SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function

Raza, Sayyid; Jokl, Elliot; Pritchett, James; Martin, Katherine J.; Su, Kim; Simpson, Kara; Birchall, Lindsay; Mullan, Aoibheann; Athwal, Varinder; Doherty, Daniel T.; Zeef, Leo; Henderson, Neil C.; Kalra, Philip A.; Hanley, Neil A.; Hanley, Karen Piper

doi:10.1126/scisignal.abb4282

Cited by 25 publications

(24 citation statements)

References 56 publications

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“…Mitophagy promotes the removal of fragmented mitochondria and therefore play anti-oxidative and/or anti-apoptotic roles in endothelial cells [ 11 , 63 ]. However, at the stage of myocardial reperfusion, mitophagy is largely suppressed due to multiple mechanisms [ 11 , 22 , 45 , 64 ]. Interestingly, we found that empagliflozin restored mitophagy by inducing the AMPKa1/ULK1/FUNDC1 pathway during I/R injury, thus reducing mitochondrial damage in CMECs.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

et al. 2022

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“…Additionally, the role of SOX9 in the epithelial progenitor population in IPF must be determined to therapeutically target this molecule. The pathogenic role of SOX9 in inducing fibrosis was confirmed in other organs such as the liver, kidney, and heart (32,(50)(51)(52). In the heart, SOX9 is predominantly expressed by cardiomyocytes and cardiac fibroblasts after myocardial infarction injury in mice.…”

Section: Discussionmentioning

confidence: 87%

“…However, further studies are needed to identify the potential associations between cell-specific SOX9 targets and the decline in lung function which could potentially assist in the stratification of patients with IPF. Nevertheless, the pathological role of SOX9 in activating fibroblasts and orchestrating fibrosis in multiple organs might open up opportunities for drug discovery, precision targets, and therapeutic interventions (32,(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Dysregulated overexpression of Sox9 induces fibroblast activation in pulmonary fibrosis

et al. 2021

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Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease associated with unremitting fibroblast activation including fibroblast-to-myofibroblast transformation (FMT), migration, resistance to apoptotic clearance, and excessive deposition of extracellular matrix (ECM) proteins in the distal lung parenchyma. Aberrant activation of lung-developmental pathways is associated with severe fibrotic lung disease; however, the mechanisms through which these pathways activate fibroblasts in IPF remain unclear.Sox9 is a member of the HMG box family of DNA-binding transcription factors that are selectively expressed by epithelial cell progenitors to modulate branching morphogenesis during lung development. We demonstrate that Sox9 is upregulated via MAPK/PI3Kdependent signaling and by the transcription factor Wilms' tumor 1 in distal lung-resident fibroblasts in IPF. Mechanistically, using fibroblast activation assays, we demonstrate that Sox9 functions as a positive regulator of FMT, migration, survival, and ECM production. Importantly, our in vivo studies demonstrate that fibroblast-specific deletion of Sox9 is sufficient to attenuate collagen deposition and improve lung function during TGFαinduced pulmonary fibrosis. Using a mouse model of bleomycin-induced pulmonary fibrosis, we show that myofibroblast-specific Sox9 overexpression augments fibroblast activation and pulmonary fibrosis. Thus, Sox9 functions as a profibrotic transcription factor in activating fibroblasts, illustrating the potential utility of targeting Sox9 in IPF treatment.

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“…Remarkably, it has been also described that SOX9 directly induces CCN2 transcription in chondrocytes and nucleus pulposus cells [ 26 ], and FOXL1 deletion decreases CCN2 expression in lung fibroblast [ 27 ]. Coming back with fibrotic disorders, increased levels of SOX9 have been observed in lung and kidney fibrosis, postulating SOX9 inhibition as a therapeutic target [ 28 , 29 ]. By contrast, reduced SOX9 levels associated with fibulin-5 downregulation have been found in human aortic aneurysms [ 30 ], highlighting the different role of this factor depending on the pathology.…”

Section: Discussionmentioning

confidence: 99%

The CCN2 Polymorphism rs12526196 Is a Risk Factor for Ascending Thoracic Aortic Aneurysm

Tejera‐Muñoz

Rodriguez

Río-García

et al. 2022

IJMS

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Cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a downstream mediator of other profibrotic factors including transforming growth factor (TGF)-β and angiotensin II. However, recent evidence from our group demonstrated the direct role of CCN2 in maintaining aortic wall homeostasis and acute and lethal aortic aneurysm development induced by angiotensin II in the absence of CCN2 in mice. In order to translate these findings to humans, we evaluated the potential association between three polymorphisms in the CCN2 gene and the presence of a thoracic aortic aneurysm (TAA). Patients with and without TAA retrospectively selected were genotyped for rs6918698, rs9402373 and rs12526196 polymorphisms related to the CCN2 gene. Multivariable logistic regression models were performed. In our population of 366 patients (69 with TAA), no associations were found between rs6918698 and rs9402373 and TAA. However, the presence of one C allele from rs12526196 was associated with TAA comparing with the TT genotype, independently of risk factors such as sex, age, hypertension, type of valvulopathy and the presence of a bicuspid aortic valve (OR = 3.17; 95% CI = 1.30–7.88; p = 0.011). In conclusion, we demonstrated an association between the C allele of rs12526196 in the CCN2 gene and the presence of TAA. This study extrapolates to humans the relevance of CCN2 in aortic aneurysm observed in mice and postulates, for the first time, a potential protective role to CCN2 in aortic aneurysm pathology. Our results encourage future research to explore new variants in the CCN2 gene that could be predisposed to TAA development.

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SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function

Cited by 25 publications

References 56 publications

Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

Dysregulated overexpression of Sox9 induces fibroblast activation in pulmonary fibrosis

The CCN2 Polymorphism rs12526196 Is a Risk Factor for Ascending Thoracic Aortic Aneurysm

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