Renal interstitial cells,proteinuria and progression of lupus nephritis: new frontiers for old factors

Abstract

Interstitial cells, inflammatory-immune cells, tubular cells and endothelial cells of the peritubular capillaries have arisen as possible major players of the nephron damage in lupus nephritis. Increased ICAM-1, Von Willebrand factor, soluble endothelial protein C receptors and decreased ADAMS-13 point to a diffuse vascular damage. Albuminuria elicits a rapid generation of hydrogen peroxide in proximal tubular cells along with nuclear factor-kB activation, endothelin-1 and transforming growth factor (TGF-β1) upregulation. TGF-β1 enhances epithelial-to-mesenchymal transdifferentiation. Albuminuria also enhances the expression of macrophage chemotactic protein-1 and macrophage inflammatory protein-1α, thus leading to increased interstitial inflammation. TGF-β1 and thrombospondin-1, a putative activator of TGF-β, induce apoptosis of peritubular capillaries, as well as of glomerular endothelial cells. All these events can be counteracted by hepatocyte growth factor (HGF), which is expressed by the epithelial tubular cells and stimulates the growth of epithelial cells (mitogen), enhances the motility of epithelial cells (motogen), induces renal epithelial tubule regeneration (morphogen) and enhances angiogenesis (angiogen). The balance between TGF-β1 and HGF could be a key to define the prognostic value of kidney histopathology at baseline and during follow-up, in lupus nephritis. Therapeutic strategies aiming at altering the biological balance in the patients are at hand to test and prove the experimental evidences.

Keywords

hepatocyte growth factor interstitial damage prognosis systemic lupus erythematosus transforming growth factor β1

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References

1 Dooley MA Hogan S Jennette C Falk R . Cyclophosphamide therapy for lupus nephritis: poor renal survival in Black Americans. Glomerular Disease Collaborative Network. Kidney Int 1997; 51: 1188–1195.

2 Korbet SM Lewis EJ Scwartz MM Reichlin M Evans J Rhode RD . Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis 2000; 35: 904–914.

3 Hogarth PM . Fc receptors are major mediators of antibody based inflammation in autoimmunity. Curr Opin Immunol 2002; 14: 798–802.

4 Hahn BH . Mechanisms of disease: antibodies to DNA. N Engl J Med 1998; 338: 1359–1368.

5 Trouw LA Groeneveld TWL Seelen MA . Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q containing immune complexes. J Clin Invest 2004; 114: 679–688.

6 Holers VM Girardi G Mo L . Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 2002; 195: 211–220.

7 Merkel P Polisson R Chang Y Skates S Niles J . Prevalence of antineutrophil cytoplasmic antibodies in a large inception cohort of patients with connective tissue disease. Ann Intern Med 1997; 126: 866–873.

8 Cines DB Lyss AP Reeber M Bina M DeHoratius RJ . Presence of complement-fixing anti-endothelial cell antibodies in systemic lupus erythematosus. J Clin Invest 1984; 73: 611–625.

9 Cortés-Hernández J Ordi-Ros J Labrador M . Predictors of poor renal outcome in patients with lupus nephritis treated with combined pulses of cyclophosphamide and methylprednisolone. Lupus 2003; 12: 287–296.

10.

10 Yoo CW Kim M-K Lee HS . Predictors of renal outcome in diffuse proliferative lupus nephropathy: data from repeat renal biopsy. Nephrol Dial Transplant 2000; 15: 1604–1608.

11.

11 Chan TM Tse KC Tang CSO Lai KN Li FK . Long-term outcome of patients with diffuse proliferative lupus nephritis treated with prednisolone and oral cyclophosphamide followed by azathioprine. Lupus 2005; 14: 265–272.

12.

12 Austin HA Boumpas DT Vaughan EM Balow JE . Predicting renal outcomes in severe lupus nephritis: contributions of clinical and histologic data. Kidney Int 1994; 45: 544–550.

13.

13 Hill GS Delahousse M Nochy D . Outcome of relapse in lupus nephritis: Roles of reversal of renal fibrosis and response of inflammation to therapy. Kidney Int 2002: 61: 2176–2186.

14.

14 Esdaile JM Levinto C Federgreen W Hayslett JP Kashgarian M . The clinical and renal biopsy predictors of long-term outcome in lupus nephritis: A study of 87 patients and review of the literature. Q J Med 1989; 72: 779–833.

15.

15 Daniel L Sichez H Giorgi R . : Tubular lesions and tubular cell adhesion molecules for the prognosis of lupus nephritis. Kidney Int 2001; 60: 2215–2221.

16.

16 Hill GS Delahousse M Nochy D . A new morphologic index for the evaluation of renal biopsies in lupus nephritis. Kidney Int 2000; 58: 1160–1173.

17.

17 Cameron JS . Lupus nephritis. J Am Soc Nephrol 1999; 10: 413–424.

18.

