Abstract
Background and Purpose
We previously showed that mice with reduced levels of the transforming growth factor-beta
(TGF-β) co-receptor endoglin (Eng+/− mice) develop less fibrosis and vascular damage after kidney irradiation than their
wild type (Eng+/+ mice) littermates; however, the underlying mechanism was unclear. Results from current
studies suggest that this occurs via modulation of the radiation-induced inflammatory
response.
Materials and methods
Kidneys of Eng+/+ and Eng+/− mice were irradiated with 16 Gy. Mice were sacrificed at 20 weeks after irradiation and gene expression and protein levels were analyzed.
Results
Kidney irradiation triggered the infiltration of macrophages in both Eng+/+ and Eng+/− mice, however, levels of macrophage-produced cytokines interleukin 1 beta (Il1b) and interleukin 6 (Il6) were reduced in irradiated Eng+/− compared to Eng+/+ mice. Double immuno-stainings confirmed that IL-6 was produced by macrophages, whereas
IL-1β was mainly detected in other cell types. Accordingly, inflammatory cell precursors
derived from the bone marrow of Eng+/− mice showed impaired ability to express Il1b and Il6 compared to wild type mice.
Conclusions
Endoglin promotes kidney inflammation after irradiation by regulating macrophage infiltration
and interleukin production, thereby promoting pathogenic changes after radiation exposure.
Keywords
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References
- Radiation nephropathy.Semin Nephrol. 2003; 23: 486-499
- Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells.J Biol Chem. 1992; 267: 19027-19030
- Identification of a human endothelial cell antigen with monoclonal antibody 44G4 produced against a pre-B leukemic cell line.J Immunol. 1988; 141: 1925-1933
- CD105 antagonizes the inhibitory signaling of transforming growth factor beta1 on human vascular endothelial cells.FASEB J. 2000; 14: 55-64
- A new 180-kDa dermal endothelial cell activation antigen: in vitro and in situ characteristics.J Invest Dermatol. 1993; 100: 27-34
- Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury.Blood. 2002; 100: 4001-4010
- Endoglin is overexpressed after arterial injury and is required for transforming growth factor-beta-induced inhibition of smooth muscle cell migration.Arterioscler Thromb Vasc Biol. 2000; 20: 2546-2552
- Endoglin regulates renal ischaemia-reperfusion injury.Nephrol Dial Transplant. 2006; 21: 2106-2119
- Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development.Dev Biol. 2000; 217: 42-53
- A murine model of hereditary hemorrhagic telangiectasia.J Clin Invest. 1999; 104: 1343-1351
- Defective angiogenesis in mice lacking endoglin.Science. 1999; 284: 1534-1537
- Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1.Nat Genet. 1994; 8: 345-351
- Mutation analysis in Spanish patients with hereditary hemorrhagic telangiectasia: deficient endoglin up-regulation in activated monocytes.Clin Chem. 2004; 50: 2003-2011
- Inducible expression of human endoglin during inflammation and wound healing in vivo.Inflamm Res. 2002; 51: 464-470
- Effect of the long-term treatment with trandolapril on endoglin expression in rats with experimental renal fibrosis induced by renal mass reduction.Kidney Blood Press Res. 2005; 28: 32-40
- Temporal changes in renal endoglin and TGF-beta1 expression following ureteral obstruction in rats.J Physiol Biochem. 2005; 61: 457-467
- Endoglin, a transforming growth factor-beta-binding protein, is upregulated in chronic progressive renal disease.Exp Nephrol. 1997; 5: 55-60
- Endoglin haploinsufficiency reduces radiation-induced fibrosis and telangiectasia formation in mouse kidneys.Radiother Oncol. 2009; 92: 484-491
- Regulated expression on human macrophages of endoglin, an Arg-Gly-Asp-containing surface antigen.Eur J Immunol. 1992; 22: 393-397
- Endoglin: a 180-kD endothelial cell and macrophage restricted differentiation molecule.Clin Exp Immunol. 1992; 90: 154-159
- Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily.J Immunol. 1995; 154: 3821-3835
- Renovascular disease, microcirculation and the progression of renal injury: role of angiogenesis.Am J Physiol Regul Integr Comp Physiol. 2011;
- Insights into the mechanisms of renal fibrosis: is it possible to achieve regression?.Am J Physiol Renal Physiol. 2005; 289: F227-F234
- Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis.Kidney Int. 2011; 80: 915-925
- Renal toxicity in children undergoing total body irradiation for bone marrow transplant.Radiother Oncol. 2009; 90: 242-246
- Renal insufficiency after total body irradiation for pediatric bone marrow transplantation.Radiother Oncol. 1990; 18: 139-142
- Effect of dose and dose-distribution in damage to the kidney following abdominal radiotherapy.Int J Radiat Biol. 2002; 78: 695-702
- Impact of drug therapy, radiation dose, and dose rate on renal toxicity following bone marrow transplantation.Int J Radiat Oncol Biol Phys. 2008; 71: 1436-1443
- Prospective study on late renal toxicity following postoperative chemoradiotherapy in gastric cancer.Int J Radiat Oncol Biol Phys. 2007; 67: 781-785
- Renal toxicity of adjuvant chemoradiotherapy with cisplatin in gastric cancer.Int J Radiat Oncol Biol Phys. 2007; 69: 1429-1435
- Renal atrophy secondary to chemoradiotherapy of abdominal malignancies.Int J Radiat Oncol Biol Phys. 2010; 78: 539-546
- Captopril to mitigate chronic renal failure after hematopoietic stem cell transplantation: a randomized controlled trial.Int J Radiat Oncol Biol Phys. 2008; 70: 1546-1551
- Evidence for a renovascular component in hypertensive patients with late radiation nephropathy.Int J Radiat Oncol Biol Phys. 1994; 30: 677-683
- Role of cytokines in the pathogenesis of acute and chronic kidney disease, glomerulonephritis, and end-stage kidney disease.Int J Interferon Cytokine Mediator Res. 2010; 2: 49-62
- Macrophages: master regulators of inflammation and fibrosis.Semin Liver Dis. 2010; 30: 245-257
- Role of immunocompetent cells in nonimmune renal diseases.Kidney Int. 2001; 59: 1626-1640
- Macrophages in renal disease.J Am Soc Nephrol. 2011; 22: 21-27
- Macrophages and progressive tubulointerstitial disease.Kidney Int. 2005; 68: 437-455
- Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury.Kidney Int. 2004; 65: 116-128
- Blockade of CCR2 ameliorates progressive fibrosis in kidney.Am J Pathol. 2004; 165: 237-246
- Expression and function of CD105 during the onset of hematopoiesis from Flk1(+) precursors.Blood. 2001; 98: 3635-3642
- Cytokines as communication signals between leukocytes and endothelial cells.Immunol Today. 1989; 10: 370-375
- Cytokine regulation of endothelial cell function.FASEB J. 1992; 6: 2591-2599
- Evolving functions of endothelial cells in inflammation.Nat Rev Immunol. 2007; 7: 803-815
- Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor.Circ Res. 2004; 94: 534-541
- Interleukin-6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin-1 in human vascular endothelial cells.J Hypertens. 2010; 28: 940-951
- Stat3 mediates interleukin-6 inhibition of human endothelial nitric-oxide synthase expression.J Biol Chem. 2006; 281: 30057-30062
- Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines.Circ Res. 2005; 96: 1233-1239
- Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment.Immunity. 1997; 6: 315-325
- Administration of interleukin-1 receptor antagonist ameliorates renal ischemia-reperfusion injury.Transpl Int. 2008; 21: 572-580
- Suppression of experimental crescentic glomerulonephritis by the interleukin-1 receptor antagonist.Kidney Int. 1993; 43: 479-485
- IL-1RI deficiency ameliorates early experimental renal interstitial fibrosis.Nephrol Dial Transplant. 2009; 24: 3024-3032
- Maladaptive role of IL-6 in ischemic acute renal failure.J Am Soc Nephrol. 2005; 16: 3315-3325
- IL-6/IL-6R axis plays a critical role in acute kidney injury.J Am Soc Nephrol. 2008; 19: 1106-1115
- Endogenous interleukin-6 enhances the renal injury, dysfunction, and inflammation caused by ischemia/reperfusion.J Pharmacol Exp Ther. 2005; 312: 1170-1178
- Interleukin 6: presence and future.Int J Clin Lab Res. 1992; 22: 143-151
- Intrinsic renal cells are the major source of interleukin-1 beta synthesis in normal and diseased rat kidney.Nephrol Dial Transplant. 1997; 12: 1109-1115
- Transforming growth factor-beta regulation of immune responses.Annu Rev Immunol. 2006; 24: 99-146
Article info
Publication history
Published online: October 01, 2012
Accepted:
August 17,
2012
Received in revised form:
August 16,
2012
Received:
March 20,
2012
Identification
Copyright
© 2012 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.