Rac1 promotes kidney collecting duct repair by mechanically coupling cell morphology to mitotic entry
Fabian Bock,
Xinyu Dong,
Shensen Li
et al.
Abstract:Prolonged obstruction of the ureter, which leads to injury of the kidney collecting ducts, results in permanent structural damage, while early reversal allows for repair. Cell structure is defined by the actin cytoskeleton, which is dynamically organized by small Rho guanosine triphosphatases (GTPases). In this study, we identified the Rho GTPase, Rac1, as a driver of postobstructive kidney collecting duct repair. After the relief of ureteric obstruction, Rac1 promoted actin cytoskeletal reconstitution, which … Show more
Purpose of review
Postnatal renal tubule development is critical to adult kidney function. Several postnatal changes regulate the differentiation and proliferation of renal tubular cells. Here, we review the literature and our efforts on thick ascending limb (TAL) development in Bartter syndrome (BS).
Recent findings
Glomerular filtrate quickly increases after birth, imposing fluid shear stress and circumferential stretch on immature renal tubules. Recent studies showed that kidney organoids under flow (superfusion) have better development of tubular structures and the expression of cilia and solute transporters. These effects are likely mediated by mechanosensors, such as cilia and the piezo1 channel. Improved renal oxygenation and sodium pump-dependent active transport can stimulate mitochondrial respiration and biogenesis. The functional coupling between transport and mitochondria ensures ATP supply for energy-demanding reactions in tubular cells, including cell cycle progression and proliferation. We recently discovered that postnatal renal medulla maturation and TAL elongation are impaired in Clc-k2-deficient BS mice. Primary cultured Clc-k2-deficient TAL cells have G1-S transition and proliferation delay. These developmental defects could be part of the early pathogenesis of BS and worsen the phenotype.
Summary
Understanding how tubular flow and transepithelial ion fluxes regulate renal tubule development may improve the treatment of congenital renal tubulopathies.
Purpose of review
Postnatal renal tubule development is critical to adult kidney function. Several postnatal changes regulate the differentiation and proliferation of renal tubular cells. Here, we review the literature and our efforts on thick ascending limb (TAL) development in Bartter syndrome (BS).
Recent findings
Glomerular filtrate quickly increases after birth, imposing fluid shear stress and circumferential stretch on immature renal tubules. Recent studies showed that kidney organoids under flow (superfusion) have better development of tubular structures and the expression of cilia and solute transporters. These effects are likely mediated by mechanosensors, such as cilia and the piezo1 channel. Improved renal oxygenation and sodium pump-dependent active transport can stimulate mitochondrial respiration and biogenesis. The functional coupling between transport and mitochondria ensures ATP supply for energy-demanding reactions in tubular cells, including cell cycle progression and proliferation. We recently discovered that postnatal renal medulla maturation and TAL elongation are impaired in Clc-k2-deficient BS mice. Primary cultured Clc-k2-deficient TAL cells have G1-S transition and proliferation delay. These developmental defects could be part of the early pathogenesis of BS and worsen the phenotype.
Summary
Understanding how tubular flow and transepithelial ion fluxes regulate renal tubule development may improve the treatment of congenital renal tubulopathies.
Branching morphogenesis orchestrates organogenesis in many tissues including kidney, where ureteric bud branching determines kidney size and nephron number. We characterized 3D epithelial cell morphology, mechanisms regulating cell shape changes and their contribution to novel branch initiation in normal and branching incompetent bud tips. Machine learning-based segmentation of tip epithelia identified geometrical round-to-elliptical transformation as a key cellular mechanism facilitating growth direction changes in gaining optimal branching complexity. Cell shape and molecular analyses in branching incompetent epithelia demonstrated a failure to condense cell size and conformation, which with altered adhesive forces, defective actin dynamics, and MYH9-based microtubule organization suggest stiff cellular niche with disturbed sensing of and responses to biomechanical cues. The data collectively propose a model where epithelial cell crowding in tandem with stretching transform individual cells into elliptical and elongated shapes. This creates local curvatures that drive new branch formation during the ampulla-to-asymmetric ampulla transition of ureteric bud.
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