Deregulation of Hippo–TAZ pathway during renal injury confers a fibrotic maladaptive phenotype

Anorga, Sandybell; Overstreet, Jessica M.; Falke, Lucas L.; Tang, Jiaqi; Goldschmeding, Roel; Higgins, Paul J.; Samarakoon, Rohan

doi:10.1096/fj.201700722r

Cited by 75 publications

(82 citation statements)

References 49 publications

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“…Rac1-NOX-mediated free radical generation, in such circumstances, directs ATM, p53, EGFR, and c-Src phosphorylation. TGF-b1-stimulated SMAD3 and non-SMAD cooperation result in the formation of p53-SMAD2/3 transcriptional complexes that initiate the expression of target genes including PAI-1 in renal cells (16,(26)(27)(28)(29). Furthermore, Rac-1/NOX-mediated PAI-1 induction orchestrates the TGF-b1-induced epithelial cytostasis.…”

Section: Discussionmentioning

confidence: 99%

“…pathways [e.g., NOX, p53, ataxia telangiectasia mutated (ATM), epidermal growth factor receptor (EGFR), c-Src, YAP/TAZ] (14,16,(25)(26)(27)(28)(29), induces rapid Rac1-GTP loading (4-fold increase at 5 min poststimulation; P , 0.05) in HK-2 human renal tubular epithelial cells (Fig. 1A, B).…”

Section: Critical Role Of Rac1-gtpases In Renal Tgf-b1 Signalingmentioning

confidence: 99%

“…Recent studies have identified several non-SMAD effectors (e.g., p53, ATM, EGFR, and c-Src) activated by TGF-b1 that contribute to fibrosis progression (16,(25)(26)(27)(28)(29). TGF-b1-induced phosphorylation of p53 Ser15 (Fig.…”

Section: Rac1 Activates Several Non-smad Pathways Downstream Of Tgf-b1mentioning

confidence: 99%

“…8A, M; P , 0.01). p53, EGFR, and YAP/TAZ are causative factors of CKD (38)(39)(40)(41)(42)(43) and prominent non-SMAD control elements of the TGF-b1 pathway in progressive renal disease (16,(25)(26)(27)(28)(29).…”

Section: Elevated Renal Rac1b Expression Is Associated With Renal Malmentioning

confidence: 99%

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Rac‐GTPase promotes fibrotic TGF‐β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways

Patel

Tang

Overstreet³

et al. 2019

FASEB j.

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Rac‐GTPases are major regulators of cytoskeletal remodeling and their deregulation contributes to numerous pathologies. Whether or how Rac promotes tubulointerstitial fibrosis and chronic kidney disease (CKD) is currently unknown. We showed that the major profibrotic cytokine, TGF‐β1 promoted rapid Rac1‐GTP loading in human kidney 2 (HK‐2) human renal epithelial cells. A Rac‐specific chemical inhibitor, EHT 1864, blocked TGF‐β1‐induced fibrotic reprogramming in kidney epithelial cells and fibroblasts. Stable Rac1 depletion in HK‐2 cells, moreover, eliminated TGF‐β1‐mediated non‐SMAD pathway activation [e.g., Src, epidermal growth factor receptor (EGFR), p53] and subsequent plasminogen activator inhibitor‐1 (PAI‐1), connective tissue growth factor, fibronectin, and p21 induction. Rac1 and p22phox knockdown abrogated free radical generation by TGF‐β1 in HK‐2 cells, consistent with the role of Rac1 in NAPD(H). TGF‐β1‐induced renal epithelial cytostasis was also completely bypassed by Rac1, p22phox, p47phox, and PAI‐1 silencing. Rac1b isoform expression was robustly induced in the fibrotic kidneys of mice and humans. Intraperitoneal administration of EHT 1864 in mice dramatically attenuated ureteral unilateral obstruction‐driven EGFR, p53, Rac1b, yes‐associated protein/transcriptional coactivator with PDZ‐binding motif activation/expression, dedifferentiation, cell cycle arrest, and renal fibrogenesis evident in vehicle‐treated obstructed kidneys. Thus, the Rac1‐directed redox response is critical for TGF‐β1‐driven epithelial dysfunction orchestrated, in part, via PAI‐1 up‐regulation. Rac pathway inhibition suppressed renal oxidative stress and maladaptive repair, identifying Rac as a novel therapeutic target against progressive CKD.—Patel, S., Tang, J., Overstreet, J. M., Anorga, S., Lian, F., Arnouk, A., Goldschmeding, R., Higgins, P. J., Samarakoon, R. Rac‐GTPase promotes fibrotic TGF‐β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways. FASEB J. 33, 9797–9810 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Section: Critical Role Of Rac1-gtpases In Renal Tgf-b1 Signalingmentioning

confidence: 99%

Section: Rac1 Activates Several Non-smad Pathways Downstream Of Tgf-b1mentioning

confidence: 99%

Section: Elevated Renal Rac1b Expression Is Associated With Renal Malmentioning

confidence: 99%

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Rac‐GTPase promotes fibrotic TGF‐β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways

Patel

Tang

Overstreet³

et al. 2019

FASEB j.

