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Rac-GTPase promotes fibrotic TGF-?1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways.

ABSTRACT: 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-?1 promoted rapid Rac1-GTP loading in human kidney 2 (HK-2) human renal epithelial cells. A Rac-specific chemical inhibitor, EHT 1864, blocked TGF-?1-induced fibrotic reprogramming in kidney epithelial cells and fibroblasts. Stable Rac1 depletion in HK-2 cells, moreover, eliminated TGF-?1-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 p22^phox knockdown abrogated free radical generation by TGF-?1 in HK-2 cells, consistent with the role of Rac1 in NAPD(H). TGF-?1-induced renal epithelial cytostasis was also completely bypassed by Rac1, p22^phox, p47^phox, 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-?1-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-?1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways.

SUBMITTER: Patel S

PROVIDER: S-EPMC6704447 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Rac-GTPase promotes fibrotic TGF-β1 signaling and chronic kidney disease <i>via</i> EGFR, p53, and Hippo/YAP/TAZ pathways.

Patel Samik S Tang Jiaqi J Overstreet Jessica M JM Anorga Sandybell S Lian Fei F Arnouk Alex A Goldschmeding Roel R Higgins Paul J PJ Samarakoon Rohan R

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20190516 9

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 fibrob ...[more]

PMID: 31095421

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Project description:BACKGROUND:Osteosarcoma (OSA) is the most common bone cancer in canines. Both transforming growth factor beta (TGF?) and Hippo pathway mediators have important roles in bone development, stemness, and cancer progression. The role of Hippo signalling effectors TAZ and YAP has never been addressed in canine OSA. Further, the cooperative role of TGF? and Hippo signalling has yet to be explored in osteosarcoma. To address these gaps, this study investigated the prognostic value of TAZ and YAP alone and in combination with pSmad2 (a marker of active TGF? signalling), as well as the involvement of a TGF?-Hippo signalling crosstalk in tumourigenic properties of OSA cells in vitro. An in-house trial tissue microarray (TMA) which contained 16 canine appendicular OSA cases undergoing standard care and accompanying follow-up was used to explore the prognostic role of TAZ, YAP and pSmad2. Published datasets were used to test associations between TAZ and YAP mRNA levels, metastasis, and disease recurrence. Small interfering RNAs specific to TAZ and YAP were utilized in vitro alone or in combination with TGF? treatment to determine their role in OSA viability, proliferation and migration. RESULTS:Patients with low levels of both YAP and pSmad2 when evaluated in combination had a significantly longer time to metastasis (log-rank test, p?=?0.0058) and a longer overall survival (log rank test, p?=?0.0002). No similar associations were found for TAZ and YAP mRNA levels. In vitro, TAZ knockdown significantly decreased cell viability, proliferation, and migration in metastatic cell lines, while YAP knockdown significantly decreased viability in three cell lines, and migration in two cell lines, derived from either primary tumours or their metastases. The impact of TGF? signaling activation on these effects was cell line-dependent. CONCLUSIONS:YAP and pSmad2 have potential prognostic value in canine appendicular osteosarcoma. Inhibiting YAP and TAZ function could lead to a decrease in viability, proliferation, and migratory capacity of canine OSA cells. Assessment of YAP and pSmad2 in larger patient cohorts in future studies are needed to further elucidate the role of TGF?-Hippo signalling crosstalk in canine OSA progression.

Dataset Information

Rac-GTPase promotes fibrotic TGF-?1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways.

Publications

Rac-GTPase promotes fibrotic TGF-β1 signaling and chronic kidney disease <i>via</i> EGFR, p53, and Hippo/YAP/TAZ pathways.

Similar Datasets

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