Evidence for conserved gene expression and biological processes operative in human podocytes and adult brain

Abstract

BackgroundPodocytes are essential for the proper functioning of the glomerular filtration barrier and are characterized by their intricate structure which includes well-organized primary and secondary foot processes. The brain expresses podocyte-associated proteins such as Nephrin, and Synaptopodin which are well documented. Processing of information and inter-cellular communication between podocytes and neurons employ similar molecular mechanisms which include actin-based projections, adhesion molecules, and signaling pathways. MethodsIn this study, we analysed brain-associated biological processes, transcription factors and pathways significantly regulated in UdPodocytes, i.e. podocytes differentiated from SIX2-positive UdRPCs (urine-derived renal progenitor cells). We compared gene expression in iPSC-derived brain and kidney organoids with UdPodocytes and mapped the overlapping 344 genes to brain regions via the GTEX (Genotype-Tissue Expression) database and investigated their regulation induced by the mediator of the renin-angiotensin system-angiotensin II (ANG II) ResultsThe protein interaction network of UdPodocytes genes associated with brain in GTEX contains modules for pre-synapse, post-synapse, endocrine processes and neural crest differentiation. We also found that the genes overlapping between brain and podocytes are also expressed in iPSC-derived kidney and brain organoids and could map the involved genes to all regions of the brain with the frontal cortex as the most enriched. The genes SUZ12, NFKB1 and PAX2 were the most significantly over-represented transcription factors. We independently confirmed the conserved expression of PAX6, KCNQ3, TUJ1,MAP2, TAU and ACTN4 in Udpodocytes as shown by Western blotting, Immunofluorescence and RT-PCR. We further investigated if the conserved genes are also regulated by ANGII. This unveiled genes down-regulated upon ANGII-stimulation of Udpodocytes to be associated with axon guidance, Calcium, Hippo and cGMP-PKG signaling as over-represented pathways. ConclusionIn conclusion, we have identified 344 genes with overlapping expression in brain and podocytes. These are mainly associated with synaptic signaling and cell projections. This implies that human urine-derived SIX2-renal progenitor cells differentiated into podocytes can serve as a platform for dissecting and understanding the relevance of conserved biological processes in podocytes which are currently annotated as neuron projection, axons, neurogenesis and synaptic signaling.