In situ hybridization of connective tissue growth factor mRNA in IgA nephropathy

Connective tissue growth factor (CTGF) is a member of the new family of growth regulators. It plays an important role of the pathogenesis of mesangial matrix accumulation and progressive glomerulosclerosis in IgA nephropathy (IgAN).
We investigated the expression and localization of CTGF mRNA in renal tissues of patients with IgAN and normal human kidneys (NHK), using in situ hybridization with digoxigenin-labelled oligonucleotide. Open renal biopsy tissues were obtained from 16 patients with IgAN. The renal pathology was categorized into four grades by light microscopic findings. The expression level of CTGF mRNA was quantified by counting all nuclei, as well as nuclei surrounded by CTGF mRNA-positive cytoplasm in randomly selected non-sclerotic glomeruli and expressing the results as the percentage of total cells.
Connective tissue growth factor mRNA was mainly expressed in glomerular mesangial and epithelial cells in both IgAN and NHK, and cells of Bowman's capsule. In IgAN, CTGF mRNA-positive cells were increased in tubulointerstitial fibrotic areas. The percentage of positive cells for CTGF mRNA was significantly higher in IgAN than in NHK. The percentage of positive cells for CTGF mRNA in each IgAN grade was significantly higher than that in NHK. Furthermore, the percentage of positive cells for CTGF mRNA was significantly greater in IgAN with moderate mesangial proliferative lesions (grade 2, grade 3) than in IgAN with mild mesangial proliferative lesions.
Our study suggests that CTGF may play an important role in the development and progression of glomerulosclerosis and tubulointerstitial fibrosis in IgAN.     

Glomerular expression of connective tissue growth factor mRNA in various renal diseases

SUMMARY:   Connective tissue growth factor (CTGF) is a cysteine-rich member of a new family of growth regulators. It is an important factor in the pathogenesis of mesangial matrix accumulation and progressive glomerulosclerosis. The present study was designed to elucidate the role of CTGF in diabetic nephropathy (DN), immunoglobulin A nephropathy (IgA-N), membranous nephropathy (MN), and minimal change nephrotic syndrome (MCNS). We evaluated the expression and localization of CTGF mRNA in surgically excised renal tissue samples from 10 patients with DN, 10 with IgA-N, 10 with MN, 10 with MCNS, and 10 normal human kidney (NHK) tissue samples, by using high-resolution in situ hybridization with digoxigenin-labelled oligonucleotide. To quantify CTGF mRNA expression, we counted all nuclei, and nuclei surrounded by CTGF-positive cytoplasm, in at least 10 randomly selected cross-sections of non-sclerotic glomeruli, and expressed the results as a percentage of total glomerular cells. In all glomeruli, CTGF mRNA was expressed mainly in glomerular intrinsic cells, including glomerular mesangial and epithelial cells and some cells of Bowman's capsule. The percentage of cells positive for CTGF mRNA was significantly higher in DN and IgA-N than in MN, MCNS and NHK. However, there was no significant difference in the percentage of CTGF mRNA-positive cells between DN and IgA-N. Our study indicates that CTGF may play an important role in the development and progression of glomerulosclerosis in DN and IgA-N, which are both accompanied by mesangial matrix expansion and comprise two major causes of end-stage renal failure.     

Localization of connective tissue growth factor mRNA in human diabetic nephropathy by in situ hybridization

Background. Progressive expansion of the mesangial matrix is one of the most characteristic histological features of diabetic nephropathy (DN). Connective tissue growth factor (CTGF) is an important factor in the pathogenesis of mesangial matrix expansion and progressive glomerulosclerosis. Methods. To evaluate the expression and localization of CTGF mRNA in the renal tissues of 23 patients with DN and in normal human kidney (NHK), high-resolution in situ hybridization, using a digoxigenin-labeled oligonucleotide, was performed. The patients with DN were classified into three groups based on the histopathological severity of the DN: mild (grade I; n = 9), moderate (grade II; n = 10), and severe (grade III; n = 4). Mesangial expansion and tubulointerstitial injury were evaluated histologically. To quantitate the expression of CTGF mRNA, all nuclei as well as nuclei surrounded by CTGF-positive cytoplasm, in at least ten randomly selected cross-sections of nonsclerotic glomeruli were counted, and the results were expressed as a percentage of the total number of glomerular cells. Results. In both DN and NHK, CTGF mRNA was expressed mainly in intrinsic glomerular cells, including glomerular mesangial cells, epithelial cells and cells of Bowman's capsule. In the tubulointerstitial area, some tubules, particularly atrophic tubules, and some infiltrating cells in DN, were positively stained for CTGF mRNA, especially in DN grade III. The percentage of CTGF mRNA-positive cells was significantly higher in DN than in NHK, and the percentage of these cells was higher in grades I and II DN than in grade III DN. Conclusions. Our results suggest that the expression of CTGF mRNA may be associated with the development and progression of human diabetic nephropathy. Received: April 3, 2001 / Accepted: October 20, 2001     

