Abstract
Diabetic nephropathy (DN) is the major cause of end-stage renal failure and is associated with increased morbidity and mortality compared with other causes of renal diseases. We previously found that Smad1 plays a critical role in the development of DN both in vitro and in vivo. However, functional interaction between Smad1 and Smad3 signaling in DN is unclear. Here, we addressed the molecular interplay between Smad1 and Smad3 signaling under a diabetic condition by using Smad3-knockout diabetic mice. Extracellular matrix (ECM) protein overexpression and Smad1 activation were observed in the glomeruli of db/db mice but were suppressed in the glomeruli of Smad3+/−; db/db mice. Smad3 activation enhanced the phosphorylation of Smad1 C-terminal domain but decreased the phosphorylation of linker domain, thus regulating Smad1 activation in advanced glycation end product-treated mesangial cells (MCs). However, forced phosphorylation of the Smad1 linker domain did not affect Smad3 activation in MCs. Phosphorylation of the Smad1 linker domain increased in Smad3+/−; db/db mice and probucol-treated db/db mice, which was consistent with the attenuation of ECM overproduction. These results indicate that Smad3 expression and activation or probucol treatment alters Smad1 phosphorylation, thus suggesting new molecular mechanisms underlying DN development and progression.
Highlights
We previously showed that Smad[1] transcriptionally regulates the expression of Col[4], a major component of excessive mesangial Extracellular matrix (ECM) protein deposition in Diabetic nephropathy (DN), and other ECM proteins such as Col[1] and Col[314,15]
The values are expressed as the mean ± S.E. (NS, not significant, *p < 0.05, t test). (c) Effects of Smad[3] deletion on the modulation in Smad[1] and Smad[3] signaling pathways in BSA- or AGE-treated Smad3-null mesangial cells (MCs) (KO)
DN is a severe progressing renal disease characterized by glomerular MCs proliferation and excessive ECM protein production[2]
Summary
We previously showed that Smad[1] transcriptionally regulates the expression of Col[4], a major component of excessive mesangial ECM protein deposition in DN, and other ECM proteins such as Col[1] and Col[314,15]. Smad[1] is an intracellular molecule that was originally detected as a signal transducer of the TGF-β superfamily[16]. These stimuli induce the phosphorylation of Smad[1] C-terminal domain[17], its interaction with Smad[4], and its translocation into the nucleus where it regulates the transcription of specific target genes[18]. In the present study, we evaluated the effect of antioxidant probucol, which ameliorates glomerulosclerosis[23], on the phosphorylation of the Smad[1] linker domain
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