Rac1 promotes kidney collecting duct integrity by limiting actomyosin activity

2021 ◽  
Vol 220 (11) ◽  
Author(s):  
Fabian Bock ◽  
Bertha C. Elias ◽  
Xinyu Dong ◽  
Diptiben V. Parekh ◽  
Glenda Mernaugh ◽  
...  
Keyword(s):  
Rho Gtpase ◽  
Collecting Duct ◽  
Myosin Ii ◽  
Ureteric Bud ◽  
Epithelial Integrity ◽  
Epithelial Morphology ◽  
Cytoskeletal Regulation ◽  
Intact Kidney ◽  
And Function

A polarized collecting duct (CD), formed from the branching ureteric bud (UB), is a prerequisite for an intact kidney. The small Rho GTPase Rac1 is critical for actin cytoskeletal regulation. We investigated the role of Rac1 in the kidney collecting system by selectively deleting it in mice at the initiation of UB development. The mice exhibited only a mild developmental phenotype; however, with aging, the CD developed a disruption of epithelial integrity and function. Despite intact integrin signaling, Rac1-null CD cells had profound adhesion and polarity abnormalities that were independent of the major downstream Rac1 effector, Pak1. These cells did however have a defect in the WAVE2–Arp2/3 actin nucleation and polymerization apparatus, resulting in actomyosin hyperactivity. The epithelial defects were reversible with direct myosin II inhibition. Furthermore, Rac1 controlled lateral membrane height and overall epithelial morphology by maintaining lateral F-actin and restricting actomyosin. Thus, Rac1 promotes CD epithelial integrity and morphology by restricting actomyosin via Arp2/3-dependent cytoskeletal branching.

The role of metalloproteinases and their inhibitors in regulating mammary epithelial morphology and function in vivo

1995 ◽  
Vol 2 (3) ◽  
pp. 401-411 ◽  
Author(s):  
Carolyn J. Sympson ◽  
Rabih S. Talhouk ◽  
Mina J. Bissell ◽  
Zena Werb
Keyword(s):  
Mammary Epithelial ◽  
Epithelial Morphology ◽  
And Function

scholarly journals A Pivotal Role of Rho GTPase in the Regulation of Morphology and Function of Dendritic Cells

2001 ◽  
Vol 167 (7) ◽  
pp. 3585-3591 ◽  
Author(s):  
Michihiro Kobayashi ◽  
Eiichi Azuma ◽  
Masaru Ido ◽  
Masahiro Hirayama ◽  
Qi Jiang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Rho Gtpase ◽  
Pivotal Role ◽  
And Function

scholarly journals The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 265 ◽  
Author(s):  
Sathish Murali ◽  
Takwa Aroankins ◽  
Hanne Moeller ◽  
Robert Fenton
Keyword(s):  
Collecting Duct ◽  
Water Channel ◽  
Mouse Kidney ◽  
Body Water ◽  
Mrna Levels ◽  
E3 Ligases ◽  
Water Homeostasis ◽  
And Function

Aquaporin 2 (AQP2) mediates the osmotic water permeability of the kidney collecting duct in response to arginine vasopressin (VP) and is essential for body water homeostasis. VP effects on AQP2 occur via long-term alterations in AQP2 abundance and short-term changes in AQP2 localization. Several of the effects of VP on AQP2 are dependent on AQP2 phosphorylation and ubiquitylation; post-translational modifications (PTM) that modulate AQP2 subcellular distribution and function. Although several protein kinases, phosphatases, and ubiquitin E3 ligases have been implicated in AQP2 PTM, how AQP2 is deubiquitylated or the role of deubiquitylases (DUBS) in AQP2 function is unknown. Here, we report a novel role of the ubiquitin-specific protease USP4 in modulating AQP2 function. USP4 co-localized with AQP2 in the mouse kidney, and in mpkCCD14 cells USP4 and AQP2 abundance are increased by VP. AQP2 and USP4 co-immunoprecipitated from mpkCCD14 cells and mouse kidney, and in vitro, USP4 can deubiquitylate AQP2. In mpkCCD14 cells, shRNA mediated knockdown of USP4 decreased AQP2 protein abundance, whereas no changes in AQP2 mRNA levels or VP-induced cAMP production were detected. VP-induced AQP2 membrane accumulation in knockdown cells was significantly reduced, which was associated with higher levels of ubiquitylated AQP2. AQP2 protein half-life was also significantly reduced in USP4 knockdown cells. Taken together, the data suggest that USP4 is a key regulator of AQP2 deubiquitylation and that loss of USP4 leads to increased AQP2 ubiquitylation, decreased AQP2 levels, and decreased cell surface AQP2 accumulation upon VP treatment. These studies have implications for understanding body water homeostasis.