Expression of megsin mRNA, a novel mesangium-predominant gene, in the renal tissues of various glomerular diseases

Mesangial cells play an important role in maintaining a structure and function of the glomerulus and in the pathogenesis of glomerular diseases. Recently, we discovered a new mesangium-predominant gene termed "megsin." Megsin is a novel protein that belongs to the serine protease inhibitor (serpin) superfamily. To elucidate the pathophysiologic role of megsin in the kidney, the expression and localization of megsin mRNA in renal tissues of patients with IgA nephropathy (IgA-N), diabetic nephropathy (DN), minimal change nephrotic syndrome (MCNS), membranous nephropathy (MN), and normal human kidney (NHK) was evaluated by in situ hybridization using digoxigenin-labeled oligonucleotide. Individual cells positive for megsin mRNA were observed only in glomeruli in all renal tissues. Their localization coincided with those of mesangial cells. The percentage of positive cells for megsin mRNA in total glomerular cells was significantly greater in IgA-N than in MCNS, MN, and NHK. It was also significantly greater in DN than in MCNS and NHK. In IgA-N, the percentage of megsin mRNA-positive cells was greater in tissues from those with mesangial cell proliferation and slightly mesangial matrix expansion (periodic acid-Schiff-positive area in the total glomerulus area, <30%; cell number in mesangial matrix area, >30; assessed in cross-sections through their vascular poles) than in tissues from those with severe mesangial matrix expansion (periodic acid-Schiff-positive area in total glomerulus area, >30%; cell number in mesangial matrix area, <30). In conclusion, megsin mRNA was predominantly expressed in glomerular mesangial cells in all renal tissues. The expression of megsin mRNA was upregulated in IgA-N and DN, both of which are diseases accompanied with mesangial cell proliferation and/or mesangial matrix expansion. These data suggest a link of megsin expression to the pathogenesis of IgA-N and DN, two major causes of end-stage renal failure.     

Glomerular expression of platelet-derived growth factor (PDGF)-A, -B chain and PDGF receptor-Α, -Β in human diabetic nephropathy

Background Mesangial expansion is thought to be a major cause of diabetic nephropathy (DN). Platelet-derived growth factor (PDGF) plays an important role in the production of extracellular matrix proteins in renal diseases. The present study was designed to determine the expression of PDGF and PDGF receptor (PDGFR) mRNA in the renal tissues of type 2 diabetic patients with DN.Methods We examined open renal biopsies of 20 type 2 diabetic patients with DN, and 10 normal human kidneys (NHK). Histopathologically, the severity of DN was classified as grade I (DN I, n = 10; mild mesangial expansion) or grade II (DN II, n = 10; moderate mesangial expansion). We evaluated the expression and localization of PDGF-A, -B, and PDGFR-, - using in situ hybridization, and quantified PDGF and PDGFR mRNA expression by counting all nuclei, and nuclei surrounded by PDGF-positive cytoplasm and PDGFR-positive cytoplasm, in at least ten randomly selected cross-sections of nonsclerotic glomeruli.Results In all glomeruli, PDGF and PDGFR mRNAs were expressed mainly in glomerular resident cells, predominantly glomerular mesangial and epithelial cells. The percentages of cells positive for PDGF-A and PDGFR- mRNA in DN were similar to those in NHK. In contrast, the percentages of PDGF-B and PDGFR- mRNA-positive cells in DN were significantly higher than those in NHK, and were significantly higher in DN I than in DN II. The percentages of cells positive for PDGF-B correlated with the PDGFR- mRNA level.Conclusions Our results suggest that the expression of PDGF-B and PDGFR- is an important factor in histologically early glomerular lesions of DN.     

