1,25-Dihydroxyvitamin D3 inhibits the proliferation of rat mesangial cells induced by high glucose via DDIT4

Abstract

// Da-Peng Chen 1, 2, * , Ye-Ping Ma 1, 2, * , Li Zhuo 2 , Zheng Zhang 1, 2 , Gu-Ming Zou 2 , Yue Yang 2 , Hong-Mei Gao 2 and Wen-Ge Li 1, 2 1 Graduate School of Peking Union Medical College, Beijing 100730, China 2 Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China * These authors share co-first authorship Correspondence to: Wen-Ge Li, email: wenge_lee2002@126.com Keywords: diabetic nephropathy; 1,25-Dihydroxyvitamin D 3 ; proliferation; DDIT4; mTOR Received: July 31, 2017      Accepted: November 14, 2017      Published: December 09, 2017 ABSTRACT 1,25-Dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) is a secosteroid with antiproliferative property. It also plays a pivotal renoprotective role in diabetic nephropathy. We investigated whether 1,25(OH) 2 D 3 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 D 3 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 D 3 treatment. siRNA knockdown of DDIT4 suppressed antiproliferative responses to 1,25(OH) 2 D 3 . These results suggest that 1,25(OH) 2 D 3 inhibits the proliferation of rat mesangial cells induced by high glucose via the DDIT4/mTOR signaling pathway.