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Endocrine
Published in: Endocrine 2/2016

01-11-2016 | Original Article

In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D3 to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway

Authors: Hang Wang, Jianmin Wang, Hua Qu, Huili Wei, Baolan ji, Zesong Yang, Jing Wu, Qin He, Yuanyuan Luo, Dan Liu, Yang Duan, Fang Liu, Huacong Deng

Published in: Endocrine | Issue 2/2016

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Abstract

We investigated whether 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) could improve early diabetic nephropathy through the DNA-damage-inducible transcript 4/tuberous sclerosis 2/mammalian target of rapamycin pathway. Rat mesangial cells were cultured in media containing normal glucose or high glucose and were treated with or without 1,25(OH)2D3. Mesangial cells proliferation was measured. Streptozotocin-induced diabetic rats were injected intravenously with a recombinant lentivirus against the rat vitamin D receptor gene. Urinary and serum albumin, fasting plasma glucose, serum triglyceride, total cholesterol, calcium, parathyroid hormone and serum 25-dihydroxy-vitamin D (25(OH)D) levels, mean glomerular volume, glomerular basement membrane thickness and total kidney volume were determined. The expressions of vitamin D receptor, DNA-damage-inducible transcript 4, and mammalian target of rapamycin were measured. 1,25(OH)2D3 inhibited the proliferation of mesangial cells induced by hyperglycemia. 1,25(OH)2D3 also significantly reduced albumin excretion, mean glomerular volume, glomerular basement membrane, and total kidney volume in rats with diabetic nephropathy. The expression of DNA-damage-inducible transcript 4 was elevated by 1,25(OH)2D3 treatment. The phosphorylation of mammalian target of rapamycin was reduced by 1,25(OH)2D3 treatment. Vitamin D receptor gene silencing blocked all of the above results. The current study demonstrates that 1,25(OH)2D3 can effectively inhibit mesangial cells proliferation induced by hyperglycemia, thus suppressing the development of diabetic nephropathy. This study also shows that the nephron-protective effect of 1,25(OH)2D3 occurs partly through the DDIT4/TSC2/mTOR pathway.
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Literature
1.
U. Krairittichai, S. Potisat, A. Jongsareejit, C. Sattaputh, Prevalence and risk factors of diabetic nephropathy among Thai patients with type 2 diabetes mellitus. J. Med. Assoc. Thai. 94 (2011)
2.
F.P. Schena, L. Gesualdo, Pathogenetic mechanisms of diabetic nephropathy. J. Am. Soc. Nephrol. 16 (2005)
3.
M.W. Steffes, R. Østerby, B. Chavers, S.M. Mauer, Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients. Diabetes 38, 1077–1081 (1989)PubMedCrossRef
4.
S.Y. Goh, M.E. Cooper, Clinical review: The role of advanced glycation end products in progression and complications of diabetes. J. Clin. Endocrinol. Metab. 93(4), 1143 (2008)PubMedCrossRef
5.
K. Fukami, S. Ueda, S. Yamagishi, S. Kato, Y. Inagaki, M. Takeuchi, Y. Motomiya, R. Bucala, S. Iida, K. Tamaki, T. Imaizumi, M.E. Cooper, S. Okuda, AGEs activate mesangial TGF-beta-Smad signaling via an angiotensin II type I receptor interaction. Kidney Int. 66(6), 2137–2147 (2004)PubMedCrossRef
6.
R. Yacoub, K.N. Campbell, Inhibition of RAS in diabetic nephropathy. Int. J. Nephrol. Renovasc. Dis. 8, 29–40 (2015)
7.
B. Fernandez-Fernandez, A. Ortiz, C. Gomez-Guerrero, J. Egido, Therapeutic approaches to diabetic nephropathy–beyond the RAS. Nat. Rev. Nephrol. 10(6), 325–346 (2014)PubMedCrossRef
