Similarities between podocytes and brain reside in biological processes related to actin-based projections such as podocyte foot processes, axons and dendritic spines. Further similarities are associated with cell-cell contacts in synapses and the slit diaphragm where podocalyxin, neurexin, cadherins/protocadherins and Ig-like proteins are crucial for these adhesion processes. Additionally, podocytes employ signaling mechanisms involving neurotransmitters as found in brain synapses such as the glutamate receptors. In 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). The 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 and TUBB3 mRNA in UdPodocytes, biopsy-derived kidney and brain samples. MAP2, TAU and TUBB3 expression is shown by Western blotting and Immunofluorescence analysis. 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. In 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.
Wruck et al. (Wed,) studied this question.