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Localization of fibroblast growth factor-2 (basic FGF) and FGF receptor-1 in adult human kidney.BackgroundThe expression pattern of fibroblast growth factor-2 (FGF-2; basic FGF), a pleiotrophic growth factor, as well as one of its receptors (FGFR1), in the kidney is highly controversial.MethodsUsing an approach that combines multiple antibodies for immunohistochemistry and correlative in situ hybridization, we assessed the intrarenal expression of both FGF-2 and FGFR1 in 13 specimens of adult kidney removed during tumor nephrectomy.ResultsThe FGF-2 expression pattern in the kidneys as detected by immunohistochemistry was variable and depended on the antibody used. The most consistent expression of FGF-2 protein was demonstrated in glomerular parietal epithelial cells, tubular cells (mainly of the distal nephron), as well as arterial endothelial cells. These locations also corresponded to areas of FGF-2 mRNA expression. Additionally, by immunohistochemistry, FGF-2 protein was detected in arterial smooth muscle cells and occasional podocytes. The expression of FGFR1 protein and mRNA was most consistently present in tubular cells of the distal nephron and in vascular smooth muscle cells. In situ hybridization, but not immunohistochemistry, also suggested FGFR1 expression in cells that could not be precisely identified within the glomerular tuft as well as some interstitial cells.ConclusionThese data suggest potential autocrine and paracrine pathways within the FGF-2 system, particularly within the vascular walls and in the distal nephron, and thereby provide information for further mechanistic understanding of the role of the FGF-2 system in human renal disease.

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Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10−11) and C1GALT1C1 (rs5910940, P = 2.7 x 10−8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.