8.
K. Inoki, M. Haneda, S. Maeda, D. Koya, R. Kikkawa, TGF-β1 stimulates glucose uptake by enhancing GLUT1 expression in mesangial cells. Kidney Int. 55(5), 1704–1712 (1999)PubMedCrossRef
9.
S. Di Paolo, L. Gesualdo, E. Ranieri, G. Grandaliano, F.P. Schena, High glucose concentration induces the overexpression of transforming growth factor-beta through the activation of a platelet-derived growth factor loop in human mesangial cells. Am. J. Pathol. 149(6), 2095–2106 (1996)PubMedPubMedCentral
10.
S.B. Connolly, D. Sadlier, N.E. Kieran, P. Doran, H.R. Brady, Transcriptome profiling and the pathogenesis of diabetic complications. J. Am. Soc. Nephrol. 14, S279–S283 (2003)PubMedCrossRef
11.
J.M. Forbes, M.T. Coughlan, M.E. Cooper, Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 57(6), 1446–1454 (2008)PubMedCrossRef
12.
Z. Wang, T. Jiang, J. Li, G. Proctor, J.L. McManaman, S. Lucia, S. Chua, M. Levi, Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. Diabetes 54(8), 2328–2335 (2005)PubMedCrossRef
13.
D. Dubois, P. Chanson, J. Timsit, D. Chauveau, D. Nochy, P.J. Guillausseau, J. Lubetzki, Remission of proteinuria following correction of hyperlipidemia in NIDDM patients with nondiabetic glomerulopathy. Diabetes Care 17(8), 906–908 (1994)PubMedCrossRef
14.
15.
K. Nagai, T. Matsubara, A. Mima, E. Sumi, H. Kanamori, N. Iehara, A. Fukatsu, M. Yanagita, T. Nakano, Y. Ishimoto, T. Kita, T. Doi, H. Arai, Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy. Kidney Int. 68(2), 552–561 (2005)PubMedCrossRef
16.
R. Zoncu, A. Efeyan, D.M. Sabatini, mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12(1), 21–35 (2011)PubMedCrossRef
17.
H. Mori, K. Inoki, K. Masutani, Y. Wakabayashi, K. Komai, R. Nakagawa, K.L. Guan, A. Yoshimura, The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem. Biophys. Res. Commun. 384(4), 471–475 (2009)PubMedCrossRef
18.
A. Eisenreich, U. Rauch, PI3K inhibitors in cardiovascular disease. Cardiovasc. Ther. 29(1), 29–36 (2011)PubMedCrossRef
19.
W. Lieberthal, J.S. Levine, The role of the mammalian target of rapamycin (mTOR) in renal disease. J. Am. Soc. Nephrol. 20(12), 2493–2502 (2009)PubMedCrossRef
20.
Y. Yang, J. Wang, L. Qin, Z. Shou, J. Zhao, H. Wang, Y. Chen, J. Chen, Rapamycin prevents early steps of the development of diabetic nephropathy in rats. Am. J. Nephrol. 27(5), 495–502 (2007)PubMedCrossRef
21.
S. Langer, R. Kreutz, A. Eisenreich, Metformin modulates apoptosis and cell signaling of human podocytes under high glucose conditions. J. Nephrol. (2016) [Epub ahead of print 5 Jan]
22.
M. Fraenkel, M. Ketzinel-Gilad, Y. Ariav, O. Pappo, M. Karaca, J. Castel, M.F. Berthault, C. Magnan, E. Cerasi, N. Kaiser, G. Leibowitz, mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolicstate in type 2 diabetes. Diabetes 57(4), 945–957 (2008)PubMedCrossRef
23.
M.C. Borges, L.A. Martini, M.M. Rogero, Current perspectives on vitamin D, immune system, and chronic diseases. Nutrition 27(4), 399–404 (2011)PubMedCrossRef
24.
T.S. Lisse, T. Liu, M. Irmler, J. Beckers, H. Chen, J.S. Adams, M. Hewison, Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTORsignaling. FASEB J. 25(3), 937–947 (2011)PubMedPubMedCentralCrossRef
25.
26.
V.A. Diaz, A.G. Mainous 3rd, P.J. Carek, A.M. Wessell, C.J. Everett, The association of vitamin D deficiency and insufficiency with diabetic nephropathy: implications for healthdisparities. J. Am. Board Fam. Med. 22(5), 521–527 (2009)PubMedCrossRef
27.
