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Rho Family Proteins and Their Regulators in Kidney Physiology and Pathology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 September 2021) | Viewed by 19743

Special Issue Editors

Dr. Katalin Szászi

E-Mail Website
Guest Editor
Keenan Research Centre for Biomedical Science, Toronto, ON, Canada
Interests: Tubular epithelial biology; Rho family small GTPases; tight junctions; inflammatory signalling; guanine nucleotide exchange factors; claudins; epithelial-mesenchymal transition
Dr. Andras Kapus

E-Mail Website
Guest Editor
Keenan Research Centre for Biomedical Science, Toronto, ON, Canada
Interests: renal fibrosis; epithelium; profibrotic epithelial phenotype; transcription factors; Myocardin-related transcription factor; Yap/TAZ signaling; cytoskeleton; fibrogenic cytokines; primary cilium; polycystic kidney disease
Dr. Tomoko Takano

E-Mail Website
Guest Editor
Department of Medicine, Division of Nephrology, Faculty of Medicine, McGill University, Montreal, QC, Canada
Interests: nephrotic syndrome; proteinuria; podocytes; Rho-GTPases; cytoskeleton

Special Issue Information

Dear Colleagues,

Rho GTPase proteins form a subgroup of the Ras superfamily. In mammals, this group consists of 20 members that can be divided into subfamilies, including the best characterized Rac, Cdc42, and RhoA subfamilies as well as the lesser known groups of Rnd, RhoD/F, RhoH, RhoU/V, RhoBTB, and RhoT proteins. These proteins are at the center of an ever-increasing array of vital biological processes. The best studied members, RhoA, Rac1, and Cdc42, were initially characterized as central regulators of actin dynamics. Members of the Rho family subsequently emerged as vital orchestrators of diverse general cells functions, including gene transcription, vesicular trafficking, cell cycle progression, migration, polarity and differentiation control, as well as more specialized functions such as the control of enzymes generating reactive oxygen species. These diverse downstream effects are achieved through a multitude of effectors. In fact, Rho proteins and their regulators and effectors form complex, highly plastic, intertwined signaling networks. We have only started unraveling the details of how regulatory proteins finetune stimulus-specific Rho GTPase activation, selectively connecting a multitude of regulatory inputs to specific effectors. Detailed characterization of the spatiotemporal control and coordination of these networks will yield improved understanding of their physiological and pathological roles.

In recent years, our understanding of the vital roles of the Rho family in kidney biology has significantly increased, although our knowledge is mostly limited to the best characterized members of this large family. Accumulating evidence now implicates many Rho protein-dependent pathways in various kidney diseases, including glomerular diseases, kidney fibrosis, and developmental disorders. The aim of this Special Issue is to collect original contributions and review articles on all aspects of research on Rho family GTPases, as well as their regulators and effectors, in the broad context of kidney biology and pathology.

Suggested topics include but are not limited to research exploring the role and regulation of Rho proteins, regulators, and effectors in:

Podocyte biology

Tubular transport and its disorders

Glomerular diseases

Acute kidney injury

Inflammatory processes

Chronic kidney disease and fibrosis

Diabetic nephropathy

Polycystic kidney disease

Dr. Katalin Szászi
Dr. Andras Kapus
Dr. Tomoko Takano
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Rho family small GTPases
  • Rho-related signalling in renal cells
  • Renal (patho)physiology
  • acute and chronic kidney disease
  • hereditary kidney diseases
  • glomerulopathy
  • diabetic nephropathy

Published Papers (5 papers)

