Abstract
There is increasing evidence that platelets are involved in the pathogenesis of glomerulonephritis. Intraglomerular platelets or their degradation products are observed in biopsies from patients with lupus nephritis, mesangioproliferative, membranous or IgA nephropathy. Moreover shortened platelet survival in patients with various glomerular diseases has also been described. In models of experimental glomerulonephritis, platelets may participate in glomerular injury, together with other mediators, by complex mechanisms. As extensively documented, platelets release within the glomerulus vasoactive, chemotactic and mitogenic substances that interact with a number of soluble mediators generated by renal resident or inflammatory cells and contribute to amplify glomerular injury. Thus platelet-activating factor and other platelet secretory products, polycationic macromolecules, platelet factor 4 and β-thromboglobulin, alter glomerular permeability to proteins and enhance immune-mediated glomerular injury. Platelet-derived factors, like platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ) mediate renal disease progression in experimental and human glomerulonephritis via their chemotactic activity for infiltrating leucocytes and their effect of promoting extracellular matrix synthesis by resident renal cells. In these settings increased renal expression of PDGF and TGFβ has correlated with clinical features. Specific PDGF and TGFβ inhibitors ameliorated experimental glomerular disease. A wide variety of therapies to inhibit platelet function have been employed over the years, however the results of clinical studies are controversial and do not allow conclusions to be drawn about the efficacy of anti-platelet agents in progressive renal disease. Identification of specific platelet inhibitors or interventions specific for platelet secretory products and their target cells will be crucial for understanding the exact role of platelets and their products in glomerular disease.
Similar content being viewed by others
References
Ardlie NG (1972) Mechanism of platelet aggregation and release. their possible role in vascular injury. In: Kincaid-Smith P, Mathew TH, Becker EL (eds) Glomerulonephritis. Morphology, natural history, and treatment. Wiley, New York, p 891
Cochrane CG (1971) Mechanisms involved in the deposition of immune complexes in tissues. J Exp Med 134: 75–89
Clark WF, Friesen M, Linton AL, Lindsay RM (1976) The platelets as mediator of tissue damage in immune-complex glomerulonephritis. Clin Nephrol 6: 287–289
Parbtani A, Cameron JS (1980) Platelet involvement in glomerulonephritis. In: Remuzzi G, Mecca G de Gaetano G (eds) Hemostasis, prostaglandins and renal disease. Raven, New York, p 45
Duffy JL, Cinque T, Grishman E, Churg J (1970) Intraglomerular fibrin, platelet aggregation and subendothelial deposits in lipoid nephrosis. J Clin Invest 49: 251–258
Kincaid-Smith P (1972) Coagulation and renal disease. Kidney Int 2: 183–189
Nakajima M, Hewitson TD, Mathews DC, Kincaid-Smith P (1991) Platelet-derived growth factor mesangial deposits in mesangial IgA glomerulonephritis. Nephrol Dial Transplant 6: 11–16
Mustard JF, Packham MA (1975) The role of blood and platelets in atherosclerosis and the complications of atherosclerosis. Thromb Diath Haemorrh 33: 444–456
Vermylen J, Carreras LO (1982) The process of hemostasis. In: Herman AG, Vanhoutte PM, Denolin H, Goossens A (eds) Cardiovascular pharmacology of the prostaglandins. Raven, New York, p 79
Wu X, Pippin J, Lefkowith JB (1993) Platelets and neutrophils are critical to the enhanced glomerular arachidonate metabolism in acute nephrotoxic nephritis in rats. J Clin Invest 91: 766–773
Wu X, Helfrich MH, Horton MA, Feigen LP, Lefkowith JB (1994) Fibrinogen mediates platelet-polymorphonuclear leukocyte cooperation during immune-complex glomerulonephritis in rats. J Clin Invest 94: 928–936
Israels ED, Nisli G, Paraskevas F, Israaels LG (1973) Platelet Fe receptors as a mechanism for Ag-Ab complex induced platelet injury. Thromb Diath Haemorrh 29: 434–444
Schlondorff D, Newirth P (1986) Platelet activating factor and the kidney. Am J Physiol 251: F1-F11
Moncada S, Vane JR (1979) Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 30: 293–331