Changes in urinary and serum concentrations of macrophage-colony stimulating factor (M-CSF) in patients with renal diseases

Background. The infiltration of monocytes/macrophages into renal tissues is a typical feature of progressive renal diseases. Macrophage-colony stimulating factor (M-CSF) is one of the cytokines that are required for the activation of macrophages. It was previously reported that the glomerular expression of M-CSF was increased in patients with mesangial proliferative glomerulonephritis and that the urinary and serum M-CSF concentrations were increased in IgA nephropathy. In this study, we measured the urinary and serum M-CSF concentrations in patients with renal diseases to elucidate the role of M-CSF and macrophages in the progression of renal diseases. Methods. We examined urinary and serum M-CSF concentrations in patients with IgA nephropathy (IgA-N), lupus nephritis (LN), minimal change nephrotic syndrome (MCNS), and membranous nephropathy (MN), and in normal controls. The M-CSF concentrations were compared with the clinical parameters and the histological changes. These concentrations were also compared with the number of glomerular macrophages in the IgA-N group. In addition, the effects of prednisolone therapy on the M-CSF concentrations were examined in the patients with IgA-N. Results. Urinary and serum M-CSF concentrations were increased in the severe IgA-N group, the severe LN group, and the MCNS group (nephrotic) compared with concentrations in the control group. Urinary and serum M-CSF concentrations were correlated with the degree of proteinuria, mesangial proliferation, and the number of glomerular macrophages in IgA-N and LN. In addition, the urinary and serum M-CSF concentrations were decreased with prednisolone therapy in the patients with IgA-N. Conclusions. Urinary and serum M-CSF concentrations were elevated in patients with severe stage of mesangial proliferative glomerulonephritis and were correlated with the amount of urinary protein excretion, mesangial proliferation, and glomerular macrophage infiltration. Urinary and serum M-CSF concentrations may be useful markers with which to assess the extent of glomerular changes in mesangial proliferative glomerulonephritis. Received: August 20, 2001 / Accepted: January 8, 2002     

Glomerular expression of CTGF, TGF-beta 1 and type IV collagen in diabetic nephropathy

BACKGROUND: In development of progressive extracellular matrix accumulation, connective tissue growth factor (CTGF) may act as a downstream mediator of transforming growth factor-beta 1 (TGF-beta 1). However, the association and the correlation of these cytokines and extracellular matrix accumulation in human diabetic nephropathy (DN) is not fully understood. METHODS: To explore the possible involvement of TGF-beta 1 and CTGF in extracellular matrix accumulation in DN, high-resolution in situ hybridization with digoxigenin-labeled antisense oligonucleotides to CTGF, TGF-beta 1 and type IV collagen mRNAs were performed in DN and in histologically normal human kidney (NHK). To quantify expression of each mRNA, the fraction of all nuclear cells that were positively stained in the cytoplasm was determined in at least 10 randomly selected cross-sections of nonsclerotic glomeruli. RESULTS: Both in DN and in NHK, CTGF, TGF-beta 1 and type IV collagen mRNAs were mainly expressed by glomerular mesangial, visceral epithelial and parietal epithelial cells. The percentages of positive glomerular resident cells were significantly higher for each mRNA in DN compared with NHK. Especially, the expression of CTGF mRNA was also notably increased in case of DN with only mild histopathologic lesions. The extent of expression of each mRNA was significantly correlated to that of each other mRNA examined. CONCLUSION: Our study indicated that CTGF and TGF-beta may play an important role in glomerular histopathologic change in DN.     

In-situ hybridization studies of protein kinase C α and β I isoforms in human diabetic nephropathy

Background. Hyperglycemia is the most important contributor to the development of diabetic nephropathy (DN). The activation of protein kinase C (PKC) caused by hyperglycemia is implicated in the pathogenesis of DN. PKC, which comprises a family of enzymes, plays a role in many signal transduction pathways and is involved in the regulation of cell growth and differentiation. However, the precise role of PKC in the progression of human DN is not fully understood. Methods. To evaluate the pathological role of PKC in DN, we examined the mRNA expression levels of PKC α and PKC β I isoforms in normal renal tissues and in renal tissues affected by DN. Tissues from open renal biopsies were obtained from 20 type 2 diabetic patients with DN. The expression levels of PKC α and PKC β I mRNA in kidneys with DN and in normal human kidney (NHK) were evaluated by in-situ hybridization, using digoxigenin-labeled oligonucleotide probes. Results. Cells positive for PKC α and β I mRNA were mainly observed in glomeruli, and some mRNA was also detected in the tubulointerstitium. The percentages of glomerular cells positive for PKC α and β I mRNA were higher in kidneys with DN than in NHK. In the glomeruli of kidneys with DN, the percentage of cells positive for PKC β I mRNA, but not the percentage of cells positive for PKC α mRNA, tended to be decreased with the degree of mesangial expansion. Conclusions. Our results suggest that the expression of mRNA for PKC α and/or β I may be associated with the progression of DN. Received: March 26, 2001 / Accepted: September 17, 2001     

