Inhibition of the Akt1-mTORC1 Axis Alters Venous Remodeling to Improve Arteriovenous Fistula Patency

Overview

Journal Sci Rep

Specialty Science

Date 2019 Aug 1

PMID 31363142

Citations 26

Authors

Xiangjiang Guo

Arash Fereydooni

Toshihiko Isaji

Jolanta Gorecka

Shirley Liu

Haidi Hu

Shun Ono

Michelle Alozie

Shin Rong Lee

Ryosuke Taniguchi

Bogdan Yatsula

Naiem Nassiri

Lan Zhang

Alan Dardik

Affiliations

Soon will be listed here.

Abstract

Arteriovenous fistulae (AVF) are the most common access created for hemodialysis, but up to 60% do not sustain dialysis within a year, suggesting a need to improve AVF maturation and patency. In a mouse AVF model, Akt1 regulates fistula wall thickness and diameter. We hypothesized that inhibition of the Akt1-mTORC1 axis alters venous remodeling to improve AVF patency. Daily intraperitoneal injections of rapamycin reduced AVF wall thickness with no change in diameter. Rapamycin decreased smooth muscle cell (SMC) and macrophage proliferation; rapamycin also reduced both M1 and M2 type macrophages. AVF in mice treated with rapamycin had reduced Akt1 and mTORC1 but not mTORC2 phosphorylation. Depletion of macrophages with clodronate-containing liposomes was also associated with reduced AVF wall thickness and both M1- and M2-type macrophages; however, AVF patency was reduced. Rapamycin was associated with improved long-term patency, enhanced early AVF remodeling and sustained reduction of SMC proliferation. These results suggest that rapamycin improves AVF patency by reducing early inflammation and wall thickening while attenuating the Akt1-mTORC1 signaling pathway in SMC and macrophages. Macrophages are associated with AVF wall thickening and M2-type macrophages may play a mechanistic role in AVF maturation. Rapamycin is a potential translational strategy to improve AVF patency.

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References

Achneck H, Sileshi B, Li M, Partington E, Peterson D, Lawson J . Surgical aspects and biological considerations of arteriovenous fistula placement. Semin Dial. 2010; 23(1):25-33. DOI: 10.1111/j.1525-139X.2009.00651.x. View

Allon M, Robbin M . Increasing arteriovenous fistulas in hemodialysis patients: problems and solutions. Kidney Int. 2002; 62(4):1109-24. DOI: 10.1111/j.1523-1755.2002.kid551.x. View

Protack C, Foster T, Hashimoto T, Yamamoto K, Lee M, Kraehling J . Eph-B4 regulates adaptive venous remodeling to improve arteriovenous fistula patency. Sci Rep. 2017; 7(1):15386. PMC: 5684317. DOI: 10.1038/s41598-017-13071-2. View

Jadlowiec C, Feigel A, Yang C, Feinstein A, Kim S, Collins M . Reduced adult endothelial cell EphB4 function promotes venous remodeling. Am J Physiol Cell Physiol. 2012; 304(7):C627-35. PMC: 3625716. DOI: 10.1152/ajpcell.00333.2012. View

Thomson A, Turnquist H, Raimondi G . Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol. 2009; 9(5):324-37. PMC: 2847476. DOI: 10.1038/nri2546. View

Mercalli A, Calavita I, Dugnani E, Citro A, Cantarelli E, Nano R . Rapamycin unbalances the polarization of human macrophages to M1. Immunology. 2013; 140(2):179-90. PMC: 3784164. DOI: 10.1111/imm.12126. View

Hancock W, Adams D, Wyner L, Sayegh M, Karnovsky M . CD4+ mononuclear cells induce cytokine expression, vascular smooth muscle cell proliferation, and arterial occlusion after endothelial injury. Am J Pathol. 1994; 145(5):1008-14. PMC: 1887438. View

Saemann M, Haidinger M, Hecking M, Horl W, Weichhart T . The multifunctional role of mTOR in innate immunity: implications for transplant immunity. Am J Transplant. 2009; 9(12):2655-61. DOI: 10.1111/j.1600-6143.2009.02832.x. View

Paulson W, Kipshidze N, Kipiani K, Beridze N, DeVita M, Shenoy S . Safety and efficacy of local periadventitial delivery of sirolimus for improving hemodialysis graft patency: first human experience with a sirolimus-eluting collagen membrane (Coll-R). Nephrol Dial Transplant. 2012; 27(3):1219-24. DOI: 10.1093/ndt/gfr667. View

10.

Kondo Y, Jadlowiec C, Muto A, Yi T, Protack C, Collins M . The Nogo-B-PirB axis controls macrophage-mediated vascular remodeling. PLoS One. 2013; 8(11):e81019. PMC: 3835671. DOI: 10.1371/journal.pone.0081019. View

11.

Kaygin M, Halici U, Aydin A, Dag O, Binici D, Limandal H . The relationship between arteriovenous fistula success and inflammation. Ren Fail. 2013; 35(8):1085-8. DOI: 10.3109/0886022X.2013.815100. View

12.

Powell J, Delgoffe G . The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity. 2010; 33(3):301-11. PMC: 2962404. DOI: 10.1016/j.immuni.2010.09.002. View

13.

Okamoto E, Couse T, De Leon H, Vinten-Johansen J, GOODMAN R, Scott N . Perivascular inflammation after balloon angioplasty of porcine coronary arteries. Circulation. 2001; 104(18):2228-35. DOI: 10.1161/hc4301.097195. View

14.

Rothuizen T, Wong C, Quax P, van Zonneveld A, Rabelink T, Rotmans J . Arteriovenous access failure: more than just intimal hyperplasia?. Nephrol Dial Transplant. 2013; 28(5):1085-92. DOI: 10.1093/ndt/gft068. View

15.

Kuwahara G, Hashimoto T, Tsuneki M, Yamamoto K, Assi R, Foster T . CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation. Arterioscler Thromb Vasc Biol. 2017; 37(6):1147-1156. PMC: 5467640. DOI: 10.1161/ATVBAHA.117.309385. View

16.

Gibson K, Gillen D, Caps M, Kohler T, Sherrard D, Stehman-Breen C . Vascular access survival and incidence of revisions: a comparison of prosthetic grafts, simple autogenous fistulas, and venous transposition fistulas from the United States Renal Data System Dialysis Morbidity and Mortality Study. J Vasc Surg. 2001; 34(4):694-700. DOI: 10.1067/mva.2001.117890. View

17.

Bashar K, Clarke-Moloney M, Burke P, Kavanagh E, Walsh S . The role of venous diameter in predicting arteriovenous fistula maturation: when not to expect an AVF to mature according to pre-operative vein diameter measurements? A best evidence topic. Int J Surg. 2015; 15:95-9. DOI: 10.1016/j.ijsu.2015.01.035. View

18.

Chang C, Ko Y, Ko P, Hsu L, Chen C, Yang C . Thrombosed arteriovenous fistula for hemodialysis access is characterized by a marked inflammatory activity. Kidney Int. 2005; 68(3):1312-9. DOI: 10.1111/j.1523-1755.2005.00529.x. View

19.

Aoki Y, Nakahara T, Asano D, Ushikubo H, Mori A, Sakamoto K . Preventive effects of rapamycin on inflammation and capillary degeneration in a rat model of NMDA-induced retinal injury. Biol Pharm Bull. 2015; 38(2):321-4. DOI: 10.1248/bpb.b14-00631. View

20.

Motwani J, Topol E . Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation. 1998; 97(9):916-31. DOI: 10.1161/01.cir.97.9.916. View