18 D’Amico G Minetti L Ponticelli C . Prognostic indicators in idiopathic IgA mesangial nephropathy. Q J Med 1986; 59: 363–378.

19.

19 Isenberg DA Manson JJ Ehrenstein MR Rahman A . Fisty years of antids-DNA antibodies: are approaching the journey’s end? Rheumatology 2007; 46: 1052–1056.

20.

20 Benigni A Caroli C Longaretti L . Involvement of renal tubular Toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus. Arthritis Rheum 2007; 56: 1569–1578.

21.

21 Egerer K Feist E Rohr U Pruss A Burmester GR Dorner T . Increased serum soluble CD14, ICAM-1 and E-selectin correlate with disease activity and prognosis in systemic lupus erythematosus. Lupus 2000; 9: 614–621.

22.

22 Mannucci PM Vanoli M Forza I Canciani MT Scorza R . Von Willebrand factor cleaving protease (ADAMTS-13) in 123 patients with connective tissue diseases (systemic lupus erythematosus and systemic sclerosis). Haematologica 2003; 88: 914–918.

23.

23 Leibovich SJ . Vasculopathy and renal injury in lupus erythematosus: does shedding of the endothelial protein C receptor play a role? Kidney Int 2005; 68: 407–408.

24.

24 Ertenli I Kiraz S Celik IC . Changes in the concentration and distribution of tissue factor pathway inhibitor in Behcet’s disease and systemic lupus erythematosus: effect on the prethrombotic state. Ann Rheum Dis 2001; 60: 1149–1151.

25.

25 Ferro D Saliola M Meroni PL . Enhanced monocyte expression of tissue factor by oxidative stress in patients with antiphospholipid antibodies: effect of antioxidant treatment. J Thromb Haemost 2003; 1: 523–531.

26.

26 Jamin C Dugue C Alard JE . Induction of endothelial cell apoptosis by the binding of anti-endothelial cell antibodies to Hsp60 in vasculitis-associated systemic autoimmune diseases. Arthritis Rheum 2005; 52: 4028–4038.

27.

27 Zheng L Sinniah R . I-Hong Hsu, S. Renal cell apoptosis and proliferation may be linked to nuclear factor-kappaB activation and expression of inducible nitric oxide synthase in patients with lupus nephritis. Hum Pathol 2006; 37: 637–647.

28.

28 Tang S Leung JC Abe K . Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo. J Clin Invest 2003; 111: 515–527.

29.

29 Yard BA Chorianopoulos E Herr D Van der Woude FJ . Regulation of endothelin 1 and transforming growth factor beta 1 production in cultured proximal tubular cells by albumin and heparan sulphate glycosaminoglycans. Nephrol Dial Transplant 2001; 16: 1769–1775.

30.

30 Tiruppathi C Naqvi T Wu Y Vogel SM Minshall RD Malik AB . Albumin mediates the transcytosis of myeloperoxidase by means of caveolae in endothelial cells. Proc Natl Acad Sci U S A. 2004; 101: 7699–7704.

31.

31 Schiffer M Bitzer M Roberts IS . Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest 2001; 108: 807–816.

32.

32 Diwakar R Pearson AD Colville-Nash P Brunskill NJ Dockrell ME . The role played by endocytosis in albumin induced secretion of TGF{beta}-1 by proximal tubular epithelial cells. Am J Physiol Renal Physiol; 2007; 292: F1464–1470.

33.

33 Kim JS Kim JG Moon MY . Transforming growth factor-beta1 regulates macrophage migration via RhoA. Blood 2006; 108: 1821–1829.

34.

34 Forino M Torregrossa R Ceol M . TGFbeta1 induces epithelial-mesenchymal transition, but not myofibroblast transdifferentiation of human kidney tubular epithelial cells in primary culture. Int J Exp Pathol 2006; 87: 197–208.

35.

35 Docherty NG O’Sullivan OE Healy DA . TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation. Am J Physiol Renal Physiol 2006; 290: F1202–F1212.

36.

36 Montinaro V Lopez A Monno R . Renal C3 synthesis in idiopathic membranous nephropathy: correlation to urinary C5b-9 excretion. Kidney Int 2000; 57: 137–146.

37.

37 Pratt JR Abe K Miyazaki M Zhou W Sacks SH . In situ localization of C3 synthesis in experimental acute renal allograft rejection. Am J Pathol 2000; 157: 825–831.

38.

38 Bao L Wang Y Chang A . Unrestricted C3 activation occurs in Crry-deficient kidneys and rapidly leads to chronic renal failure. J Am Soc Nephrol; 2007; 18: 811–822.

39.

39 Li J Deane JA Campanale NV Bertram JF Ricardo SD . Blockade of p38 mitogen-activated protein kinase and TGF-beta1/Smad signaling pathways rescues bone marrow-derived peritubular capillary endothelial cells in adriamycin-induced nephrosis. J Am Soc Nephrol 2006; 17: 2799–2811.

