Abstract
Backgrounds/Aims: Heme oxygenase-1 (HO-1) has been shown to protect against fibrotic proliferation and apoptosis in several models of renal damage. The purpose of this study was to evaluate the impact of a treatment with the HO-1 inducer hemin on the progression of chronic kidney disease in nephrectomized rats versus the AT1 receptor antagonist losartan. Methods: The rats underwent 5/6 renal ablation and after the procedure received either losartan (20 mg/kg/day; n = 9), hemin (50 mg/kg/twice a week; n = 8) or vehicle (n = 8) over a 12-week period. At week 12, blood pressure was measured, urine, blood and remnant kidney were collected for biochemical (proteinuria, urea, creatinine) and histopathological (degrees of glomerulosclerosis and tubular atrophy) analysis. The expressions of HO-1, bone morphogenic protein 7 (BMP-7) and TGF-β were assessed by immunochemistry, and the level of the apoptosis marker protein caspase-3 by Western blot, on the remnant kidney. Results: Hemin significantly reduced blood pressure, proteinuria, inhibited the expression of TGF-β and caspase-3 protein and increased BMP-7 expression protein. Hemin-treated rats had lower glomerulosclerosis and tubular atrophy indexes than controls. Conclusion: Hemin treatment attenuates the progression of chronic kidney disease and appears more efficient than losartan in our rat model hypothetically because of the impact of hemin on the renal expression of BMP-7.
Journal Section:
Original Paper
References
1.
Kikuchi G, Yoshida T, Noguchi M: Heme oxygenase and heme degradation. Biochem Biophys Res Commun 2005;338:558–567.
[PubMed]
2.
Morita T: Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 2005;25:1786–1795.
[PubMed]
3.
Otterbein LE, et al: Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 2000;6:422–428.
[PubMed]
4.
Duckers HJ, et al: Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med 2001;7:693–698.
[PubMed]
5.
Morita T, et al: Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells. J Biol Chem 1997;272:32804–32809.
[PubMed]
6.
Peyton KJ, et al: Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth. Blood 2002;99:4443–4448.
[PubMed]
7.
Tulis DA, et al: Local administration of carbon monoxide inhibits neointima formation in balloon injured rat carotid arteries. Cell Mol Biol 2005;51:441–446.
[PubMed]
8.
Brouard S, et al: Heme oxygenase-1-derived carbon monoxide requires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosis factor-alpha-mediated apoptosis. J Biol Chem 2002;277:17950–17961.
[PubMed]
9.
Brouard S, et al: Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med 2000;192:1015–1026.
[PubMed]
10.
Silva G, et al: The antiapoptotic effect of heme oxygenase-1 in endothelial cells involves the degradation of p38 alpha MAPK isoform. J Immunol 2006;177:1894–1903.
[PubMed]
11.
Brune B, Ullrich V: Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol Pharmacol 1987;32:497–504.
[PubMed]
12.
Desbuards N, et al: Heme oxygenase-1 inducer hemin prevents vascular thrombosis. Thromb Haemost 2007;98:614–620.
[PubMed]
13.
Mansouri A, Perry CA: Alteration of platelet aggregation by cigarette smoke and carbon monoxide. Thromb Haemost 1982;48:286–288.
[PubMed]
14.
Datta PK, et al: Heme oxygenase-1 induction attenuates inducible nitric oxide synthase expression and proteinuria in glomerulonephritis. J Am Soc Nephrol 1999;10:2540–2550.
[PubMed]
15.
Remuzzi G, Ruggenenti P, Benigni A: Understanding the nature of renal disease progression. Kidney Int 1997;51:2–15.
[PubMed]
16.
Wesson LG: Compensatory growth and other growth responses of the kidney. Nephron 1989;51:149–184.
[PubMed]
17.
Yang N, et al: Local macrophage proliferation in human glomerulonephritis. Kidney Int 1998;54:143–151.
[PubMed]
18.
Yang N, et al: Local macrophage and myofibroblast proliferation in progressive renal injury in the rat remnant kidney. Nephrol Dial Transplant 1998;13:1967–1974.
[PubMed]
19.
Miyajima A, et al: Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int 2000;58:2301–2313.
[PubMed]
20.
Bassols A, Massague J: Transforming growth factor beta regulates the expression and structure of extracellular matrix chondroitin/dermatan sulfate proteoglycans. J Biol Chem 1988;263:3039–3045.
[PubMed]
21.
Bitzer M, Sterzel RB, Bottinger EP: Transforming growth factor-beta in renal disease. Kidney Blood Press Res 1998;21:1–12.
22.
Fan JM, et al: Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int 1999;56:1455–1467.
[PubMed]
23.
Schiffer M, et al: Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest 2001;108:807–816.
[PubMed]
24.
Wang SN, Lapage J, Hirschberg R: Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy. J Am Soc Nephrol 2001;12:2392–2399.
[PubMed]
25.