A. Levin, M. Le Barbier, L. Er, D. Andress, M.K. Sigrist, O. Djurdjev, Incident isolated 1,25(OH)(2)D(3) deficiency is more common than 25(OH)D deficiency in CKD. J. Nephrol. 25(2), 204–210 (2012)PubMedCrossRef
28.
Nirmalya Dey, Nandini Ghosh-Choudhury, Falguni Das, Xiaonan Li, Balachandar Venkatesan, Jeffrey L. Barnes, Balakuntalam S. Kasinath, Goutam Ghosh Choudhury, PRAS40 acts as a nodal regulator of high glucose-induced TORC1 activation in glomerular mesangial cell hypertrophy. J. Cell Physiol. 225(1), 27–41 (2010)PubMedPubMedCentralCrossRef
29.
S.I. Jeong, D.H. Kwak, S. Lee, Y.K. Choo, W.H. Woo, K.S. Keum, B.K. Choi, K.Y. Jung, Inhibitory effects of Cnidium officinale Makino and Tabanus fulvus Meigan on the high glucose-induced proliferation of glomerular mesangial cells. Phytomedicine 12(9), 648–655 (2005)PubMedCrossRef
30.
Kojiro Nagai, Takeshi Matsubara, Akira Mima, Eriko Sumi, Hiroshi Kanamori et al. Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy. Kidney Int 68(2), 552–561 (2005)PubMedCrossRef
31.
T.W. Lee, Y.H. Kao, T.I. Lee, C.J. Chang, G.S. Lien, Y.J. Chen, Calcitriol modulates receptor for advanced glycation end products (RAGE) in diabetic hearts. Int. J. Cardiol. 173(2), 236–241 (2014)PubMedCrossRef
32.
G.Y. Oudit, G.C. Liu, J. Zhong, R. Basu, F.L. Chow, J. Zhou, H. Loibner, E. Janzek, M. Schuster, J.M. Penninger, A.M. Herzenberg, Z. Kassiri, J.W. Scholey, Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes 59(2), 529–538 (2010)PubMedCrossRef
33.
S. Okada, S. Inaga, Y. Kawaba, T. Hanada, A. Hayashi, H. Nakane, T. Naguro, T. Kaidoh, S. Kanzaki, A novel approach to the histological diagnosis of pediatric nephrotic syndrome by low vacuum scanning electronmicroscopy. Biomed. Res. 35(4), 227–236 (2014)PubMedCrossRef
34.
D. Sankaran, N. Bankovic-Calic, C.Y. Peng, M.R. Ogborn, H.M. Aukema, Dietary flax oil during pregnancy and lactation retards disease progression in rat offspring with inherited kidneydisease. Pediatr. Res. 60(6), 729–733 (2006)PubMedCrossRef
35.
R.R. Singh, L.A. Cullen-McEwen, M.M. Kett, W.M. Boon, J. Dowling, J.F. Bertram, K.M. Moritz, Prenatal corticosterone exposure results in altered AT1/AT2, nephron deficit and hypertension in the rat offspring. J. Physiol. 579, 503–513 (2007)PubMedPubMedCentralCrossRef
36.
Z. Yang, F. Liu, H. Qu, H. Wang, X. Xiao, H. Deng, 1, 25(OH)2D3 protects β cell against high glucose-induced apoptosis through mTOR suppressing. Mol. Cell Endocrinol. 414, 111–119 (2015)PubMedCrossRef
37.
H. Derakhshanian, S. Shab-Bidar, J.R. Speakman, H. Nadimi, K. Djafarian, Vitamin D and diabetic nephropathy: A systematic review and meta-analysis. Nutrition 31(10), 1189–1194 (2015)PubMedCrossRef
38.
D.K. Deb, Y. Chen, Z. Zhang, Y. Zhang, F.L. Szeto, K.E. Wong, J. Kong, Y.C. Li, 1,25-Dihydroxyvitamin D3 suppresses high glucose-induced angiotensinogen expression in kidney cells byblocking the NF-{kappa}B pathway. Am. J. Physiol. Renal. Physiol. 296(5), F1212–F1218 (2009)PubMedPubMedCentralCrossRef
39.
Z. Zhang, W. Yuan, L. Sun, F.L. Szeto, K.E. Wong, X. Li, J. Kong, Y.C. Li, 1,25-Dihydroxyvitamin D3 targeting of NF-kappaB suppresses high glucose-induced MCP-1 expression in mesangial cells. Kidney Int. 72(2), 193–201 (2007)PubMedCrossRef
40.
A.K. Bhalla, E.P. Amento, B. Serog, L.H. Glimcher, 1,25-Dihydroxyvitamin D3 inhibits antigen-induced T cell activation. J. Immunol. 133(4), 1748–1754 (1984)PubMed
41.
M. Kajikawa, H. Ishida, S. Fujimoto, E. Mukai, M. Nishimura, J. Fujita, Y. Tsuura, Y. Okamoto, A.W. Norman, Y. Seino, An insulinotropic effect of vitamin D analog with increasing intracellular Ca2+ concentration in pancreatic beta-cells through nongenomic signal transduction. Endocrinology 140(10), 4706–4712 (1999)PubMed