Roth GJ (1992) Platelets and blood vessels: the adhesion event. Immunol Today 13: 100–105
Ware JA, Heistad DD (1993) Platelet-endothelium interactions. N Engl J Med 328: 628–635
Camussi G (1986) Potential role of platelet-activating factor in renal pathophysiology. Kidney Int 29: 469–477
Braquet P, Touqui L, Shen TY, Vargaftig BB (1987) Perspectives in platelet-activating factor research. Pharmacol Rev 39: 97–145
Camussi G, Tetta C, Deregitus C, Bussolino F, Segoloni G, Vercellone A (1982) Platelet-activating factor (PAF) in experimentally-induced rabbit acute serum sickness: role of basopbil-derived PAF in immune complex deposition. J Immunol 128: 86–94
Yoshimura A, Ideura T, Sato M, Kitaoka T, Koshikawa S (1987) The effect of platelet activating factor (PAF) on BSA nephritis of rabbits (abstract). 10th International Congress on Nephrology, London, 26–31 July, The Alden Press, Oxford, p 369
Lianos EA, Zanglis A (1990) Glomerular platelet-activating factor levels and origin in experimental glomerulonephritis. Kidney Int 37: 736–740
Bertani T, Livio M, Macconi D, Morigi M, Bisogno G, Patrono C, Remuzzi G (1987) Platelet activating factor (PAF) as a mediator of injury in nephrotoxic nephritis. Kidney Ont 31: 1248–1256
Camussi G, Tetta C, Coda R, Segoloni GP, Vercellone A (1984) Platelet-activating factor-induced loss of glomerular anionic charges. Kidney Int 25: 73–81
Perico N, Delaini F, Tagliaferri M, Abbate M, Cucchi M, Bertani T, Remuzzi G (1988) Effect of platelet-activating factor and its specific receptor antagonist on glomerular permeability to proteins in isolated perfused rat kidney. Lab Invest 58: 163–171
Perico N, Remuzzi A, Dadan J, Battaglia C, Remuzzi G (1991) Platelet-activaring factor alters glomerular barrier size selectivity for macromolecules in rats. Am J Physiol 261: F85-F90
Yoo J, Schlondorff D, Neugarten J (1990) Protective effects of specific platelet-activating factor receptor antagonists in experimental glomerulonephritis. J Pharmacol Exp Ther 256: 841–844
Stahl RAK, Thaiss F, Oberle G, Brecht HM, Schoeppe W, Wenzel U, Helmchen UM (1991) The platelet activating factor receptor antagonist WEB 2170 improves glomerular hemodynamics and morphology in a proliferative model of mesangial cell injury. J Am Soc Nephrol 2: 37–44
Baldi E, Emancipator SN, Hassan MO, Dunn MJ (1990) Platelet activating factor receptor blockade ameliorates murine systemic lupus crythematosus. Kidney Int 38: 1030–1038
Morigi M, Macconi D, Riccardi E, Boccardo P, Zilio P, Bertani T, Remuzzi G (1991) Platelet-activating factor receptor blocking reduces proteinura and improves survival in lupus autoimmune mice. J Pharmacol Exp Ther 258: 601–606
Macconi D, Noris M, Benfenati E, Quaglia R, Pagliarino G, Remuzzi G (1991) Increased urinary excretion of platelet activating factor in mice with lupus nephritis. Life Sci 48: 1429–1427
Barnes JL, Levine SP, Venkatachalam MA (1984) Binding of platelet factor four (PF4) to glomerular polyanion. Kidney Int 25: 759–765
Tetta C, Coda R, Camussi G (1985) Human platelet cationic proteins bind to rat glomeruli, induce loss of anionic charges and increase glomerular permeability. Agents Actions 16: 24–26
Barnes JL, Camussi G, Tetta C, Venkatachalam MA (1990) Glomerular localization of platelet cationic proteins after immune complex-induced platelet activation. Lab Invest 63: 755–761
Barnes JL (1993) Platelets in renal disease. In: Tetta C (ed) Immunopharmacology of the renal system. Academic Press, London, p 87
Abboud HE (1993) Growth factors in glomerulonephritis. Kidney Int 43: 252–267
Ross R (1989) Platelet-derived growth factor. Lancet I: 1179–1182
Johnson R, Iida H, Yoshimura A, Floege J, bowen-Pope DF (1992) Platelet-derived growth factor: a potentially important cytokine in glomerular disease. Kidney Int 41:590–594
Johnson RJ (1991) Platelets in inflammatory glomerular injury. Semin Nephrol 11: 276–284
Shultz PJ, DiCorleto PE, Silver BJ, Abboud HE (1988) Mesangial cell express PDGF mRNAs and proliferate in response to PDGF. Am J Physiol 255: F674-F684
Silver BJ, Jaffer FE, Abboud HE (1989) Platelet-derived growth factor (PDGF) synthesis in mesangial cells: induction by multiple peptide mitogens. Proc Natl Acad Sci US 86: 1056–1060
DiCorleto PE, Bowen-Pope DF (1983) Cultured endothelial cells produce a platelet-derived growth factor-like protein. Proc Natl Acad Sci USA 80: 1919–1923