Renal pathology patterns in type II diabetes mellitus: relationship with retinopathy

Background. The glomerular and retinal vessels are both affected in patients with type I and type II diabetes mellitus. However, the prevalence of the nodular form of diabetic glomerular sclerosis (Kimmelstiel-Wilson lesion) and other forms of glomerular pathology including diffuse mesangial sclerosis and their clinical correlates in type II diabetes are less well known. In addition, although recent studies have suggested that non-diabetic glomerular disease was a common cause of proteinuria in type II diabetes, the prevalence of other disease is unknown. The literature on this subject is clouded by clinical bias regarding patients with diabetes who undergo renal biopsy. Methods. Glomerular and retinal pathology and clinical correlates were studied in 36 patients enrolled in a prospective clinical trial of patients with type II diabetes mellitus, proteinuria, renal insufficiency, and hypertension. Results. Seventeen biopsies had diabetic glomerular sclerosis with Kimmelstiel-Wilson nodules; 15 biopsies had glomerular changes characteristic of the diabetic state including enlarged glomeruli and an increase in mesangial matrix without Kimmelstiel-Wilson nodules (mesangial sclerosis lesion); and two had other primary glomerular diseases (IgA and membranous nephropathy). Patients with Kimmelstiel-Wilson nodules had elevated serum creatinines compared to patients with mesangial sclerosis lesions, but there were no other significant differences. Patients with Kimmelstiel-Wilson nodules had more severe overall retinopathy than those with mesangial sclerosis lesions (P=0.0043): six of seven with proliferative retinopathy had Kimmelstiel-Wilson nodules, and seven of the eight patients without retinopathy had mesangial sclerosis lesions. Conclusions. The two discrete patterns of glomerular pathology and the correlation between diabetic retinopathy and the Kimmelstiel-Wilson lesion but not the mesangial sclerosis lesion suggest that the Kimmelstiel-Wilson and mesangial sclerosis lesions of diabetic glomerulosclerosis are caused by different pathogenetic mechanisms. In this study, diabetic glomerulosclerosis was responsible for the clinical renal abnormalities in 94% of patients with type II diabetes mellitus. Keywords: diabetes mellitus; glomerulopathy; Kimmelstiel-Wilson; retinopathy; type II; renal failure      

Renal in situ hybridization studies of extracellular matrix related molecules in type 1 diabetes mellitus

BACKGROUND/AIM: Progressive expansion of mesangial matrix and glomerular basement membrane thickening represent alterations in the balance between synthesis and degradation of glomerular extracellular matrix (ECM) protein and are hallmarks of diabetic nephropathy. In order to elucidate the basis for this imbalance between the synthesis and the degradation of ECM in renal tissues from patients of type 1 diabetes mellitus (type 1D) with diabetic nephropathy (DN), we examined the expression of alpha1 chain of type IV collagen (IV-C), matrix metalloproteinase-2 and -3 (MMP-2, MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and beta-actin mRNA using a high-resolution in situ hybridization with digoxigenin-labeled oligonucleotide. METHODS: Patients were divided into two groups based on both of degree of mesangial expansion using electron microscopic point counting morphometric methods and duration of type 1D: 7 'fast-track' patients were selected for their very rapid development of DN structural changes and 8 'slow-track' patients for their very slow development of DN structural changes. Seven normal human kidney (NHK) tissues were used as controls. RESULTS: Positive cells for each mRNA were observed in glomerular resident cells, including glomerular mesangial, epithelial and endothelial cells and cells of Bowman's capsule. The percentage of glomerular cells positive for IV-C, MMP-2 and MMP-3 mRNA was significantly greater in the 'slow-track' vs. 'fast-track' patients. No significant differences in percentage positive cells was seen for beta-actin mRNA. Furthermore, to elucidate the total number of positive cells per glomerulus for each mRNA, we estimated total cell number of glomerulus using morphometric techniques on light microscopy tissues. The total cell number per glomerulus was significantly greater in 'fast-track' than that in 'slow-track' patients and NHK. The total number of positive cells per glomerulus for MMP-2 in NHK was significantly greater than that in 'slow-track' and 'fast-track' patients. CONCLUSIONS: Thus, IV-C, MMP-2, MMP-3 and TIMP-1 mRNA are expressed in resident glomerular cells in renal tissues from NHK and type 1D. Glomerular alterations in these in situ mRNA expressions sufficient to explain ECM accumulation and DN risk were not uncovered. These largely negative results could be due to methodologic quantitative imprecision or could indicate that post-translational differences account for ECM imbalance in DN. However, these studies make it clear that unraveling the nature of the ECM production/removal imbalance in DN will require careful consideration of alterations in glomerular cell number.     