42.
A. Cardus, S. Panizo, M. Encinas, X. Dolcet, C. Gallego, M. Aldea, E. Fernandez, J.M. Valdivielso, 1,25-dihydroxyvitamin D3 regulates VEGF production through a vitamin D response element in the VEGFpromoter. Atherosclerosis 204(1), 85–89 (2009)PubMedCrossRef
43.
M. Garsen, R. Sonneveld, A.L. Rops, S. Huntink, T.H. van Kuppevelt, T.J. Rabelink, J.G. Hoenderop, J.H. Berden, T. Nijenhuis, J. van der Vlag, Vitamin D attenuates proteinuria by inhibition of heparanase expression in the podocyte. J. Pathol 237(4), 472–481 (2015)PubMedCrossRef
44.
X.X. Wang, T. Jiang, Y. Shen, H. Santamaria, N. Solis, C. Arbeeny, M. Levi, Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism. Am. J. Physiol. Renal Physiol. 300(3), F801–F810 (2011)PubMedPubMedCentralCrossRef
45.
A. Kuhlmann, C.S. Haas, M.L. Gross, U. Reulbach, M. Holzinger, U. Schwarz, E. Ritz, K. Amann, 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomizedrat. Am. J. Physiol. Renal Physiol. 286(3), F526–F533 (2004)PubMedCrossRef
46.
F. Marampon, G.L. Gravina, C. Festuccia, V.M. Popov, E.A. Colapietro, P. Sanità, D. Musio, F. De Felice, A. Lenzi, E.A. Jannini, E. Di Cesare, V. Tombolini, Vitamin D protects endothelial cells from irradiation-induced senescence and apoptosis by modulating MAPK/SirT1 axis. J. Endocrinol Invest 39(4), 411–422 (2015)PubMedCrossRef
47.
Y. Zhang, D.K. Deb, J. Kong, G. Ning, Y. Wang, G. Li, Y. Chen, Z. Zhang, S. Strugnell, Y. Sabbagh, C. Arbeeny, Y.C. Li, Long-term therapeutic effect of vitamin D analog doxercalciferol on diabetic nephropathy: strong synergism with AT1 receptor antagonist. Am. J. Physiol. Renal Physiol. 297(3), F791–F801 (2009)PubMedPubMedCentralCrossRef
48.
M. Fraenkel, M. Ketzinel-Gilad, Y. Ariav, O. Pappo, M. Karaca, J. Castel, M.F. Berthault, C. Magnan, E. Cerasi, N. Kaiser, G. Leibowitz, mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57(4), 945–957 (2008)PubMedCrossRef
49.
O.A. Adegoke, H.E. Bates, M.A. Kiraly, M. Vranic, M.C. Riddell, E.B. Marliss, Exercise in ZDF rats does not attenuate weight gain, but prevents hyperglycemia concurrent with modulation of amino acid metabolism and AKT/mTOR activation in skeletal muscle. Eur. J. Nutr. 54(5), 751–759 (2015)PubMedCrossRef
50.
B.A. Heller, M. Ghidinelli, J. Voelkl, S. Einheber, R. Smith, E. Grund, G. Morahan, D. Chandler, L. Kalaydjieva, F. Giancotti, R.H. King, A.N. Fejes-Toth, G. Fejes-Toth, M.L. Feltri, F. Lang, J.L. Salzer, Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system. J. Cell Biol 204(7), 1219–1236 (2014)PubMedPubMedCentralCrossRef
51.
Y. Weisman, A. Harell, S. Edelstein, M. David, Z. Spirer, A. Golander, 1 alpha, 25-Dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 in vitro synthesis by human decidua andplacenta. Nature 281(5729), 317–319 (1979)PubMedCrossRef
52.
J.L. Omdahl, H.A. Morris, B.K. May, Hydroxylase enzymes of the vitamin D pathway: expression, function, and regulation. Annu. Rev. Nutr. 22, 139–166 (2002)PubMedCrossRef
Metadata
Title
In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D3 to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway
Authors
Hang Wang
Jianmin Wang
Hua Qu
Huili Wei
Baolan ji
Zesong Yang
Jing Wu
Qin He
Yuanyuan Luo
Dan Liu
Yang Duan
Fang Liu
Huacong Deng
Publication date
01-11-2016
Publisher
Springer US
Published in
Endocrine / Issue 2/2016
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-016-0999-1

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