New insights into the immune functions of podocytes: the role of complement

Abstract

Podocytes are differentiated epithelial cells which play an essential role to ensure a normal function of the glomerular filtration barrier (GFB). In addition to their adhesive properties in maintaining the integrity of the filtration barrier, they have other functions, such as synthesis of components of the glomerular basement membrane (GBM), production of vascular endothelial growth factor (VEGF), release of inflammatory proteins, and expression of complement components. They also participate in the glomerular crosstalk through multiple signalling pathways, including endothelin-1, VEGF, transforming growth factor β (TGFβ), bone morphogenetic protein 7 (BMP-7), latent transforming growth factor β-binding protein 1 (LTBP1), and extracellular vesicles.Growing literature suggests that podocytes share many properties of innate and adaptive immunity, supporting a multifunctional role ensuring a healthy glomerulus. As consequence, the "immune podocyte" dysfunction is thought to be involved in the pathogenesis of several glomerular diseases, referred to as "podocytopathies." Multiple factors like mechanical, oxidative, and/or immunologic stressors can induce cell injury. The complement system, as part of both innate and adaptive immunity, can also define podocyte damage by several mechanisms, such as reactive oxygen species (ROS) generation, cytokine production, and endoplasmic reticulum stress, ultimately affecting the integrity of the cytoskeleton, with subsequent podocyte detachment from the GBM and onset of proteinuria.Interestingly, podocytes are found to be both source and target of complement-mediated injury. Podocytes express complement proteins which contribute to local complement activation. At the same time, they rely on several protective mechanisms to escape this damage. Podocytes express complement factor H (CFH), one of the main regulators of the complement cascade, as well as membrane-bound complement regulators like CD46 or membrane cofactor protein (MCP), CD55 or decay-accelerating factor (DAF), and CD59 or defensin. Further mechanisms, like autophagy or actin-based endocytosis, are also involved to ensure podocyte homeostasis and protection against injury.This review will provide an overview of the immune functions of podocytes and their response to immune-mediated injury, focusing on the pathogenic link between complement and podocyte damage.

Keywords: Complement; Immune system; Podocyte.

Fig. 1

Main components of the slit diaphragm and podocyte-endothelial cell cross talk in healthy versus damaged podocytes. Podocyte slit diaphragm, glomerular basement membrane (GBM), and endothelial cells are the main components of the glomerular filtration barrier. Podocyte effacement/detachment, secondary to mechanical, oxidative, and/or immunologic triggers, is characterized by loss of silt diaphragm integrity, disruption of actin cytoskeleton and focal adhesions, and interruption of the physiological podocyte-endothelial cell cross talk (dashed arrows). Abbreviations: GBM, glomerular basement membrane; Ang, angiopoietin; ANGPTL, angiopoietin-like protein; IGF, insulin-like growth factor; IGFBP-rP1, insulin-like growth factor-binding protein-related protein 1; ET-1, endothelin-1; HGF, hepatocyte growth factor; IL-1, interleukin-1; NO, nitric oxide; TNF-a, tumor necrosis factor-a; VEGF, vascular endothelial growth factor