Renovascular hypertension induced by 2 Kidney-1 Clip (2K-1C) is a renin-angiotensin-system (RAS)-dependent model, leading to renal vascular rarefaction and renal failure. RAS inhibitors are not able to reduce arterial pressure (AP) and/or preserve the renal function, and thus, alternative therapies are needed. Three weeks after left renal artery occlusion, fluorescently tagged mesenchymal stem cells (MSC) (2×105 cells/animal) were injected weekly into the tail vein in 2K-1C hypertensive rats. Flow cytometry showed labeled MSC in the cortex and medulla of the clipped kidney. MSC prevented a further increase in the AP, significantly reduced proteinuria and decreased sympathetic hyperactivity in 2K-1C rats. Renal function parameters were unchanged, except for an increase in urinary volume observed in 2K-1C rats, which was not corrected by MSC. The treatment improved the morphology and decreased the fibrotic areas in the clipped kidney and also significantly reduced renal vascular rarefaction typical of 2K-1C model. Expression levels of IL-1β, TNF-α angiotensinogen, ACE, and Ang II receptor AT1 were elevated, whereas AT2 levels were decreased in the medulla of the clipped kidney. MSC normalized these expression levels. In conclusion, MSC therapy in the 2K-1C model (i) prevented the progressive increase of AP, (ii) improved renal morphology and microvascular rarefaction, (iii) reduced fibrosis, proteinuria and inflammatory cytokines, (iv) suppressed the intrarenal RAS, iv) decreased sympathetic hyperactivity in anesthetized animals and v) MSC were detected at the CNS suggesting that the cells crossed the blood-brain barrier. This therapy may be a promising strategy to treat renovascular hypertension and its renal consequences in the near future.
References
[1]
Chade AR, Rodriguez-Porcel M, Grande JP, Krier JD, Lerman A, et al. (2002) Distinct renal injury in early atherosclerosis and renovascular disease. Circulation 106: 1165–1171.
[2]
Chade AR, Rodriguez-Porcel M, Grande JP, Zhu X, Sica V, et al. (2003) Mechanisms of renal structural alterations in combined hypercholesterolemia and renal artery stenosis. Arterioscler Thromb Vasc Biol 23: 1295–1301.
[3]
Chade AR, Zhu X, Mushin OP, Napoli C, Lerman A, et al. (2006) Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia. Faseb J 20: 1706 –1708.
[4]
Goldblatt H, Lynch J, Hanzal RF, Summerville WW (1934) Studies on experimental hypertension. The production of persistent elevation systolic blood pressure by means of renal ischemia. J Exp Med 59: 347–378.
[5]
Ploth DW (1983) Angiotensin-dependent renal mechanisms in two-kidney one-clip renal vascular hypertension. Am J Physiol 245: 131–141.
[6]
Mitchell KD, Navar LG (1995) Intrarenal actions of Angiotensin II in the pathogenesis of experimental hypertension. In: Hypertension: Pathophysiology, Diagnosis, and Management, edited by J.H. Laragh and B. M. Brenner. New York: Raven, 1437– 1450.
[7]
Navar LG, Zou L, Von Thun A, Tarng Wang C, Imig JD, et al. (1998) Unraveling the mystery of Goldblatt hypertension. News Physiol Sci 13: 170–176.
[8]
Navar LG, Prieto MC, Satou R, Kobori H (2011) Intrarenal angiotensin II and its contribution to the genesis of chronic hypertension. Current Opinion In Pharmacology 11: 180–186.
[9]
Lerman LO, Chade AR, Sica V, Napoli C (2005) Animals models of hypertension: an overview. J Lab Clin Med 146: 160–173.
[10]
Oliveira-Sales EB, Dugaich AP, Carillo BA, Abreu NP, Boim MA, et al. (2008) Oxidative stress contributes to renovascular hypertension. Am J Hypertens 21(1): 98–104.
[11]
Oliveira-Sales EB, Nishi EE, Carillo BA, Boim MA, Dolnikoff MS, et al. (2009) Oxidative Stress in the Sympathetic Premotor Neurons Contributes to Sympathetic Activation in Renovascular Hypertension. Am J Hypertens. 22: : 484 – 492.
[12]
Oliveira-Sales EB, Colombari DSA, Davisson RL, Kasparov S, Hirata AE, et al. (2010) Kidney-Induced Hypertension Depends on Superoxide Signaling in the Rostral Ventrolateral Medulla. Hypertension 56: : 290 – 296.
[13]
Semedo P, Correa-Costa M, Antonio Cenedeze M, Maria Avancini Costa Malheiros D, Antonia dos Reis M, et al. (2009) Mesenchymal stem cells attenuate renal fibrosis through immune modulation and remodeling properties in a rat remnant kidney model. Stem Cells 27(12): 3063–73.
