Immunolocalization of fibroblast growth factor-1 (FGF-1), its receptor (FGFR-1), and fibroblast-specific protein-1 (FSP-1) in inflammatory renal disease.
BACKGROUND
The fibroblast growth factor (FGF) family has functions in development, cell proliferation, migration, and differentiation. While FGF-2 induces fibrosis, the role of FGF-1 in inflammation and fibrosis is less defined. We examined the expression of FGF-1 and FGF receptor (FGFR-1) to determine if renal diseases with varying etiologies of inflammation, including lupus nephritis (LN), acute interstitial nephritis (AIN) and acute rejection superimposed on chronic allograft nephropathy (CAN), showed varying patterns of expression. We also examined the expression of fibroblast-specific protein-1 (FSP-1), which has been linked to epithelial-mesenchymal transition (EMT) and fibrosis, to determine whether it was linked to potential profibrotic and inflammatory FGF-1 mechanisms.


METHODS
Proliferative LN (PLN) (N= 12), nonproliferative lupus nephritis (NPLN) (N= 5), AIN (N= 6), CAN (N= 4), and normal kidneys (N= 3) were studied. FGF, FGFR-1, and FSP-1 were localized by immunohistochemistry, and intensity scored on a 0 to 3+ scale. Double staining with CD68 and separate immunohistochemical staining for CD4 and CD8 with serial sections analysis were done to identify if T lymphocytes or macrophages showed staining for FGF-1 and FGFR-1 or FSP-1.


RESULTS
In normal kidneys, FGF-1 was expressed in mesangial cells (0.67 +/- 0.58), glomerular endothelial (0.67 +/- 0.58), visceral, and parietal epithelial cells (1.67 +/- 0.58). FGFR-1 showed a similar pattern of staining but also was expressed in tubular epithelium, and arterial endothelium and smooth muscle. Expression of FGF-1 was increased over normal in glomerular parenchymal cells only in CAN in podocytes (2.30 +/- 0.58 vs. 3.00 +/- 0.00) (P < 0.05) and parietal epithelial cells (1.67 +/- 0.58 vs. 2.25 +/- 0.50) (P < 0.05). Infiltrating glomerular and interstitial inflammatory cells in diseased glomeruli also expressed FGF-1 and FGFR-1. Tubular cells expressed slightly increased FGFR-1 in renal diseases vs. normal, whereas tubules remained negative for FGF-1 in diseased kidneys. FSP-1 expression was prominent in the interstitium in all kidneys with interstitial inflammation, and most prominent in CAN. Interstitial FSP-1+ cells were consistent with a myofibroblast-type morphology, and did not stain with CD-68. FSP-1 expression was closely associated with inflammatory cells expressing FGF-1 and FGFR-1. FSP-1 also showed positivity within crescents and occasional podocytes in PLN.


CONCLUSIONS
The expression of FGF-1 and FGFR-1 in infiltrating lymphocytes and macrophages, and of FGFR-1 in tubules, is supportive, but does not prove causality, of the possibility that FGF-1 might have both autocrine and paracrine functions in renal inflammation. However, the initial stimulus for renal inflammation, whether immune complex, hypersensitivity or rejection, did not alter expression patterns of FGF-1 or its receptor. The colocalization of inflammatory infiltrates with interstitial fibrosis supports the possibility of a contribution of FGF-1 for chemotaxis and associated fibrosis, further supported by interstitial FSP-1 expression closely associated with these inflammatory cells expressing FGF-1 and FGFR-1.
Rossini
Michele
M
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cheunsuchon
Boonyarit
B
Donnert
Ellen
E
Ma
Li-Jun
LJ
Thomas
James W
JW
Neilson
Eric G
EG
Fogo
Agnes B
AB
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002908:Chronic Disease; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D005355:Fibrosis; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009395:Nephritis, Interstitial / Q000378:metabolism* / Q000473:pathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D000071999:S100 Calcium-Binding Protein A4
D002135:Calcium-Binding Proteins; D000071999:S100 Calcium-Binding Protein A4; D016220:Fibroblast Growth Factor 1; C077591:S100A4 protein, human; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1