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Am J Physiol Renal Physiol 283: F1075-F1084, 2002; doi:10.1152/ajprenal.00349.2001
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Vol. 283, Issue 5, F1075-F1084, November 2002

Existence of a regulatory loop between MCP-1 and TGF-beta in glomerular immune injury

Gunter Wolf, Thomas Jocks, Gunther Zahner, Ulf Panzer, and Rolf A. K. Stahl

Division of Nephrology, Department of Medicine, University of Hamburg, 20246 Hamburg, Germany

Glomerular upregulation of monocyte chemotactic protein-1 (MCP-1), followed by an influx of monocytes resulting eventually in extracellular matrix deposition is a common sequel of many types of glomerulonephritis. However, it is not entirely clear how early expression of MCP-1 is linked to the later development of glomerulosclerosis. Because transforming growth factor-beta (TGF-beta ) is a key regulator of extracellular matrix proteins, we hypothesized that there might be a regulatory loop between early glomerular MCP-1 induction and subsequent TGF-beta expression. To avoid interference with other cytokines that may be released from infiltrating monocytes, isolated rat kidneys were perfused with a polyclonal anti-thymocyte-1 antiserum (ATS) and rat serum (RS) as a complement source to induce glomerular injury. Renal TGF-beta protein and mRNA expressions were strongly stimulated after perfusion with ATS-RS. This effect was attenuated by coperfusion with a neutralizing anti-MCP-1 but was partly mimicked by perfusion with recombinant MCP-1 protein. On the other hand, renal MCP-1 expression and production were stimulated by administration of ATS-RS. Additional perfusion with an anti-TGF-beta antibody further aggravated this increase, whereas application of recombinant TGF-beta protein reduced MCP-1 formation. Our data demonstrate an intrinsic regulatory loop in which increased MCP-1 levels stimulate TGF-beta formation in resident glomerular cells in the absence of infiltrating immune competent cells.

glomerulonephritis; chemokines; monocyte chemotactic protein-1; transforming growth factor-beta ; glomerulosclerosis; isolated perfused kidney


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