Daniel TO, Gibbs VC, Milfay DF, Williams LT (1987) Agents that increase cAMP accumulation block endothelial c-sis induction by thrombin and transforming growth factor-β. J Biol Chem 262: 11893–11896
Lovett DH, Ryan J, Sterzel RB (1983) Stimulation of rat mesangial cell proliferation by macrophage interleukin 1. J Immunol 131: 2830–2836
Doi T, Striker LJ, Elliot SJ, Conti FG, Striker GE (1989) Insulinlike growth factor-1 is a progression factor for human mesangial cells. Am J Pathol 134: 395–404
Abboud HE (1992) Platelet-derived growth factor and mesangial cells. Kidney Int 41: 581–583
Barnes JL, Hevey KA (1990) Glomerular mesangial cell migration in response to platelet-derived growth factor. Lab Invest 62: 379–382
Barnes JL, Hevey KA (1991) Glomerular mesangial cell migration. Response to platelet secretory products. Am J Pathol 138: 859–866
Taraboletti G, Morigi M, Figliuzzi M, Giavazzi R, Zoja C, Remuzzi G (1992) Thrombospondin induces glomerular mesangial cell adhesion and migration. Lab Invest 67: 566–571
Iida H, Seifert R, Alpers CE, Gronwald RGK, Phillips PE, Pritzl P, Gordon K, Gow AM, Ross R, Bowen-Pope DF, Johnson RJ (1991) Platelet-derived growth factor (PDGF) and PDGF receptor are induced in mesangial proliferative nephritis in the rat. Proc Natl Acad Sci USA 88: 6560–6564
Johnson RJ, Raines E, Floege J, Yoshimura A, Pritzl P, Alpers CE, Ross R (1992) Inhibition of mesangial cell proliferation and matrix expression in glomerulonephritis in the rat by antibody to platelet-derived growth factor. J Exp Med 175: 1413–1416
Johnson RJ, Garcia RL, Pritzl P, Alpers CE (1990) Platelets mediate glomerular cell proliferation in immune complex nephritis induced by anti-mesangial cell antibodies in the rat. Am J Pathol 136: 369–374
Gesualdo L, Pinzani M, Floriano JJ, Hassan MO, Nagy NU, Schena FP, Emancipator SN, Abboud HE (1991) Platelet-derived growth factor expression in mesangial proliferative glomerulonep-phritis. Lab Invest 65: 160–167
Floege J, Burns MW, Alpers CE, Yoshimura A, Pritzl P, Gordon K, Seifert RA, Bowen-Pope DF, Couser EG, Johnson RJ (1992) Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int 41: 297–309
Barnes JL, Abboud HE (1993) Temporal expression of autocrine growth factors corresponds to morphological features of mesangial proliferation in habu snake venom-induced glomerulonephritis. Am J Pathol 143: 1366–1376
Roberts AB, Sporn MB, (1990) The transforming growth factors-β. In: Sporn MB, Roberts AB (eds) Handbook of experimental pharmacology, peptide growth factors and their receptors, vol 95/I). Springer, Berlin Heidelberg New York, p 419
Wakefield LM, Smith DM, Broz S, Jackson M, Levinson AD, Sporn MB (1989) Recombinant TGF-β1 is synthesized as a two component latent complex that shares some structural features with the native platelet latent TGF-β1 complex Growth Factors 1: 203–218
Kanzaki T, Olofsson A, Moren A, Wernstedt C, Hellman U, Miyazono K, Claesson-Welsh L, Heldin C-H (1990) TGF-β1 binding protein: a component of the large latent complex of TGF-β1 with multiple repeat sequences. Cell 61: 1051–1061
Border WA, Ruoslahti E (1992) Transforming growth factor-β in disease: the dark side of tissue repair. J Clin Invest 90: 1–7
Wahl SM (1994) Transforming growth factor β: the good, the bad, and the ugly. J Exp Med 180: 1587–1590
Border WA, Noble NA (1994) Transforming growth factor β in tissue fibrosis. N Engl J Med 331: 1286–1292
Massague J (1990) The transforming growth factor-β family. Annu Rev Cell Biol 6: 597–641
MacKay K, Kondaiah P, Danielpour D, Austin HA III, Brown PD (1990) Expression of transforming growth factor-β1 and β2 in rat glomeruli. Kidney Int 38: 1095–1100
Kaname S, Uchida S, Ogata E, Kurokawa K (1992) Autocrine secretion of transforming growth factor-β in cultured rat mesanglal cells. Kidney Int 42: 1319–1327
Jaffer F, Saunders C, Shultz P, Throckmorton D, Weinshell E, Abboud HE (1989) Regulation of mesangial cell growth by polypeptide mitogens. Am J Pathol 135: 261–269
MacKay K, Striker LJ, Stauffer JW, Doi T, Agodoa LY, Striker GE (1989) Transforming growth factor-β: murine glomerular receptors and responses of isolated glomerular cells. J Clin Invest 83: 1160–1167
