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. 2018 Sep 11;5:221. doi: 10.3389/fmed.2018.00221

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Copyright © 2018 Yu, Nissaisorakarn, Husain and Jim.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Schematic interaction between slit diaphragm signal cascades and actin dynamics in healthy podocytes. In healthy podocytes, slit diaphragm (SD) is composed by various proteins and acts as a signaling hub, to maintain podocyte survival and regulated actin dynamics. For example, nephrin phosphorylation recruits AKT/PI3K and Nck/NWASP to modulate pro-survival signaling and actin organization, respectively, in concert with other SD proteins such as podocin, CD2AP, and synaptopodin. In physiological status, predominant TRPC6 offers necessary intracellular calcium and activates RhoA, an important small GTPase promoting stress fiber formation. Imbalance between RhoA and Rac1/Cdc42 (activated by TRPC5) leads to dysregulated actin formation. Upon stimulation (for example angiotensin II), G-protein coupled receptors (GPCRs) triggers second messengers' formations, further modulating intracellular calcium concentration via activating TRPC6 (yellow star). Endocytosis and recycling of proteins on slit diaphragm is controlled by serial phosphorylation and associated proteins such as β-arrestin2. PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; Rac1, ras-related C3 botulinum toxin substrate 1; Cdc42, cell division control protein 42 homolog; RhoA, ras homolog gene family, member A; CaMKII, ca²⁺/calmodulin-dependent protein kinase II; Synpo, synaptopodin; MAGI-1, membrane-associated guanylate kinase inverted-1; PIP2, phosphatidylinositol bisphosphate; PLCβ, phospholipase Cβ; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; β-ARR2, β-arrestin 2.

Inline graphic — Schematic interaction between slit diaphragm signal cascades and actin dynamics in healthy podocytes. In healthy podocytes, slit diaphragm (SD) is composed by various proteins and acts as a signaling hub, to maintain podocyte survival and regulated actin dynamics. For example, nephrin phosphorylation recruits AKT/PI3K and Nck/NWASP to modulate pro-survival signaling and actin organization, respectively, in concert with other SD proteins such as podocin, CD2AP, and synaptopodin. In physiological status, predominant TRPC6 offers necessary intracellular calcium and activates RhoA, an important small GTPase promoting stress fiber formation. Imbalance between RhoA and Rac1/Cdc42 (activated by TRPC5) leads to dysregulated actin formation. Upon stimulation (for example angiotensin II), G-protein coupled receptors (GPCRs) triggers second messengers' formations, further modulating intracellular calcium concentration via activating TRPC6 (yellow star). Endocytosis and recycling of proteins on slit diaphragm is controlled by serial phosphorylation and associated proteins such as β-arrestin2. PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; Rac1, ras-related C3 botulinum toxin substrate 1; Cdc42, cell division control protein 42 homolog; RhoA, ras homolog gene family, member A; CaMKII, ca²⁺/calmodulin-dependent protein kinase II; Synpo, synaptopodin; MAGI-1, membrane-associated guanylate kinase inverted-1; PIP2, phosphatidylinositol bisphosphate; PLCβ, phospholipase Cβ; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; β-ARR2, β-arrestin 2.