Signaling at the Slit
Authors: Thomas Weide, Tobias B. Huber
Journal: Journal of the American Society of Nephrology (2009)

Glomerular podocytes are unique in form and function. With a highly organized cytoskeleton to counteract transmural distending forces, they serve as part of a molecular sieve that establishes the permselective properties of the glomerular filter. Podocytes consist of a voluminous cell body, which bulges into the urinary space, and highly branched foot processes.1 The complex cell architecture and polarity of podocytes partly mirrors the structure of neurons.1,2 Both cell types are postmitotic and develop long microtubule-based protrusions cobbled with short actin-based foot processes or dendritic spines, respectively.3 The foot processes of neighboring podocytes regularly interdigitate, leaving meandering filtration slits between them that are bridged by the slit-diaphragm.3 In addition to the common structural organization of podocytes and neurons, both cells share several highly tissue-specific proteins such as nephrin-neph proteins, which drive the formation of slit-diaphragms in the kidney and synapse formation in Caenorhabditis elegans motorneurons,4 amino acid transporters such as CAT3 or EAAT2,5 ion channels such as BKCa,6 catecholamine receptors,7 and axonal guidance factors.8 The slit-diaphragm is linked to and tightly regulates the actin dynamics of foot processes.9 Strikingly, among these actin-linking proteins, an increasing number of "neuronal" proteins have been identified as crucial determinants of actin-based cell processes, such as synaptopodin, dendrin, or its interacting partner KIBRA—a protein recently associated with learning and memory.10 These findings emphasize the hypothesis that foot process dynamics and neuronal synaptic plasticity are regulated by an analogous set of molecules.11–14 Recent studies have changed our conception of the glomerulus from a relatively static structure to a dynamic one, whose integrity depends on signaling mechanisms at the filtration barrier.15 Typical epithelial cell layers often use gap junctions to rapidly and efficiently exchange chemical and physical signals. However, epithelial podocytes, being kept apart by slit-diaphragms, are probably not able to form gap junctions under physiologic conditions, implying a role for alternative communication pathways between cells. Thus far, very little is known of the intercellular signaling that might dynamically fine tune the complex three-dimensional foot-process network. In this issue of JASN, Giardino and colleagues demonstrate an exciting form of intercellular signaling by podocytes using neuronal glutamatergic transmission systems to regulate the maintenance of the foot process network.16 Previously, these authors found podocyte-specific expression of the small GTPase, rab3A, and its effector, rabphillin 3a; both proteins play an important role in Ca2+-dependent exocytosis of synaptic vesicles,17,18 and interestingly, synapses of neurons form a cleft of 20 to 50 nm, which is quite similar to the ∼40 nm width between foot processes. Earlier electron microscopy studies also showed the presence of "synaptic-like" vesicles in the secondary foot processes of podocytes and the expression of a functional glutamatergic synaptic transmission system, providing a clear hint that podocytes not only exhibit synaptic plasticity but also execute synaptic-like communications. Giardino et al.16 now perform an elegant in vivo study by using rab3A-null mice and pharmacologic antagonists of N-methyl-D-aspartate (NMDA) receptors to block the glutamatergic signaling system. They observe rab3A deficiency as well as the blockade of NMDA receptors results in increased albuminuria. In vitro experiments using cultured podocytes reveal the inhibition of the NMDA receptor rearranges the actin/myosin cytoskeleton and the loss of rab3A causes uncoordinated exocytosis of glutamate-containing vesicles. Taken together, the authors uncover in their pioneering work a functional synaptic transmission system that seems to bridge the slits for interpodocyte communication, supporting the idea that podocytes share not only morphologic features but also use cell communication networks similar to neuronal cells. By revealing a novel pathway of podocyte communication between cells, this study also raises several intriguing questions. What is pre- and what is postsynaptic in a podocyte? Unlike neurons—that develop distinct axonal pre- and dendritic postsynaptic structures—podocytes seem to communicate across identical structures through a soluble environment. How do individual podocytes discriminate between "self" and "nonself "neighboring foot processes? Is there an asymmetric distribution of synaptic-like receptors and neuronal transmitters? And finally, what triggers and modulates exocytosis? These questions are of particular interest because synaptic signaling between podocytes may not only represent an important physiologic feature but may also serve as a molecular guidepost for podocyte recovery following podocyte injury and foot process effacement. Neuronal-like signal transmission might not only function as autocrine, interpodocyte signaling, but also serve as paracrine feedback mechanism between podocytes and endothelial, mesangial, or tubular cells. Such paracrine interglomerular signaling pathways using soluble factors have been described before.19 In this respect, it will also be interesting to know whether these cell types express other neuronal receptors. To fully understand the functional role of neuronal-like synaptic transmission for podocyte function, it will be important not only to focus on the similarities of podocytes and neurons, but also to appreciate their fundamental differences: podocytes are of mesenchymal origin, whereas neurons are ectodermal. The slit-diaphragm is not a synapse-like, punctuate cell–cell contact zone, but a linear cell–cell contact zone intermediating highly branched foot processes. Moreover, podocytes are attached to a basement membrane reflecting their epithelial nature. One other important difference regarding synaptic signaling is that podocytes are nonexcitable cells with completely different electrophysiological properties. Despite these very exciting new findings, it is fair to say that podocytes are certainly not neurons. However, they seem to have adopted and combined many useful features of neuronal, mesenchymal, and epithelial cells to develop and maintain their spectacular structure and function. Disclosures None. We thank Hermann Pavenstädt, Giuliano Ciarimboli, and Stuart E. Dryer for carefully reading the manuscript and the members of our laboratories for helpful discussions. This work was supported in part by Innovative Medizinische Forschung (IMF) Grant I-WE110919 to T.W. and by DFG-SFB 592 to T.B.H.