4.7 Article

Latent TGF-β1 protects against diabetic kidney disease via Arkadia/Smad7 signaling

Journal

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Volume 17, Issue 13, Pages 3583-3594

Publisher

IVYSPRING INT PUBL
DOI: 10.7150/ijbs.61647

Keywords

Latent TGF-beta 1; inflammation; fibrosis; Arkadia; Smad7; Diabetic kidney disease

Funding

  1. Research Grants Council [GRF 17113416, 14163317, 14117418, 14104019, C7018-16G, R4012-18]
  2. University of Hong Kong Seed Fund for Basic Research [201611159209]
  3. Health and Medical Research Fund of Hong Kong [05161326, 14152321]
  4. Guangdong-Hong Kong-Macao-Joint Labs Program from Guangdong Science and Technology Department [2019B121205005]
  5. Lui Che Woo Institute of Innovative Medicine (CARE program)

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The study demonstrates that overexpression of latent TGF-beta 1 can protect against the development of DKD in mice, reducing microalbuminuria and inhibiting renal fibrosis and inflammation, without altering blood glucose levels. This protective effect may be associated with the prevention of Arkadia-mediated Smad7 ubiquitin degradation, suggesting a potential mechanism for the inhibition of DKD by latent TGF-beta 1.
TGF-beta 1 has long been considered as a key mediator in diabetic kidney disease (DKD) but anti-TGF-beta 1 treatment fails clinically, suggesting a diverse role for TGF-beta 1 in DKD. In the present study, we examined a novel hypothesis that latent TGF-beta 1 may be protective in DKD mice overexpressing human latent TGF-beta 1. Streptozotocin-induced Type 1 diabetes was induced in latent TGF-beta 1 transgenic (Tg) and wild-type (WT) mice. Surprisingly, compared to WT diabetic mice, mice overexpressing latent TGF-beta 1 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-beta 1 on DKD were associated with inactivation of both TGF-beta/Smad and nuclear factor-kappa B (NF-kappa B) 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-beta 1 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-beta 1 on high glucose-treated mesangial cells. Latent TGF-beta 1 may protect kidneys from TGF-beta 1/Smad3-mediated renal fibrosis and NF-kappa B-driven renal inflammation in diabetes through inhibiting Arkadia-mediated Smad7 ubiquitin degradation.

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