nphs2 genes, therefore they mimic the human disease more closely. The podocyte-specific Ldb1 knock-out mice survive longer, but then also succumb to renal failure, whereas the E2a knock-out mice show no renal symptoms for at least 6 months after birth. We conclude that LDB1, but not E2A is a promising candidate as a modifier gene in patients with nail-patella syndrome.