Stromal cells mediate retinoid-dependent functions essential for renal development

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1139-1148 ◽  
Author(s):  
C. Mendelsohn ◽  
E. Batourina ◽  
S. Fung ◽  
T. Gilbert ◽  
J. Dodd
Keyword(s):  
Vitamin A ◽  
Stromal Cells ◽  
Renal Cell ◽  
Kidney Development ◽  
Collecting Duct ◽  
Cell Types ◽  
Renal Development ◽  
Ureteric Bud ◽  
Renal Malformations

The essential role of vitamin A and its metabolites, retinoids, in kidney development has been demonstrated in vitamin A deficiency and gene targeting studies. Retinoids signal via nuclear transcription factors belonging to the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families. Inactivation of RARaplpha and RARbeta2 receptors together, but not singly, resulted in renal malformations, suggesting that within a given renal cell type, their concerted function is required for renal morphogenesis. At birth, RARalpha beta2(−) mutants displayed small kidneys, containing few ureteric bud branches, reduced numbers of nephrons and lacking the nephrogenic zone where new nephrons are continuously added. These observations have prompted us to investigate the role of RARalpha and RARbeta2 in renal development in detail. We have found that within the embryonic kidney, RARalpha and RARbeta2 are colocalized in stromal cells, but not in other renal cell types, suggesting that stromal cells mediate retinoid-dependent functions essential for renal development. Analysis of RARalpha beta2(−) mutant kidneys at embryonic stages revealed that nephrons were formed and revealed no changes in the intensity or distribution of molecular markers specific for different metanephric mesenchymal cell types. In contrast the development of the collecting duct system was greatly impaired in RARalpha beta2(−) mutant kidneys. Fewer ureteric bud branches were present, and ureteric bud ends were positioned abnormally, at a distance from the renal capsule. Analysis of genes important for ureteric bud morphogenesis revealed that the proto-oncogene c-ret was downregulated. Our results suggest that RARalpha and RARbeta2 are required for generating stromal cell signals that maintain c-ret expression in the embryonic kidney. Since c-ret signaling is required for ureteric bud morphogenesis, loss of c-ret expression is a likely cause of impaired ureteric bud branching in RARalpha beta2(−) mutants.

scholarly journals Analysis of the role of Ser1/Ser2/Thr9 phosphorylation on myosin II assembly and function in live cells

2011 ◽  
Vol 12 (1) ◽  
pp. 52 ◽  
Author(s):  
Jordan R Beach ◽  
Lucila S Licate ◽  
James F Crish ◽  
Thomas T Egelhoff
Keyword(s):  
Myosin Ii ◽  
Live Cells ◽  
And Function

scholarly journals Role of Survivin in cytokinesis revealed by a separation-of-function allele

2011 ◽  
Vol 22 (20) ◽  
pp. 3779-3790 ◽  
Author(s):  
Edith Szafer-Glusman ◽  
Margaret T. Fuller ◽  
Maria Grazia Giansanti
Keyword(s):  
Myosin Ii ◽  
Cell Cortex ◽  
Direct Role ◽  
Central Spindle ◽  
Ring Assembly ◽  
Chromosomal Passenger ◽  
Missense Allele ◽  
Ring Analysis ◽  
And Function

