A slit-diaphragm-associated protein network for dynamic control of renal filtration

The filtration of blood in the kidney which is crucial for mammalian life is determined by the slit-diaphragm (SD), a proteinaceous junction between the foot processes of renal podocytes. Based on studies of structure and function the SD has been hypothesized to operate as a final barrier or as a ‘molecular sensor’ of renal filtration. Using high-resolution proteomic analysis of SDs affinity-isolated from rodent kidney, we show that the native SD is built from the known junction-forming components Nephrin, Neph1 and Podocin and a co-assembled high-molecular weight network of proteins. The network constituents cover distinct classes of proteins including signaling receptors, kinases and phosphatases, transporters and scaffolds. Knock-out or knock-down of either the core components or the selected network constituents tyrosine kinase MER (MERTK), atrial natriuretic peptide receptor C (ANPRC) and protein ITM2B resulted in target-specific impairment or disruption of the filtration process. Thus, our results identify the SD as a multi-component system that is endowed with context-dependent dynamics via a co-assembled protein network.