The role of podocytes in glomerular pathobiology

Abstract

Podocytes are unique cells with a complex cellular organization. With respect to their cytoarchitecture, podocytes may be divided into three structurally and functionally different segments: cell body, major processes, and foot processes (FPs). The FPs of neighboring podocytes regularly interdigitate, leaving between them the filtration slits that are bridged by an extracellular structure, known as the slit diaphragm (SD). Podocytes cover the outer aspect of the glomerular basement membrane (GBM). They therefore form the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Chronic podocyte injury may lead to podocyte detachment from the GBM. Our knowledge of the molecular structure of the SD has been remarkably improved in the past few years. Several molecules, including nephrin, CD2AP, FAT, ZO-1, P-cadherin, Podocin, and Neph 1-3 have all been shown to be associated with the SD complex, and some of these molecules are critical for its integrity. Podocytes are injured in many forms of human and experimental glomerular disease. The early events are characterized either by alterations in the molecular composition of the SD without visible changes in morphology or, more obviously, by a reorganization of FP structure with the fusion of filtration slits and the apical displacement of the SD. Based on recent insights into the molecular pathology of podocyte injury, at least four major causes have been identified that lead to the uniform reaction of FP effacement and proteinuria: (1) interference with the SD complex and its lipid rafts; (2) direct interference with the actin cytoskeleton; (3) interference with the GBM or with podocyte-GBM interaction; and (4) interference with the negative surface charge of podocytes. There is also evidence, in focal segmental glomerular sclerosis (FSGS) and in idiopathic nephrotic syndrome in humans and rats, that podocyte damage may be caused by circulating albuminuric factors. Ongoing studies in many laboratories are aiming at an understanding of the dynamic relationship between SD proteins, the actin cytoskeleton, and the dynamics of FP structure in nephrotic syndrome and FSGS. These studies should provide us with a better understanding of the biological mechanism underlying the podocyte response to injury. Such studies will potentially translate into more refined treatment and the prevention of proteinuria and progressive glomerular disease.

Podocyte-specific Expression of C1q/TNF-α Related Protein 1 in Mice

“…The foot processes of neighboring podocytes interdigitate regularly, leaving filtration slits between them that are bridged by an extracellular structure known as the slit diaphragm. A growing number of proteins, including nephrin, CD2AP, FAT, ZO-1, Pcadherin, podocin, and Neph 1-3 have been shown to be expressed in the slit diaphragm, and some of these molecules play a major role in maintaining the structural and functional integrity of the slit diaphragm [21,22]. However, our data show that CTRP1 is expressed in the cytoplasm of podocyte cell body, not in the cell membrane of foot process or slit diaphragm.…”

Clues to CD2-associated Protein Involvement in Cytokinesis

“…CD2AP is involved in the foot process maintenance as revealed by the regression of these specialized structures in the kidney of CD2AP Ϫ/Ϫ mice (Shih et al, 1999). Interestingly, in podocyte foot processes a complete actin-based contractile apparatus is present (Asanuma and Mundel, 2003). The same protein composition (actin, myosin II, and ␣-actinin) is found in this podocyte apparatus and in the contractile ring apparatus of dividing cells.…”

mVps34 Deletion in Podocytes Causes Glomerulosclerosis by Disrupting Intracellular Vesicle Trafficking

“…Although alterations in structural proteins of the podocyte are now recognized to contribute to kidney disease, much of the podocyte's functions remain incompletely understood. 1,2 Autophagy is a tightly regulated intracellular process in which portions of cytoplasm, including proteins and organelles, are sequestered within double-membrane vesicles termed autophagosomes and are delivered to lysosomes for degradation and recycling of cellular components. 3,4 Mammalian cells are postulated to use autophagy as a mechanism for turnover of long-lived proteins and removal of protein aggregates and damaged organelles, and as a survival strategy under metabolic stress, including conditions of nutrient deprivation.…”