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Research

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13 pages, 3384 KiB  
Article
The Pathophysiologic Role of Gelsolin in Chronic Kidney Disease: Focus on Podocytes
by Chia-Jung Yu, Dian W. Damaiyanti, Shian-Jang Yan, Chih-Hsing Wu, Ming-Jer Tang, Dar-Bin Shieh, Peter P. Liu and Ping-Yen Liu
Int. J. Mol. Sci. 2021, 22(24), 13281; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413281 - 10 Dec 2021
Cited by 2 | Viewed by 2913
Abstract
Chronic kidney disease (CKD) is normally related to proteinuria, a common finding in a compromised glomerular filtration barrier (GFB). GFB is a structure composed of glomerular endothelial cells, the basement membrane, and the podocytes. CKD with podocyte damage may be associated with actin [...] Read more.
Chronic kidney disease (CKD) is normally related to proteinuria, a common finding in a compromised glomerular filtration barrier (GFB). GFB is a structure composed of glomerular endothelial cells, the basement membrane, and the podocytes. CKD with podocyte damage may be associated with actin cytoskeleton reorganization, resulting in podocyte effacement. Gelsolin plays a critical role in several diseases, including cardiovascular diseases and cancer. Our current study aimed to determine the connection between gelsolin and podocyte, and thus the mechanism underlying podocyte injury in CKD. Experiments were carried out on Drosophila to demonstrate whether gelsolin had a physiological role in maintaining podocyte. Furthermore, the survival rate of gelsolin-knocked down Drosophila larvae was extensively reduced after AgNO3 exposure. Secondly, the in vitro podocytes treated with puromycin aminonucleoside (PAN) enhanced the gelsolin protein expression, as well as small GTPase RhoA and Rac1, which also regulated actin dynamic expression incrementally with the PAN concentrations. Thirdly, we further demonstrated in vivo that GSN was highly expressed inside the glomeruli with mitochondrial dysfunction in a CKD mouse model. Our findings suggest that an excess of gelsolin may contribute to podocytes damage in glomeruli. Full article
(This article belongs to the Special Issue Rho Family Proteins and Their Regulators in Kidney Physiology and Pathology)
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12 pages, 1901 KiB  
Communication
Activin A and Cell-Surface GRP78 Are Novel Targetable RhoA Activators for Diabetic Kidney Disease
by Asfia Soomro, Jackie Trink, Kian O’Neil, Renzhong Li, Safaa Naiel, Bo Gao, Kjetil Ask and Joan C. Krepinsky
Int. J. Mol. Sci. 2021, 22(6), 2839; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062839 - 11 Mar 2021
Cited by 4 | Viewed by 2100
Abstract
Diabetic kidney disease (DKD) is the leading cause of kidney failure. RhoA/Rho-associated protein kinase (ROCK) signaling is a recognized mediator of its pathogenesis, largely through mediating the profibrotic response. While RhoA activation is not feasible due to the central role it plays in [...] Read more.
Diabetic kidney disease (DKD) is the leading cause of kidney failure. RhoA/Rho-associated protein kinase (ROCK) signaling is a recognized mediator of its pathogenesis, largely through mediating the profibrotic response. While RhoA activation is not feasible due to the central role it plays in normal physiology, ROCK inhibition has been found to be effective in attenuating DKD in preclinical models. However, this has not been evaluated in clinical studies as of yet. Alternate means of inhibiting RhoA/ROCK signaling involve the identification of disease-specific activators. This report presents evidence showing the activation of RhoA/ROCK signaling both in vitro in glomerular mesangial cells and in vivo in diabetic kidneys by two recently described novel pathogenic mediators of fibrosis in DKD, activins and cell-surface GRP78. Neither are present in normal kidneys. Activin inhibition with follistatin and neutralization of cell-surface GRP78 using a specific antibody blocked RhoA activation in mesangial cells and in diabetic kidneys. These data identify two novel RhoA/ROCK activators in diabetic kidneys that can be evaluated for their efficacy in inhibiting the progression of DKD. Full article
(This article belongs to the Special Issue Rho Family Proteins and Their Regulators in Kidney Physiology and Pathology)
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Review