The chromosomal passenger complex (CPC), containing Aurora B kinase, Inner Centromere Protein, Survivin, and Borealin, regulates chromosome condensation and interaction between kinetochores and microtubules at metaphase, then relocalizes to midzone microtubules at anaphase and regulates central spindle organization and cytokinesis. However, the precise role(s) played by the CPC in anaphase have been obscured by its prior functions in metaphase. Here we identify a missense allele of Drosophila Survivin that allows CPC localization and function during metaphase but not cytokinesis. Analysis of mutant cells showed that Survivin is essential to target the CPC and the mitotic kinesin-like protein 1 orthologue Pavarotti (Pav) to the central spindle and equatorial cell cortex during anaphase in both larval neuroblasts and spermatocytes. Survivin also enabled localization of Polo kinase and Rho at the equatorial cortex in spermatocytes, critical for contractile ring assembly. In neuroblasts, in contrast, Survivin function was not required for localization of Rho, Polo, or Myosin II to a broad equatorial cortical band but was required for Myosin II to transition to a compact, fully constricted ring. Analysis of this “separation-of-function” allele demonstrates the direct role of Survivin and the CPC in cytokinesis and highlights striking differences in regulation of cytokinesis in different cell systems.

scholarly journals The Renal Physiology of Pendrin-Positive Intercalated Cells

2020 ◽  
Vol 100 (3) ◽  
pp. 1119-1147 ◽  
Author(s):  
Susan M. Wall ◽  
Jill W. Verlander ◽  
Cesar A. Romero
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Pressor Response ◽  
Collecting Duct ◽  
Renal Physiology ◽  
Intercalated Cells ◽  
Acid Base Balance ◽  
Base Balance ◽  
And Function

Intercalated cells (ICs) are found in the connecting tubule and the collecting duct. Of the three IC subtypes identified, type B intercalated cells are one of the best characterized and known to mediate Cl− absorption and HCO3− secretion, largely through the anion exchanger pendrin. This exchanger is thought to act in tandem with the Na+-dependent Cl−/HCO3− exchanger, NDCBE, to mediate net NaCl absorption. Pendrin is stimulated by angiotensin II and aldosterone administration via the angiotensin type 1a and the mineralocorticoid receptors, respectively. It is also stimulated in models of metabolic alkalosis, such as with NaHCO3 administration. In some rodent models, pendrin-mediated HCO3− secretion modulates acid-base balance. However, of probably more physiological or clinical significance is the role of these pendrin-positive ICs in blood pressure regulation, which occurs, at least in part, through pendrin-mediated renal Cl− absorption, as well as their effect on the epithelial Na+ channel, ENaC. Aldosterone stimulates ENaC directly through principal cell mineralocorticoid hormone receptor (ligand) binding and also indirectly through its effect on pendrin expression and function. In so doing, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. In addition to its role in Na+ and Cl− balance, pendrin affects the balance of other ions, such as K+ and I−. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contribution of pendrin-positive ICs in the kidney to distal nephron function and blood pressure.

scholarly journals Early studies of airway submucosal glands

2019 ◽  
Vol 316 (6) ◽  
pp. L990-L998 ◽  
Author(s):  
Jonathan H. Widdicombe
Keyword(s):  
Collecting Duct ◽  
Tracheobronchial Tree ◽  
Gland Secretion ◽  
Submucosal Glands ◽  
Collecting Duct Epithelium ◽  
And Function ◽  
The 19Th Century ◽  
Comparative Information

This historical article provides a comprehensive review of early research on the structure and function of airway submucosal glands. The literature before 1950 or so, is virtually unknown, but in addition to being of historical interest it contains much of relevance to current research. Airway glands were first mentioned in 1602. The first description of their general form, size, and distribution was in 1712. Gland morphology was determined in 1827 by injecting mercury into their openings. Wax was later used. Detailed comparative information for all regions of the tracheobronchial tree was provided by Frankenhauser in 1879 ( Untersuchungen uber den bau der Tracheo-Bronchial-Schleimhaut). Histological studies began in 1870, and by the end of the 19th century, all the major histological features had been described. The first physiological studies on airway mucous secretion were published in 1892. Kokin, in 1896 ( Archiv für die gesamte Physiologie des Menschen und der Tiere 63: 622–630), was the first to measure secretion from individual glands. It was not, however, until 1933 that gland secretion was quantified. This early literature raises important questions as to the role of the collecting duct epithelium in modifying primary secretions. It also provides perhaps the most accurate measure of basal gland secretion in vivo.