Border WA, Okuda S, Languino LR, Ruoslahti E (1990) Transforming growth factor-β regulates production of proteoglycans by mesangial cells. Kidney Int 37: 689–695
Nakamura T, Miller D, Ruoslahti E, Border WA (1992) Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-β1. Kidney Int 41: 1213–1221
Okuda S, Languino LR, Ruoslahti E, Border WA (1990) Elevated expression of transforming growth factor-β and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix. J Clin Invest 86: 453–462
Border WA, Okuda S, Lauguino L, Sporn MB, Ruoslahti E (1990) Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1. Nature 346: 371–374
Border WA, Noble NA, Yamamoto T, Harper J, Yamaguchi Y, Pierschbacher MD, Ruoslahti E (1992) Natural inhibitor of transforming growth factor-β protects against scarring in expenmental kidney disease. Nature 360: 361–364
Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA (1993) Expression of transforming growth factor β is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci USA 90: 1814–1818
Tamaki K, Okuda S, Audo T, Iwamoto T, Nakayama M, Fujishima M (1994) TGF-β1 in glomerulosclerosis and interstitial fibrosis of Adriamycin nephropathy. Kidney Int 45: 525–536
Isaka Y, Fujiwara Y, Ueda N, Kaneda Y, Kamada T, Imai E (1993) Glomerulosclerosis induced by in vivo transfection of transforming growth factor-β or platelet-derived growth factor gene into the rat kidney. J Clin Invest 92: 2597–2601
Kincaid-Smith P (1972) The treatment of chronic mesangiocapillary (membranoproliferative) glomerulonephritis with impaired renal function. Med J Aust 2: 587–592
Tiller DJ, Clarkson AR, Mathew T (1981) A prospective randomized trial in the use of cyclophosphamide, dipyridamole and warfarin in membranous and mesangio capillary glomerulonephritis. In: Zurukzoglu W, Papadimitriou M, Sion M (eds) Eighth International Congress of Nephrology: advances in basis and clinical nephrology. Karger, Basel, p 345
Cattran D, Charron R, Cardella C (1981) Controlled trial in mesangio-capillary glomerulonephritis (MCGN) (abstract). In: Zurukzoglu W, Papadimitriou M, Sion M (eds) Eighth International Congress of Nephrology: advances in basic and clinical nephrology. Karger, Basel, p 287
Zimmerman SW, Moorthy AV, Dreher WH, Friedman A, Varanasi U (1983) Prospective trial of warfarin and dipyridamole in patients with membranoproliferative glomerulonephritis. Am J Med 75: 920–927
Donadio JV Jr, Anderson CF, Mitchell JC, Holley KE, Ilstrupd M, Fuster V, Chesebro JH (1984) Membranoproliferative glomerulonephritis. A prospective clinical trial of platelet-inhibitor therapy. N Engl J Med 310: 1421–1426
Levenson DJ, Simmons LE, Brenner BM (1982) Arachidonic acid metabolism, prostaglandins and the kidney. Am J Med 72: 354–374
Ciabattoni G, Cinotti GA, Pierucci A, Simonetti BM, Manzi M, Pugliese F, Barsotti P, Pecci G, Taggi F, Patrono C (1984) Effect of sulindac and ibuprofen in patienst with chronic glomerular disease. Evidence for the dependence of renal function on prostacyclin. N Engl J Med 310: 279–283
Grekas D, Alivanis P, Kalekou H, Syrganis C, Tourkantonis A (1987) Are antiplatelet agents of value in the treatment of chronic glomerular disease? Nephrol Transplant 2: 377–379
Bruno JJ (1983) The mechanisms of action of ticlopidine. Thromb Res [Suppl] 4: 59–67
Iovine C, D'Avenia V, Turco S, Mattioli PL, Di Minno G (1984) Ex vivo effects of ticlopidine on human platelets: inhibition of fibrinogen binding by a mechanism independent of thromboxane formation. Agents Actions [Suppl] 15: 105
Izumino K, Iida H, Asaka M, Mizumura Y, Sasayama S (1986) Effect of the antiplatelet agents ticlopidine and dipyridamole on experimental immune complex glomerulonephritis in rats. Nephron 43: 56–61
Izumino K, Iida H, Asaka M, Sasayama S (1987) Effect of the antiplatelet agents ticlopidine and dipyridamole on nephrotoxic serum nephritis in rats. Nephron 45: 306–310
Zoja C, Perico N, Bergamelli A, Pasini M, Morigi M, Dadan J, Belloni A, Bertani T, Remuzzi G (1990) Ticlopidine prevents renal disease progression in rats with reduced renal mass. Kidney Int 37: 934–942
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Zoja, C., Remuzzi, G. Role of platelets in progressive glomerular diseases. Pediatr Nephrol 9, 495–502 (1995). https://doi.org/10.1007/BF00866739
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00866739