ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2021; 17(13):3583-3594. doi:10.7150/ijbs.61647 This issue Cite
Research Paper
Latent TGF-β1 protects against diabetic kidney disease via Arkadia/Smad7 signaling
1. School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
2. Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
3. Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China.
4. Department of Pathology, University of Colorado Denver, Aurora, CO, United States.
5. School of Pharmacy, Anhui Medical University, Anhui, China.
Citation:
Wu W, Huang XR, You Y, Xue L, Wang XJ, Meng X, Lin X, Shen J, Yu X, Lan HY, Chen H. Latent TGF-β1 protects against diabetic kidney disease via Arkadia/Smad7 signaling. Int J Biol Sci 2021; 17(13):3583-3594. doi:10.7150/ijbs.61647. https://www.ijbs.com/v17p3583.htm
Other stylesAbstract
TGF-β1 has long been considered as a key mediator in diabetic kidney disease (DKD) but anti-TGF-β1 treatment fails clinically, suggesting a diverse role for TGF-β1 in DKD. In the present study, we examined a novel hypothesis that latent TGF-β1 may be protective in DKD mice overexpressing human latent TGF-β1. Streptozotocin-induced Type 1 diabetes was induced in latent TGF-β1 transgenic (Tg) and wild-type (WT) mice. Surprisingly, compared to WT diabetic mice, mice overexpressing latent TGF-β1 were protected from the development of DKD as demonstrated by lowing microalbuminuria and inhibiting renal fibrosis and inflammation, although blood glucose levels were not altered. Mechanistically, the renal protective effects of latent TGF-β1 on DKD were associated with inactivation of both TGF-β/Smad and nuclear factor-κB (NF-κB) signaling pathways. These protective effects were associated with the prevention of renal Smad7 from the Arkadia-induced ubiquitin proteasomal degradation in the diabetic kidney, suggesting protection of renal Smad7 from Arkadia-mediated degradation may be a key mechanism through which latent TGF-β1 inhibits DKD. This was further confirmed in vitro in mesangial cells that knockdown of Arkadia failed but overexpression of Arkadia reversed the protective effects of latent TGF-β1 on high glucose-treated mesangial cells. Latent TGF-β1 may protect kidneys from TGF-β1/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation in diabetes through inhibiting Arkadia-mediated Smad7 ubiquitin degradation.
Keywords: Latent TGF-β1, inflammation, fibrosis, Arkadia, Smad7, Diabetic kidney disease
Citation styles
APA
Wu, W., Huang, X.R., You, Y., Xue, L., Wang, X.J., Meng, X., Lin, X., Shen, J., Yu, X., Lan, H.Y., Chen, H. (2021). Latent TGF-β1 protects against diabetic kidney disease via Arkadia/Smad7 signaling. International Journal of Biological Sciences, 17(13), 3583-3594. https://doi.org/10.7150/ijbs.61647.
ACS
Wu, W.; Huang, X.R.; You, Y.; Xue, L.; Wang, X.J.; Meng, X.; Lin, X.; Shen, J.; Yu, X.; Lan, H.Y.; Chen, H. Latent TGF-β1 protects against diabetic kidney disease via Arkadia/Smad7 signaling. Int. J. Biol. Sci. 2021, 17 (13), 3583-3594. DOI: 10.7150/ijbs.61647.
NLM
Wu W, Huang XR, You Y, Xue L, Wang XJ, Meng X, Lin X, Shen J, Yu X, Lan HY, Chen H. Latent TGF-β1 protects against diabetic kidney disease via Arkadia/Smad7 signaling. Int J Biol Sci 2021; 17(13):3583-3594. doi:10.7150/ijbs.61647. https://www.ijbs.com/v17p3583.htm
CSE
Wu W, Huang XR, You Y, Xue L, Wang XJ, Meng X, Lin X, Shen J, Yu X, Lan HY, Chen H. 2021. Latent TGF-β1 protects against diabetic kidney disease via Arkadia/Smad7 signaling. Int J Biol Sci. 17(13):3583-3594.
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