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“…inhibitor-1 (PAI-1), endothelin-1, and CTGF (54)(55)(56)(57)(58). Increasing stromal stiffness and cytoskeletal tension create a feed-forward mechanosensitive circuit (59) contributing to myofibroblast persistence and continued organ damage.…”

Section: The Renal Fibrotic Microenvironmentmentioning

confidence: 99%

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

et al. 2019

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Chronic kidney disease affects >15% of the U.S. population and >850 million individuals worldwide. Fibrosis is the common outcome of many chronic renal disorders and, although the etiology varies (i.e., diabetes, hypertension, ischemia, acute injury, and urologic obstructive disorders), persistently elevated renal TGF‐β1 levels result in the relentless progression of fibrotic disease. TGF‐β1 orchestrates the multifaceted program of renal fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery and redifferentiation, and subsequent tubulointerstitial fibrosis, eventually leading to chronic renal disease. Recent findings implicate p53 as a cofactor in the TGF‐β1‐induced signaling pathway and a transcriptional coregulator of several TGF‐β1 profibrotic response genes by complexing with receptor‐activated SMADs, which are homologous to the small worms (SMA) and Drosophilia mothers against decapentaplegic (MAD) gene families. The cooperative p53‐TGF‐β1 genomic cluster includes genes involved in cell growth control and extracellular matrix remodeling [e.g., plasminogen activator inhibitor‐1 (PAI‐1; serine protease inhibitor, clade E, member 1), connective tissue growth factor, and collagen I]. Although the molecular basis for this codependency is unclear, many TGF‐β1‐responsive genes possess p53 binding motifs. p53 up‐regulation and increased p53 phosphorylation; moreover, they are evident in nephrotoxin‐ and ischemia/reperfusion‐induced injury, diabetic nephropathy, ureteral obstructive disease, and kidney allograft rejection. Pharmacologic and genetic approaches that target p53 attenuate expression of the involved genes and mitigate the fibrotic response, confirming a key role for p53 in renal disorders. This review focuses on mechanisms whereby p53 functions as a transcriptional regulator within the TGF‐β1 cluster with an emphasis on the potent fibrosis‐promoting PAI‐1 gene.—Higgins, C. E., Tang, J., Mian, B. M., Higgins, S. P., Gifford, C. C., Conti, D. J., Meldrum, K. K., Samarakoon, R., Higgins, P. J. TGF‐β1‐p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications. FASEB J. 33, 10596–10606 (2019). http://www.fasebj.org

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YAP/TAZ: Molecular pathway and disease therapy

Wei,

Hui,

Chen

et al. 2023

MedComm

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The Yes‐associated protein and its transcriptional coactivator with PDZ‐binding motif (YAP/TAZ) are two homologous transcriptional coactivators that lie at the center of a key regulatory network of Hippo, Wnt, GPCR, estrogen, mechanical, and metabolism signaling. YAP/TAZ influences the expressions of downstream genes and proteins as well as enzyme activity in metabolic cycles, cell proliferation, inflammatory factor expression, and the transdifferentiation of fibroblasts into myofibroblasts. YAP/TAZ can also be regulated through epigenetic regulation and posttranslational modifications. Consequently, the regulatory function of these mechanisms implicates YAP/TAZ in the pathogenesis of metabolism‐related diseases, atherosclerosis, fibrosis, and the delicate equilibrium between cancer progression and organ regeneration. As such, there arises a pressing need for thorough investigation of YAP/TAZ in clinical settings. In this paper, we aim to elucidate the signaling pathways that regulate YAP/TAZ and explore the mechanisms of YAP/TAZ‐induce diseases and their potential therapeutic interventions. Furthermore, we summarize the current clinical studies investigating treatments targeting YAP/TAZ. We also address the limitations of existing research on YAP/TAZ and propose future directions for research. In conclusion, this review aims to provide fresh insights into the signaling mediated by YAP/TAZ and identify potential therapeutic targets to present innovative solutions to overcome the challenges associated with YAP/TAZ.

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Deregulation of Hippo–TAZ pathway during renal injury confers a fibrotic maladaptive phenotype

Cited by 75 publications

References 49 publications

Rac‐GTPase promotes fibrotic TGF‐β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways

Rac‐GTPase promotes fibrotic TGF‐β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

YAP/TAZ: Molecular pathway and disease therapy

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