Transcription Factor Egr-1 Regulates Glomerular Mesangial Cell Proliferation

Abstract

Increase of glomerular mesangial cells (MCs) is a prominent histopathological finding in many types of glomerulonephritis. We have shown previously that expression of the zinc-finger transcription factor, early growth response gene-1 (egr-1), is closely correlated with the proliferation of cultured MCs. To elucidate whether Egr-1 is required for MC proliferation, we inhibited serum-induced Egr-1 expression by phosphothioate-modified antisense oligonucleotides (ODNs Mesangial hypercellularity is a prominent histological characteristic of many types of human glomerular kidney disease, such as IgA nephropathy, membranoproliferative glomerulonephritis, focal glomerulosclerosis, and lupus nephritis. Growth factors leading to a proliferative response of MCs 1 may be derived from intrinsic glomerular cells or from infiltrating leukocytes or platelets. Inadequate control of MC proliferation may be an initial step leading to progressive glomerular alterations and end stage renal disease. Potentially detrimental effects of MC hypercellularity include mechanical obstruction of glomerular capillaries, increased production of proinflammatory mediators, and disturbance of production and removal of extracellular matrix proteins promoting mesangial and glomerular sclerosis.The immediate early gene, early growth response gene-1 (egr-1), encodes a 75-80-kDa transcriptional regulator that binds DNA through three zinc-finger domains (1-6). Egr-1, also known as zif 268, Krox 24, TIS 8, and NGFI-A, is rapidly and transiently induced in response to multiple mitogenic signals (7,8). The induction of Egr-1 occurs mainly at the transcriptional level (9 -11). This activation is mediated through serum response elements in the egr-1 promoter in fibroblasts and rat MCs (9, 12, 13). Egr-1 modulates specific gene expression (14 -18).So far, only a few specific biological functions can be ascribed to Egr-1. Egr-1 is involved in differentiation processes. It was shown to be essential and restrictive for differentiation of myeloblastic HL60 cells along the macrophage lineage (19). Egr-1 has been found to suppress v-sis-dependent transformation of NIH 3T3 cells (20). In addition, Egr-1 has recently also been shown to be involved in the regulation of proliferation of T lymphocytes (21) and astrocytes (22).In previous studies, we observed a very close correlation between the stimulation of MC growth and induction of egr-1 mRNA expression by mitogens such as platelet-derived growth factor, serotonin, and arginine vasopressin. Angiotensin II, which was not mitogenic for cultured rat MCs, failed to induce egr-1 mRNA expression (7). Here, we report that different antisense oligonucleotides directed against egr-1 mRNA block mitogen-induced Egr-1 expression and inhibit proliferation of cultured MCs. This indicates that Egr-1 is an important component of the mitogenic signal transduction cascade in glomerular MCs. MATERIALS AND METHODSReagents-Phosphothioate-modified antisense and sense, scrambled, or mismatched control oligodeoxynucleotides (ODNs) were fr...

Induction of early response genes in trypsin inhibitor-induced pancreatic growth

“…Deficiency in c-jun or inhibition of c-fos in mouse fibroblasts results in defect of proliferation (4,27). The induction of Egr-1 has been demonstrated to occur in a variety of proliferating cells such as the glomerular mesangial cells and beta cells (16,22). All these results from a variety of cell types demonstrate that c-jun, JunB, c-fos, ATF-3, and Egr-1 play an important role in regulating cell proliferation.…”

“…1D), and Egr-1 (Fig. 1G), which are known to be related to cell proliferation (1,6,16,22,23,34,46). Camostat feeding rapidly upregulated the expression of 17 of 18 early response genes at the mRNA level by 2.4-to 600-fold (Table 1).…”

Epidermal-growth-factor-induced proliferation of astrocytes requires Egr transcription factors

“…In fact, induction of Egr-1 gene transcription was monitored in many cell types in response to mitogens, and a direct role of Egr-1 in controlling proliferation has been proposed for astrocytes, glioma cells, glomerular mesangial cells, keratinocytes and T-cells (Perez-Castillo et al, 1993;Biesiada et al, 1996;Hofer et al, 1996;Kaufmann and Thiel, 2002;Rössler and Thiel, 2004). Egr-1 biosynthesis is strongly stimulated by activation of ERK , the protein kinase that is activated by mitogens.…”

Vascular Smooth Muscle Cell Proliferation and Regrowth after Mechanical Injury in Vitro Are. Egr-1/NGFI-A-Dependent

“…These findings indicate that antisense Egr-1 PS-ODNs are able to inhibit SMC replication in a sequence-specific manner and are consistent with the capacity of antisense PSODNs to inhibit DNA synthesis and cell proliferation despite localization in the cytoplasm. 23 Antisense Egr-1 PS-ODN inhibition of proliferation was not due to cytotoxicity. Trypan blue was still excluded by the cells after 72 hours of exposure to the PS-ODNs (data not shown).…”