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32 pages, 1577 KiB  
Review
MRTF: Basic Biology and Role in Kidney Disease
by Maria Zena Miranda, Zsuzsanna Lichner, Katalin Szászi and András Kapus
Int. J. Mol. Sci. 2021, 22(11), 6040; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116040 - 03 Jun 2021
Cited by 17 | Viewed by 5715
Abstract
A lesser known but crucially important downstream effect of Rho family GTPases is the regulation of gene expression. This major role is mediated via the cytoskeleton, the organization of which dictates the nucleocytoplasmic shuttling of a set of transcription factors. Central among these [...] Read more.
A lesser known but crucially important downstream effect of Rho family GTPases is the regulation of gene expression. This major role is mediated via the cytoskeleton, the organization of which dictates the nucleocytoplasmic shuttling of a set of transcription factors. Central among these is myocardin-related transcription factor (MRTF), which upon actin polymerization translocates to the nucleus and binds to its cognate partner, serum response factor (SRF). The MRTF/SRF complex then drives a large cohort of genes involved in cytoskeleton remodeling, contractility, extracellular matrix organization and many other processes. Accordingly, MRTF, activated by a variety of mechanical and chemical stimuli, affects a plethora of functions with physiological and pathological relevance. These include cell motility, development, metabolism and thus metastasis formation, inflammatory responses and—predominantly-organ fibrosis. The aim of this review is twofold: to provide an up-to-date summary about the basic biology and regulation of this versatile transcriptional coactivator; and to highlight its principal involvement in the pathobiology of kidney disease. Acting through both direct transcriptional and epigenetic mechanisms, MRTF plays a key (yet not fully appreciated) role in the induction of a profibrotic epithelial phenotype (PEP) as well as in fibroblast-myofibroblast transition, prime pathomechanisms in chronic kidney disease and renal fibrosis. Full article
(This article belongs to the Special Issue Rho Family Proteins and Their Regulators in Kidney Physiology and Pathology)
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16 pages, 14040 KiB  
Review
Role of Rho GTPase Interacting Proteins in Subcellular Compartments of Podocytes
by Kana Asano-Matsuda, Sajida Ibrahim, Tomoko Takano and Jun Matsuda
Int. J. Mol. Sci. 2021, 22(7), 3656; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073656 - 01 Apr 2021
Cited by 12 | Viewed by 3311
Abstract
The first step of urine formation is the selective filtration of the plasma into the urinary space at the kidney structure called the glomerulus. The filtration barrier of the glomerulus allows blood cells and large proteins such as albumin to be retained while [...] Read more.
The first step of urine formation is the selective filtration of the plasma into the urinary space at the kidney structure called the glomerulus. The filtration barrier of the glomerulus allows blood cells and large proteins such as albumin to be retained while eliminating the waste products of the body. The filtration barrier consists of three layers: fenestrated endothelial cells, glomerular basement membrane, and podocytes. Podocytes are specialized epithelial cells featured by numerous, actin-based projections called foot processes. Proteins on the foot process membrane are connected to the well-organized intracellular actin network. The Rho family of small GTPases (Rho GTPases) act as intracellular molecular switches. They tightly regulate actin dynamics and subsequent diverse cellular functions such as adhesion, migration, and spreading. Previous studies using podocyte-specific transgenic or knockout animal models have established that Rho GTPases are crucial for the podocyte health and barrier function. However, little attention has been paid regarding subcellular locations where distinct Rho GTPases contribute to specific functions. In the current review, we discuss cellular events involving the prototypical Rho GTPases (RhoA, Rac1, and Cdc42) in podocytes, with particular focus on the subcellular compartments where the signaling events occur. We also provide our synthesized views of the current understanding and propose future research directions. Full article
(This article belongs to the Special Issue Rho Family Proteins and Their Regulators in Kidney Physiology and Pathology)
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24 pages, 1130 KiB  
Review
Role of Rho in Salt-Sensitive Hypertension
by Wakako Kawarazaki and Toshiro Fujita
Int. J. Mol. Sci. 2021, 22(6), 2958; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062958 - 15 Mar 2021
Cited by 9 | Viewed by 4829
Abstract
A high amount of salt in the diet increases blood pressure (BP) and leads to salt-sensitive hypertension in individuals with impaired renal sodium excretion. Small guanosine triphosphatase (GTP)ase Rho and Rac, activated by salt intake, play important roles in the pathogenesis of salt-sensitive [...] Read more.
A high amount of salt in the diet increases blood pressure (BP) and leads to salt-sensitive hypertension in individuals with impaired renal sodium excretion. Small guanosine triphosphatase (GTP)ase Rho and Rac, activated by salt intake, play important roles in the pathogenesis of salt-sensitive hypertension as key switches of intracellular signaling. Focusing on Rho, high salt intake in the central nervous system increases sodium concentrations of cerebrospinal fluid in salt-sensitive subjects via Rho/Rho kinase and renin-angiotensin system activation and causes increased brain salt sensitivity and sympathetic nerve outflow in BP control centers. In vascular smooth muscle cells, Rho-guanine nucleotide exchange factors and Rho determine sensitivity to vasoconstrictors such as angiotensin II (Ang II), and facilitate vasoconstriction via G-protein and Wnt pathways, leading to increased vascular resistance, including in the renal arteries, in salt-sensitive subjects with high salt intake. In the vascular endothelium, Rho/Rho kinase inhibits nitric oxide (NO) production and function, and high salt amounts further augment Rho activity via asymmetric dimethylarginine, an endogenous inhibitor of NO synthetase, causing aberrant relaxation and increased vascular tone. Rho-associated mechanisms are deeply involved in the development of salt-sensitive hypertension, and their further elucidation can help in developing effective protection and new therapies. Full article
(This article belongs to the Special Issue Rho Family Proteins and Their Regulators in Kidney Physiology and Pathology)
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