Abstract
1,25-Dihydroxyvitamin D3(1,25(OH)2 D3) is a secosteroid with antiproliferative property. It also plays a pivotal renoprotective role in diabetic nephropathy. We investigated whether 1,25(OH)2D3 could inhibit the proliferation of rat mesangial cells exposed to high glucose via the DNA-damage-inducible transcript 4/mammalian target of rapamycin(DDIT4/mTOR) pathway. The cell proliferation rate and cell cycle duration were measured using cell counting kit-8 assay and flow cytometry. Protein expression was assayed by Western blot. Glucose acted as a growth factor in rat mesangial cells, promoted cell proliferation. In parallel, the protein expression of DDIT4, TSC1/TSC2, and 4E-BP1 were decreased, and Rheb, mTOR, and p70S6K were increased. Acting via the DDIT4/mTOR signaling, 1,25(OH)2 D3 treatment reversed these pathological changes, upregulated DDIT4, TSC1/TSC2, and 4E-BP1, downregulated Rheb, mTOR, and p70S6K. The short-term overexpression of DDIT4 inhibited the proliferation of rat mesangial cells, similar to 1,25(OH)2 D3 treatment. siRNA knockdown of DDIT4 suppressed antiproliferative responses to 1,25(OH)2 D3. These results suggest that 1,25(OH)2 D3 inhibits the proliferation of rat mesangial cells induced by high glucose via the DDIT4/mTOR signaling pathway.
Highlights
Diabetic nephropathy (DN) is one of the most common complications of type 1 and type 2 diabetes and the leading cause of end-stage renal disease in the Western world [1]
The short-term overexpression of DDIT4 inhibited the proliferation of rat mesangial cells, similar to 1,25(OH)2 D3 treatment. siRNA knockdown of DDIT4 suppressed antiproliferative responses to 1,25(OH)2 D3. These results suggest that 1,25(OH)2 D3 inhibits the proliferation of rat mesangial cells induced by high glucose via the DDIT4/mammalian target of rapamycin (mTOR) signaling pathway
To investigate whether the DDIT4/mTOR signaling pathway is involved in regulating the proliferation of RMCs treated with 1,25(OH)2 D3, we examined the expression of vitamin D receptor (VDR), DDIT4, TSC1/TSC2, the mTOR mediator Rheb, mTOR, and its downstream proteins 4E binding protein 1 (4E-BP1) and p70-S6 kinase (p70S6K) by Western blot
Summary
Diabetic nephropathy (DN) is one of the most common complications of type 1 and type 2 diabetes and the leading cause of end-stage renal disease in the Western world [1]. The serine/threonine kinase mammalian target of rapamycin (mTOR) regulates cell growth, metabolism, and autophagy to maintain cellular homeostasis [9, 10]. MTORC1 regulates cell growth and proliferation by www.impactjournals.com/oncotarget directly phosphorylating two regulators of translation, p70-S6 kinase (p70S6K) and 4E binding protein 1 (4E-BP1) [11]. The induction of mTORC1 by Akt leads to the phosphorylation and the inhibition of TSC1/TSC2, thereby stimulating the mTORC1 activator Rheb and leading to downstream effects on protein synthesis and cell proliferation [13, 14]. As an essential regulator of mTOR activity, DDIT4 regulates cell growth, apoptosis, and autophagy but there have been few studies of its effects on MCs. our study examined the effects of 1,25(OH) D3 on RMCs exposed to high glucose. It sought to determine whether the effect was mediated by the DDIT4/ mTOR signaling pathway
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
