Full Text | PDF

Share on tweeters Share on facebook Share on linkedin Share on googleplus

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

Weifeng Wu1, Xiao R. Huang2,3, Yongke You1, Liang Xue1, Xiao-Jing Wang4, Xiaoming Meng5, Xiang Lin1, Jiangang Shen1, Xueqing Yu3, Hui-Yao Lan2✉, Haiyong Chen1✉

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.

✉ Corresponding authors: Dr. Haiyong Chen, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China, Tel: +852-39176413. Email: haiyonghk; Prof. Hui-Yao Lan, Department of Medicine and Therapeutics, Li Ka Shing Institute of Healt More

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 styles

File import instruction

Abstract

Graphic abstract

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.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image

©2024 Ivyspring International Publisher. Terms of use