Intrarenal synthesis of IL-6 in IgA nephropathy

Summary: Recent in vitro studies have shown the synthesis of interleukin-6 (IL-6) in glomerular mesangial and epithelial cells, and suggested the involvement of IL-6 in mesangial proliferative glomerulonephritis. However, the expression site of IL-6 mRNA in renal tissue of IgA nephropathy (IgAN), the most common chronic mesangial proliferative glomerulonephritis, remains obscure. to localize IL-6 mRNA in renal biopsy specimens of IgAN, we used nonradioactive in situ hybridization (ISH) developed in our laboratory, sensitive in detecting individual cells positive for a specific mRNA. In some sections, periodic acid-Schiff staining was performed after ISH in order to identify the topographical relation between IL-6 mRNA positive cells and glomerular basement membrane and mesangial area. In situ hybridization for IL-6 mRNA and immunohistochemistry for CD3 and CD68, markers for lymphocytes and monocytes, respectively, were also performed on serial sections to examine the contribution of infiltrated mononuclear cells to cells positive for IL-6 mRNA in glomeruli. Glomerular resident cells, including glomerular mesangial and epithelial cells and cells of Bowman's capsule, as well as tubular epithelial cells and infiltrated mononuclear cells expressed IL-6 mRNA. We also compared the localization of IL-6 mRNA and protein and showed different distribution between the gene product and protein. the expression of IL-6 mRNA correlated with the degree of mesangial cell proliferation and tubulointerstitial changes. Our results indicate that IL-6 is synthesized in renal tissues of IgAN and suggest that the increased IL-6 expression may be important in the pathogenesis of IgAN.     

Roles of connective tissue growth factor and prostanoids in early streptozotocin-induced diabetic rat kidney: the effect of aspirin treatment

Background. Connective tissue growth factor (CTGF) is a cysteine-rich growth factor induced by transforming growth factor-β (TGF-β) and is thought to play a critical role in TGF-β-stimulated extracellular matrix accumulation. To explore its involvement in early diabetic nephropathy, we investigated the time course of CTGF gene expression and its regulation in streptozotocin (STZ)-induced diabetic rat kidney. Methods. Northern blot analysis for CTGF, TGF-β, and fibronectin expression was performed in the glomeruli of STZ-induced diabetic rats from 3 days to 12 weeks after the induction of diabetes, together with histological examination. To investigate the role of prostanoids in this process, aspirin was administered in one group of diabetic rats. Furthermore, CTGF expression was analyzed in rat mesangial cells cultured under high-glucose conditions. Results. Glomerular expression of CTGF and TGF-β1 mRNA was coordinately upregulated as early as day 3, followed by fibronectin induction and mesangial matrix accumulation. Chronic aspirin treatment in diabetic rats significantly attenuated mesangial expansion, and effectively suppressed CTGF induction, as well as inhibiting the upregulation of TGF-β1 and fibronectin expression. In cultured mesangial cells, aspirin treatment abolished high glucose-stimulated CTGF upregulation. Conclusions. These results indicate that CTGF expressed in the glomeruli is upregulated in the early stage of STZ-induced diabetic nephropathy in rats, and could be a critical mediator of the development of diabetic glomerulosclerosis. In addition, the modulatory effects of aspirin during this process suggest a role of the cyclooxygenase pathway in the progression of diabetic nephropathy. Received: March 5, 2002 / Accepted: December 6, 2002 Acknowledgments We thank Ms. A. Wada, Ms. J. Nakamura, and Ms. Y. Oki for technical assistance, and Ms. S. Doi and Ms. A. Sonoda for secretarial assistance. This work was supported in part by research grants from the Japanese Ministry of Education, Science, Sports and Culture; the Japanese Ministry of Health and Welfare; “Research for the Future (RFTF)” of the Japan Society for the Promotion of Science; the Ono Foundation for Medical Research; the Smoking Research Foundation; and the Salt Science Research Foundation. Correspondence to:M. Mukoyama     