[14]
Semedo P, Donizetti-Oliveira C, Burgos-Silva M, Cenedeze MA, Avancini Costa Malheiros DM, et al. (2010) Bone marrow mononuclear cells attenuate fibrosis development after severe acute kidney injury. Lab Invest 90(5): 685–95.
[15]
Abdelli LS, Merino H, Rocher CM, Singla DK (2012) Cell therapy in the heart. Can J Physiol Pharmacol 90(3): 307–15.
[16]
Maclean S, Khan WS, Malik AA, Anand S, Snow M (2012) The potential of stem cells in the treatment of skeletal muscle injury and disease. Stem Cells Int 2012: 282348.
[17]
Glover LE, Tajiri N, Weinbren NL, Ishikawa H, Shinozuka K, et al. (2012) A Step-up Approach for Cell Therapy in Stroke: Translational Hurdles of Bone Marrow-Derived Stem Cells. Transl Stroke Res 3(1): 90–98.
[18]
Gnecchi M, Zhang Z, Ni A, Dzau V (2008). Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 103(11): 1204-19. Review.
[19]
Semedo P, Palasio CG, Oliveira CD, Feitoza CQ, Gon？alves GM, et al. (2009) Early modulation of inflammation by mesenchymal stem cell after acute kidney injury. Int Immunopharmacol 9(6): 677–82.
[20]
Aicher A, Brenner W, Zuhayra M, Badorff C, Massoudi S, et al. (2003) Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation 107: 2134–9.
[21]
Imgrund M, Grone E, Grone HJ, Kretzler M, Holzman L, et al. (1999) Reexpression of the developmental gene Pax-2 during experimental acute tubular necrosis in mice 1. Kidney Int 56: 1423–1431.
[22]
Villanueva S, Cespedes C, Vio CP (2006) Ischemic acute renal failure induces the expression of a wide range of nephrogenic proteins. Am J Physiol Regul Integr Comp Physiol 290: R861–870.
[23]
Luan Y, Zhang ZH, Wei DE, Zhao JJ, Kong F, et al. (2012) Implantation of Mesenchymal Stem Cells Improves Right Ventricular Impairments Caused by Experimental Pulmonary Hypertension. . Am J Med Sci. 343(5): 402–6.
[24]
Braga LM, Rosa K, Rodrigues B, Malfitano C, Camassola M, et al. (2008) Systemic delivery of adult stem cells improves cardiac function in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 35(2): 113–9.
[25]
Chade AR, Zhu X, Lavi R, Krier JD, Pislaru S, et al. (2009) Endothelial progenitor cells restore renal function in chronic experimental renovascular disease. Circulation 119(4): 547–57.
[26]
Chade AR, Zhu XY, Krier JD, Jordan KL, Textor SC, et al. (2010) Endothelial progenitor cells homing and renal repair in experimental renovascular disease. Stem Cells 28(6): 1039–47.
[27]
Zhu XY, Chade AR, Rodriguez-Porcel M, Bentley MD, Ritman EL, et al. (2004) Cortical microvascular remodeling in the stenotic kidney: role of increased oxidative stress. Arterioscler Thromb Vasc Biol 24: : 1854 –1859.
[28]
Rabito SF, Carretero OA, Scicli AG (1981) Evidence against a role of vasopressin in the maintenance of high blood pressure in mineralocorticoid and renovascular hypertension. Hypertension 3(1): 34–8.
[29]
Ma SK, Bae EH, Kim IJ, Choi C, Lee J, et al. (2009) Altered renal expression of aquaporin water channels and sodium transporters in rats with two-kidney, one-clip hypertension. Kidney Blood Press Res 32(6): 411–20.
[30]
Lee J, Oh Y, Kim SW (2001) Altered renal expression of aquaporin-2 water channels in rats with experimental two-kidney, one clip hypertension. J Korean Med Sci 16(4): 462–6.
[31]
Prieto-Carrasquero MC, Botros FT, Pagan J, Kobori H, Seth DM, et al. (2008) Collecting duct renin is upregulated in both kidneys of 2-kidney, 1-clip Goldblatt hypertensive rats. Hypertension 51(6): 1590–6.
[32]
Yerram P, Karuparthi PR, Chaudhary K (2012) Pathogenesis and management of renovascular hypertension and ischemic nephropathy. Minerva Urol Nefrol 64(1): 63–72.
[33]
Inumaru J, Nagano O, Takahashi E, Ishimoto T, Nakamura S, et al. (2009) Molecular mechanisms regulating dissociation of cell-cell junction of epithelial cells by oxidative stress. Genes Cells 14(6): 703–16.
[34]
Humphreys BD, Bonventre JV (2008) Mesenchymal stem cells in acute kidney injury. Annu Rev Med 59: 311–325.
