Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis

Hu, Qiulei; Lai, Jiayong; Chen, Huamu; Cai, Yuanqiang; Yue, Zhihui; Lin, Hsin-Fu; Sun, Liangzhong

doi:10.3390/ijms24043504

Cited by 2 publications

(2 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aberrant RhoA activity at the centrosome appears to play a significant role in NPHP pathogenesis through activation of its downstream target, ROCK, and by promoting abnormal actin formation and activation of the Hippo pathway ( 95 ). The human kidney proximal tubular epithelial cells with an NPHP1 knockdown and the renal tissue from Nphp1 knockout mice exhibit increased levels of GEF-H1, an important RhoA GTPase effector factor in mammalian renal epithelium that mediates RhoA activation ( 171 ). The NPHP phenotype could be rescued in these mice by a knockdown of GEF-H1, which acts upstream of RhoA, thus reducing the RhoA activity and preventing renal cystogenesis, interstitial fibrosis and inflammation ( 171 ).…”

Section: Renal Ciliopathies: Molecular Mechanisms Of Disease and Acti...mentioning

confidence: 99%

“…The human kidney proximal tubular epithelial cells with an NPHP1 knockdown and the renal tissue from Nphp1 knockout mice exhibit increased levels of GEF-H1, an important RhoA GTPase effector factor in mammalian renal epithelium that mediates RhoA activation (171). The NPHP phenotype could be rescued in these mice by a knockdown of GEF-H1, which acts upstream of RhoA, thus reducing the RhoA activity and preventing renal cystogenesis, interstitial fibrosis and inflammation (171).…”

Section: Nphp Proteins and Actin Regulationmentioning

confidence: 99%

See 1 more Smart Citation

Primary cilia and actin regulatory pathways in renal ciliopathies

Kalot,

Sentell,

Kitzler

et al. 2024

Front. Nephrol.

View full text Add to dashboard Cite

Ciliopathies are a group of rare genetic disorders caused by defects to the structure or function of the primary cilium. They often affect multiple organs, leading to brain malformations, congenital heart defects, and anomalies of the retina or skeletal system. Kidney abnormalities are among the most frequent ciliopathic phenotypes manifesting as smaller, dysplastic, and cystic kidneys that are often accompanied by renal fibrosis. Many renal ciliopathies cause chronic kidney disease and often progress to end-stage renal disease, necessitating replacing therapies. There are more than 35 known ciliopathies; each is a rare hereditary condition, yet collectively they account for a significant proportion of chronic kidney disease worldwide. The primary cilium is a tiny microtubule-based organelle at the apex of almost all vertebrate cells. It serves as a “cellular antenna” surveying environment outside the cell and transducing this information inside the cell to trigger multiple signaling responses crucial for tissue morphogenesis and homeostasis. Hundreds of proteins and unique cellular mechanisms are involved in cilia formation. Recent evidence suggests that actin remodeling and regulation at the base of the primary cilium strongly impacts ciliogenesis. In this review, we provide an overview of the structure and function of the primary cilium, focusing on the role of actin cytoskeleton and its regulators in ciliogenesis. We then describe the key clinical, genetic, and molecular aspects of renal ciliopathies. We highlight what is known about actin regulation in the pathogenesis of these diseases with the aim to consider these recent molecular findings as potential therapeutic targets for renal ciliopathies.

show abstract

Section: Renal Ciliopathies: Molecular Mechanisms Of Disease and Acti...mentioning

confidence: 99%

Section: Nphp Proteins and Actin Regulationmentioning

confidence: 99%

Primary cilia and actin regulatory pathways in renal ciliopathies

Kalot,

Sentell,

Kitzler

et al. 2024

Front. Nephrol.

View full text Add to dashboard Cite

show abstract

Regulation of the RhoA exchange factor GEF-H1 by profibrotic stimuli through a positive feedback loop involving RhoA, MRTF, and Sp1

Venugopal,

Dan,

Sri Theivakadadcham

et al. 2024

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

RhoA and its effectors, the transcriptional coactivators Myocardin-Related Transcription Factor (MRTF) and Serum Response Factor (SRF), control epithelial phenotype and are indispensable for profibrotic epithelial reprogramming during fibrogenesis. Context-dependent control of RhoA and fibrosis-associated changes in its regulators, however, remain incompletely characterized. We previously identified the guanine nucleotide exchange factor GEF-H1 as a central mediator of RhoA activation in renal tubular cells exposed to inflammatory or fibrotic stimuli. Here we found that GEF-H1 expression and phosphorylation were strongly elevated in two animal models of fibrosis. In the Unilateral Ureteral Obstruction mouse kidney fibrosis model, GEF-H1 was upregulated predominantly in the tubular compartment. GEF-H1 was also elevated and phosphorylated in a rat pulmonary artery banding model of right ventricular fibrosis. Prolonged stimulation of LLC-PK1 tubular cells with tumor necrosis factor-α or transforming growth factor β1 increased GEF-H1 expression and activated a luciferase-coupled GEF-H1 promoter. Knockdown and overexpression studies revealed that these effects were mediated by RhoA, cytoskeleton remodeling and MRTF, indicative of a positive feed-back cycle. Indeed, silencing endogenous GEF-H1 attenuated activation of the GEF-H1 promoter. Importantly, inhibition of MRTF using CCG-1423 prevented GEF-H1 upregulation in both animal models. MRTF-dependent increase in GEF-H1 was prevented by inhibition of the transcription factor Sp1, and mutating putative Sp1 binding sites in the GEF-H1 promoter eliminated its MRTF-dependent activation. Since the GEF-H1/RhoA axis is key for fibrogenesis, this novel MRTF/Sp1-dependent regulation of GEF-H1 abundance represents a potential target for reducing renal and cardiac fibrosis.

show abstract

Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis

Cited by 2 publications

References 52 publications

Primary cilia and actin regulatory pathways in renal ciliopathies

Primary cilia and actin regulatory pathways in renal ciliopathies

Regulation of the RhoA exchange factor GEF-H1 by profibrotic stimuli through a positive feedback loop involving RhoA, MRTF, and Sp1

Contact Info

Product

Resources

About