Dudley AT, Lyons KM, Robertson EJ: A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev 1995;9:2795–2807.
[PubMed]
26.
Almanzar MM, et al: Osteogenic protein-1 mRNA expression is selectively modulated after acute ischemic renal injury. J Am Soc Nephrol 1998;9:1456–1463.
[PubMed]
27.
Simon M, et al: Expression of bone morphogenetic protein-7 mRNA in normal and ischemic adult rat kidney. Am J Physiol 1999;276:F382–F389.
[PubMed]
28.
Griethe W, et al: Bone morphogenic protein-4 expression in vascular lesions of calciphylaxis. J Nephrol 2003;16:728–732.
[PubMed]
29.
Truong LD, et al: Cell apoptosis and proliferation in experimental chronic obstructive uropathy. Kidney Int 1996;50:200–207.
[PubMed]
30.
Sugiyama H, et al: Apoptosis in glomerular sclerosis. Kidney Int 1996;49:103–111.
[PubMed]
31.
Taal MW, Brenner BM: Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int 2000;57:1803–1817.
[PubMed]
32.
Kelly DJ, et al: Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J Am Soc Nephrol 2004;15:2619–2629.
[PubMed]
33.
Rochefort GY, et al: Effect of the heme oxygenase inducer hemin on blood haemostasis measured by high-frequency ultrasound. Clin Exp Pharmacol Physiol 2007;34:1272–1275.
[PubMed]
34.
You KS, et al: Effect of hemin in treating hemorrhagic anemia and toxicity (in Chinese). Zhongguo Yao Li Xue Bao 1996;17:284–286.
[PubMed]
35.
Mackie FE, Meyer TW, Campbell DJ: Effects of antihypertensive therapy on intrarenal angiotensin and bradykinin levels in experimental renal insufficiency. Kidney Int 2002;61:555–563.
[PubMed]
36.
Salom MG, et al: Heme oxygenase-1 induction improves ischemic renal failure: role of nitric oxide and peroxynitrite. Am J Physiol Heart Circ Physiol 2007;293:H3542-H3549.
[PubMed]
37.
Maines MD, Raju VS, Panahian N: Spin trap (N-t-butyl-alpha-phenylnitrone)-mediated suprainduction of heme oxygenase-1 in kidney ischemia/reperfusion model: role of the oxygenase in protection against oxidative injury. J Pharmacol Exp Ther 1999;291:911–919.
[PubMed]
38.
Johnson RA, et al: Heme oxygenase substrates acutely lower blood pressure in hypertensive rats. Am J Physiol 1996;271:H1132–H1138.
[PubMed]
39.
Levere RD, et al: Effect of heme arginate administration on blood pressure in spontaneously hypertensive rats. J Clin Invest 1990;86:213–219.
[PubMed]
40.
Motterlini R, et al: Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo. Circ Res 1998;83:568–577.
[PubMed]
41.
Diep QN, Li JS, Schiffrin EL: In vivo study of AT(1) and AT(2) angiotensin receptors in apoptosis in rat blood vessels. Hypertension 1999;34:617–624.
[PubMed]
42.
Johnson RJ, et al: Renal injury from angiotensin II-mediated hypertension. Hypertension 1992;19:464–474.
[PubMed]
43.
Park HC, et al: Effect of losartan and amlodipine on proteinuria and transforming growth factor-beta1 in patients with IgA nephropathy. Nephrol Dial Transplant 2003;18:1115–1121.
[PubMed]
44.
Bottinger EP, Bitzer M: TGF-beta signaling in renal disease. J Am Soc Nephrol 2002;13:2600–2610.
[PubMed]
45.
Hruska KA, et al: Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am J Physiol Renal Physiol 2000;279:F130–F143.
[PubMed]
46.
Vukicevic S, et al: Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat. J Clin Invest 1998;102:202–214.
[PubMed]
47.
Wang S, et al: Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int 2003;63:2037–2049.
[PubMed]
48.
Zeisberg M, et al: BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 2003;9:964–968.
[PubMed]
49.
Zeisberg M, Shah AA, Kalluri R: Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J Biol Chem 2005;280:8094–8100.
[PubMed]
50.
Gould SE, et al: BMP-7 regulates chemokine, cytokine, and hemodynamic gene expression in proximal tubule cells. Kidney Int 2002;61:51–60.
[PubMed]
51.
Cozzolino M, et al: Sevelamer hydrochloride attenuates kidney and cardiovascular calcifications in long-term experimental uremia. Kidney Int 2003;64:1653–1661.
[PubMed]
52.
Hruska KA, Mathew S, Saab G: Bone morphogenetic proteins in vascular calcification. Circ Res 2005;97:105–114.
[PubMed]
53.
Kie JH, et al: Heme oxygenase-1 deficiency promotes epithelial-mesenchymal transition and renal fibrosis. J Am Soc Nephrol 2008;19:1681–1691.
[PubMed]
© 2009 S. Karger AG, Basel
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