Synchronous expression of contractile proteins in mesangial cells and interstitial cells in IgA nephropathy

Background. Phenotypic changes in glomerular mesangial cells and interstitial cells are considered to be closely associated with the progression of glomerulosclerosis and renal fibrosis in IgA nephropathy. To further evaluate the relevance of phenotypic changes, we examined the expression of four different contractile proteins as markers of the phenotypic changes. Methods. The expression of nonmuscle myosin heavy chain isoform (SMemb), α-smooth muscle actin (α-SMA), caldesmon (CaD), and tropomyosin (TM) was evaluated by indirect immunofluorescent studies in renal biopsy specimens from 21 patients with IgA nephropathy. The relationships with the histological parameters and clinical parameters were analyzed. Results. Pronounced expression (score of 2 or more) of contractile proteins was observed in the majority of the patients (57%–90%) compared with controls. There was no significant relationship between the glomerular expression score of any contractile protein and the proliferation index or sclerotic index. Daily urinary protein excretion in the group expressing low levels of caldesmon in the glomerulus was significantly lower than that in the group expressing high levels (P < 0.05). There were significant correlations among the glomerular expressions of these contractile proteins, except for TM (P < 0.05). All contractile proteins were expressed in tubulointerstitial lesions, and only SMemb expression was detected in tubular epithelial cells. The interstitial scores of all contractile proteins increased in parallel with the degree of tubulointerstitial lesion (P < 0.05). Conclusions. Contractile proteins appeared to be coordinately expressed in the glomerulus and the interstitium in IgA nephropathy, which may reflect the mechanical stress involved with glomerulonephritis. Received: December 21, 1998 / Accepted: March 1, 1999     

补肾通络方对rIL-1β诱导的大鼠肾小球系膜细胞增殖及TGF-β_1、CTGF的影响

目的：研究补肾通络方含药血浆对重组大鼠白细胞介素-1β（r IL-1β）干预的大鼠肾小球系膜细胞（GMCs）增殖与TGF-β1和CTGF表达的影响,以探讨补肾通络方抗肾脏纤维化的分子作用机制。方法：体外培养GMCs,制备补肾通络方含药血浆,用白细胞介素对GMCs进行干预,MTT比色法检测GMCs增殖、ELISA检测TGF-β1蛋白表达,RT-PCR检测CTGF mRNA的表达。结果：与空白对照组比较,白细胞介素能诱导GMCs的增殖、促TGF-β1生成、上调CTGF表达;补肾通络方含药血浆能下调由白细胞介素介导的GMCs增殖、TGF-β1蛋白和CTGF mRNA的表达量,与白细胞介素组比差异有统计学意义（P〈0.01）,且呈时间依赖性。结论：补肾通络方抗肾脏纤维化作用与抑制TGF-β1和CTGF的表达,调节GMCs的功能密切相关。     

Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis

Transforming growth factor beta (TGF-beta) is a pivotal driver of glomerulosclerosis and tubulointerstitial fibrosis in renal diseases. Because TGF-beta also plays important anti-inflammatory and antiproliferative roles in mammalian systems, there has been a recent drive to elucidate downstream mediators of TGF-beta's pro-fibrotic effects with the ultimate goal of developing new anti-fibrotic strategies for treatment of chronic diseases. Connective tissue growth factor (CTGF) belongs to the CCN family of immediate early response genes. Several lines of evidence suggest that CTGF is an important pro-fibrotic molecule in renal disease and that CTGF contributes to TGF-beta bioactivity in this setting. CTGF expression is increased in the glomeruli and tubulointerstium in a variety of renal disease in association with scarring and sclerosis of renal parenchyma. In model systems in vitro, mesangial cell CTGF expression is induced by high extracellular glucose, cyclic mechanical strain and TGF-beta. Recombinant human CTGF augments the production of fibronectin and type IV collagen by mesangial cells and the effects of high glucose on mesangial cell CTGF expression and matrix production are attenuated, in part, by anti-TGF-beta antibody. In aggregate, these observations identify CTGF as an attractive therapeutic target in fibrotic renal diseases.