Rho GTPase regulatory proteins in podocytes

Matsuda, Jun; Asano-Matsuda, Kana; Kitzler, Thomas M.; Takano, Tomoko

doi:10.1016/j.kint.2020.08.035

Cited by 33 publications

(23 citation statements)

References 79 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Taken together, compartmentally regulated increases in actin polymerization shift MRTF to the nucleus, and unleash its transcriptional potential. A plethora of factors (e.g., guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) [ 9 , 70 , 71 , 72 ] regulate Rho GTPases and/or induce posttranslational modification of proteins involved in actin sequestering (e.g., thymosin [ 73 ]), severing (e.g., cofilin [ 36 , 74 , 75 , 76 ]) and polymerization (e.g., mDIA [ 69 , 77 ]) or modify actin itself [ 78 ]. All of these regulate MRTF, which thus emerged as a major highway connecting cytoskeletal state to gene expression.…”

Section: Mrtfs: Their Discovery and Modus Operandimentioning

confidence: 99%

“…RhoA has been documented to play a role in a wide range of kidney pathologies, and in principle dysregulation of MRTF may play a role in each of these because dysregulated RhoA signaling can disrupt gene expression primarily via MRTF. Important examples include congenital and acquired proteinuric glomerular diseases, podocyte and mesangial cell injuries [ 8 , 9 , 267 ]. Further, any pathology associated with altered cytoskeleton organization is a potential “myrtfopathy”, impacting MRTF-dependent transcription.…”

Section: Mrtf In Kidney Diseasesmentioning

confidence: 99%

“…The cytoskeleton is also the structural basis of cell motility. It is thus not surprising that alterations in the activities of Rho family proteins, either due to genetic defects or provoked by cellular injuries, are associated with, and play significant pathogenic roles in acute and chronic kidney diseases [ 6 , 7 , 8 , 9 ]. However, the cytoskeleton affects organ function not only through its structural roles; the cytoskeleton is a regulator of gene expression as well.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MRTF: Basic Biology and Role in Kidney Disease

Miranda

Lichner

Szászi

et al. 2021

IJMS

View full text Add to dashboard Cite

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.

show abstract

Section: Mrtfs: Their Discovery and Modus Operandimentioning

confidence: 99%

Section: Mrtf In Kidney Diseasesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

MRTF: Basic Biology and Role in Kidney Disease

Miranda

Lichner

Szászi

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…In humans, Rho-GTPases regulate the formation and maintenance of long cellular extensions/foot processes and their dysfunctions are associated with nephrotic syndrome (NS) (Matsuda et al, 2021). Further, following podocyte injury, Rho-GTPases orchestrate the rearrangement of the actin cytoskeleton (Matsuda et al, 2021). Interestingly, knockdown of RhoGEF64c results in loss of cytoarchitectural organization in main segment SCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

A cell atlas of the fly kidney

Liu

et al. 2021

Preprint

View full text Add to dashboard Cite

Like humans, insects rely on precise regulation of their internal environments to survive. The insect renal system consists of Malpighian tubules and nephrocytes that share similarities to the mammalian kidney. Studies of the Drosophila Malpighian tubules and nephrocytes have provided many insights into our understanding of the excretion of waste products, stem cell regeneration, protein reabsorption, and as human kidney disease models. Here, we analyzed single-nucleus RNA sequencing (snRNA-seq) data sets to characterize the cell types of the adult fly kidney. We identified 11 distinct clusters representing renal stem cells (RSCs), stellate cells (SCs), regionally specific principal cells (PCs), garland nephrocyte cells (GCs) and pericardial nephrocytes (PNs). Analyses of these clusters revealed many new interesting features. For example, we found a new, previously unrecognized cell cluster: lower segment PCs that express Esyt2. In addition, we find that the SC marker genes RhoGEF64c, Frq2, Prip and CG10939 regulate their unusual cell shape. Further, we identified transcription factors specific to each cluster and built a network of signaling pathways that are potentially involved in mediating cell-cell communication between Malpighian tubule cell types. Finally, cross-species analysis allowed us to match the fly kidney cell types to mouse kidney cell types and planarian protonephridia - knowledge that will help the generation of kidney disease models. To visualize this dataset, we provide a web-based resource for gene expression in single cells (https://www.flyrnai.org/scRNA/kidney/). Altogether, our study provides a comprehensive resource for addressing gene function in the fly kidney and future disease studies.

show abstract

“…There is accumulating evidence that disorders of multiple signaling pathways such as Wnt/β-catenin (Dai et al, 2017), mammalian target of rapamycin (mTOR) (Xiong and Zhou, 2019), cytosolic extracellular signal-regulated kinase (ERK) (Zeng et al, 2019), and Ras homolog family member A (RhoA)/Rho kinase (Peng et al, 2019), occur during DN. RhoA is a member of the Rho family of small GTPases (Rho GTPases), which have important roles in actin cytoskeleton regulation (Matsuda et al, 2021). It is well-documented that excessive activation of RhoA and its downstream Rho-Kinase, induces glomerulosclerosis by causing podocytes dysfunction, renal epithelial-mesenchymal transition, and matrix upregulation in mesangial cells (Patel et al, 2005;Peng et al, 2008;Zhu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway

et al. 2022

View full text Add to dashboard Cite

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, so there is an urgent need to suppress its development at early stage. Shenkang pills (SKP) are a hospital prescription selected and optimized from effective traditional Chinese medicinal formulas for clinical treatment of DN. In the present study, liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-Q-TOF-MS) and total contents qualification were applied to generate a quality control standard of SKP. For verifying the therapeutic effects of SKP, db/db mice were administered intragastrically with SKP at a human-equivalent dose (1.82 g/kg) for 4 weeks. Moreover, the underlying mechanism of SKP were analyzed by the renal RNA sequencing and network pharmacology. LC-Q-TOF-MS identified 46 compounds in SKP. The total polysaccharide and organic acid content in SKP were 4.60 and 0.11 mg/ml, respectively, while the total flavonoid, saponin, and protein content were 0.25, 0.31, and 0.42 mg/ml, respectively. Treatment of SKP significantly reduced fasting blood glucose, improved renal function, and ameliorated glomerulosclerosis and focal foot processes effacement in db/db mice. In addition, SKP protected podocytes from injury by increasing nephrin and podocin expression. Furthermore, transcriptome analyses revealed that 430 and 288 genes were up and down-regulated in mice treated with SKP, relative to untreated controls. Gene ontology enrichment analysis revealed that the differentially expressed genes mainly involved in modulation of cell division and chromosome segregation. Weighted gene co-expression network analysis and network pharmacology analysis indicated that aurora kinase B (AURKB), Rac GTPase activating protein 1 (RacGAP1) and SHC binding, and spindle associated 1 (shcbp1) might be the core targets of SKP. This protein and Ras homolog family member A (RhoA) were found overexpression in db/db mice, but significantly decreased with SKP treatment. We conclude that SKP can effectively treat early-stage DN and improve renal podocyte dysfunction. The mechanism may involve down-regulation of the AURKB/RacGAP1/RhoA pathway.

show abstract

Rho GTPase regulatory proteins in podocytes

Cited by 33 publications

References 79 publications

MRTF: Basic Biology and Role in Kidney Disease

MRTF: Basic Biology and Role in Kidney Disease

A cell atlas of the fly kidney

Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway

Contact Info

Product

Resources

About