40.

40 Matsumoto M Tanaka T Yamamoto T . Hypoperfusion of peritubular capillaries induces chronic hypoxia before progression of tubulointerstitial injury in a progressive model of rat glomerulonephritis. J Am Soc Nephrol 2004; 15: 1574–1581.

41.

41 Hara A Wada T Furuichi K . Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis. Kidney Int 2006; 69: 1986–1995.

42.

42 Peterson KS Huang JF Zhu J . Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli. J Clin Invest 2004; 113: 1722–1733.

43.

43 Liu Y Yang J . Hepatocyte growth factor: new arsenal in the fights against renal fibrosis? Kidney Int 2006; 70: 238–240 [review].

44.

44 Herrero-Fresneda I Torras J Franquesa M . HGF gene therapy attenuates renal allograft scarring by preventing the profibrotic inflammatory-induced mechanisms. Kidney Int 2006; 70: 265–274.

45.

45 Stracke S Ernst F Jehle DR . Differentiating and proliferative effects of HGF in renal proximal tubular cells are mediated via different signalling pathways. Nephrol Dial Transplant 1998; 13: 1398–1405.

46.

46 Zhou YJ Wang JH Zhang J . Hepatocyte growth factor protects human endothelial cells against advanced glycation end products-induced apoptosis. Biochem Biophys Res Commun 2006; 344: 658–666.

47.

47 Wang X Zhou Y Kim HP . Hepatocyte growth factor protects against hypoxia/reoxygenation-induced apoptosis in endothelial cells. J Biol Chem 2004; 279: 5237–5243.

48.

48 Karihaloo A O’Rourke DA Nickel C Spokes K Cantley LG . Differential MAPK pathways utilized for HGF- and EGF-dependent renal epithelial morphogenesis. J Biol Chem 2001; 276: 9166–9173.

49.

49 Jayasankar V Woo YJ Bish LT . Gene transfer of hepatocyte growth factor attenuates postinfarction heart failure. Circulation 2003; 108(Suppl. 1): II230–II236.

50.

50 Rampino T Gregoriani M Camussi G . Hepatocyte growth factor and its receptor Met are induced in crescentic glomerulonephritis. Nephrol Dial Transplant 2005; 20: 1066–1074.

51.

51 Liu Y . Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 2006; 69: 213–217.

52.

52 Gong R Rifai A Tolbert EM Biswas P Centracchio JN Dworkin LD . Hepatocyte growth factor ameliorates renal interstitial inflammation in rat remannt kidney by modulatine tubular expression of macrophage chemoattractant protein.1 and RANTES. J Am Soc Nephrol 2004; 15: 2868–2881.

53.

53 Dai C Yang J Bastacky S Xia J Li Y Liu Y . Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice. J Am Soc Nephrol 2004; 15: 2637–2647.

54.

54 Ma H Calderon TM Fallon JT Berman JW . Hepatocyte growth factor is a survival factor for endothelial cells and is expressed in human atherosclerotic plaques. Atherosclerosis 2002; 164: 79–87.

55.

55 Gong R Rifai A Dworkin LD . Hepatocyte growth factor suppresses acute renal inflammation by inhibition of endothelial E-selectin. Kidney Int 2006; 69: 1166–1174.

56.

56 Kuroiwa T Iwasaki T Imado T Sekiguchi M Fujimoto J Sano H . Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft versus host disease. Arthritis Res Ther 2006; 8: R123.

57.

57 Capuano A Costanzi S Peluso G . Hepatocyte growth factor and transforming growth factor beta1 ratio at baseline can predict early response to cyclophosphamide in systemic lupus erythematosus nephritis. Arthritis Rheum 2006; 54: 3633–3639.

58.

58 Gagliardini E Benigni A . Role of anti-TGF-β antibodies in the treatment of renal injury. Cytokine Growth Factor Rev 2006; 17: 89–96.

59.

59 Li Y Wen X Spataro BC Hu K Dai C Liu Y . Hepatocyte growth factor is a downstream effector that mediates the antifibrotic action of peroxisome proliferator-activated receptor-gamma agonists. J Am Soc Nephrol 2006; 17: 54–65.

60.

60 Li Y Spataro BC Yang J Dai C Liu Y . 1,25-dihydroxyvitamin D inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression. Kidney Int 2005; 68: 1500–1510.

61.

61 Wen X Li Y Hu K Dai C Liu Y . Hepatocyte growth factor receptor signaling mediates the anti-fibrotic action of 9-cis-retinoic acid in glomerular mesangial cells. Am J Pathol 2005; 167: 947–957.

62.

62 Sakiyama R Fukuta K Matsumoto K . Stimulation of hepatocyte growth factor production by heparin-derived oligosaccharides. J Biochem (Tokyo) 2007; 141: 653–660.