scholarly journals Myosin IIB and F-actin control apical vacuolar morphology and histamine-induced trafficking of H-K-ATPase-containing tubulovesicles in gastric parietal cells

2014 ◽  
Vol 306 (8) ◽  
pp. G699-G710 ◽  
Author(s):  
Paramasivam Natarajan ◽  
James M. Crothers ◽  
Jared E. Rosen ◽  
Stephanie L. Nakada ◽  
Milap Rakholia ◽  
...  
Keyword(s):  
Myosin Light Chain ◽  
Collecting Duct ◽  
Myosin Ii ◽  
Parietal Cells ◽  
Resting Cells ◽  
Neuronal Synapses ◽  
Collecting Duct Cells ◽  
Water Secretion ◽  
Gastric Parietal Cells

Selective inhibitors of myosin or actin function and confocal microscopy were used to test the role of an actomyosin complex in controlling morphology, trafficking, and fusion of tubulovesicles (TV) containing H-K-ATPase with the apical secretory canaliculus (ASC) of primary-cultured rabbit gastric parietal cells. In resting cells, myosin IIB and IIC, ezrin, and F-actin were associated with ASC, whereas H-K-ATPase localized to intracellular TV. Histamine caused fusion of TV with ASC and subsequent expansion resulting from HCl and water secretion; F-actin and ezrin remained associated with ASC whereas myosin IIB and IIC appeared to dissociate from ASC and relocalize to the cytoplasm. ML-7 (inhibits myosin light chain kinase) caused ASC of resting cells to collapse and most myosin IIB, F-actin, and ezrin to dissociate from ASC. TV were unaffected by ML-7. Jasplakinolide (stabilizes F-actin) caused ASC to develop large blebs to which actin, myosin II, and ezrin, as well as tubulin, were prominently localized. When added prior to stimulation, ML-7 and jasplakinolide prevented normal histamine-stimulated transformations of ASC/TV and the cytoskeleton, but they did not affect cells that had been previously stimulated with histamine. These results indicate that dynamic pools of actomyosin are required for maintenance of ASC structure in resting cells and for trafficking of TV to ASC during histamine stimulation. However, the dynamic pools of actomyosin are not required once the histamine-stimulated transformation of TV/ASC and cytoskeleton has occurred. These results also show that vesicle trafficking in parietal cells shares mechanisms with similar processes in renal collecting duct cells, neuronal synapses, and skeletal muscle.

scholarly journals New perspective of ClC-Kb/2 Cl− channel physiology in the distal renal tubule

2016 ◽  
Vol 310 (10) ◽  
pp. F923-F930 ◽  
Author(s):  
Oleg Zaika ◽  
Viktor Tomilin ◽  
Mykola Mamenko ◽  
Vivek Bhalla ◽  
Oleh Pochynyuk
Keyword(s):  
Collecting Duct ◽  
Electrolyte Balance ◽  
Thick Ascending Limb ◽  
Medullary Collecting Duct ◽  
New Perspective ◽  
Renal Tubular ◽  
And Function ◽  
Type 3

Since its identification as the underlying molecular cause of Bartter's syndrome type 3, ClC-Kb (ClC-K2 in rodents, henceforth it will be referred as ClC-Kb/2) is proposed to play an important role in systemic electrolyte balance and blood pressure regulation by controlling basolateral Cl− exit in the distal renal tubular segments from the cortical thick ascending limb to the outer medullary collecting duct. Considerable experimental and clinical effort has been devoted to the identification and characterization of disease-causing mutations as well as control of the channel by its cofactor, barttin. However, we have only begun to unravel the role of ClC-Kb/2 in different tubular segments and to reveal the regulators of its expression and function, e.g., insulin and IGF-1. In this review we discuss recent experimental evidence in this regard and highlight unexplored questions critical to understanding ClC-Kb/2 physiology in the kidney.

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