Abstract. Ghrelin is a novel hormone that possesses growth hormone (GH)-releasing, cardiovascular, and metabolic activities. Ghrelin is a unique acylated polypeptide, and the naked peptide, desacyl ghrelin, does not have the activity. This study examines plasma ghrelin concentrations in 41 patients with mild to severe renal diseases.

Ghrelin is a novel growth hormone-releasing peptide with a unique acylated structure. Here we reveal that preproghrelin gene is expressed in the mouse kidney and glomerulus. We also show by reverse-phase high performance liquid chromatography coupled with radioimmunoassay that the mouse kidney does produce ghrelin. The ghrelin immunoreactivity in the mouse kidney is 6.79 þ 0.48 fmol/mg (n = 5), which is much more abundant than that in the mouse plasma of 0.339 þ 0.029 fmol/W Wl (n = 6). Furthermore, prepro-ghrelin gene is expressed in cultured rat mesangial cells, fibroblast-like NRK-49F cells and mouse podocytes, but not in rat epithelial cell-like NRK-52E cells. Ghrelin receptor gene is also expressed in the rat kidney. These findings demonstrate that the kidney, glomerulus and renal cells express prepro-ghrelin gene and ghrelin is produced locally in the kidney, and suggest the endocrine and/or paracrine roles of ghrelin in the kidney. ß

Connective tissue growth factor (CTGF) is one of the candidate factors mediating downstream events of transforming growth factor-β (TGF-β), but its role in fibrogenic properties of TGF-β and in tubulointerstitial fibrosis has not yet been clarified. Using unilateral ureteral obstruction (UUO) in rats, we analyzed gene expression of TGF-β1, CTGF, and fibronectin. We further investigated the effect of blockade of endogenous CTGF on TGF-β-induced fibronectin expression in cultured rat renal fibroblasts by antisense oligodeoxynucleotide (ODN) treatment. After UUO, CTGF mRNA expression in the obstructed kidney was significantly upregulated subsequent to TGF-β1, followed by marked induction of fibronectin mRNA. By in situ hybridization, CTGF mRNA was detected mainly in the interstitial fibrotic areas and tubular epithelial cells as well as in parietal glomerular epithelial cells in the obstructed kidney. The interstitial cells expressing CTGF mRNA were also positive for α-smooth muscle actin. CTGF antisense ODN transfected into cultured renal fibroblasts significantly attenuated TGF-β-stimulated upregulation of fibronectin mRNA and protein compared with control ODN transfection, together with inhibited synthesis of type I collagen. With the use of a reporter assay, rat fibronectin promoter activity was increased by 2.5-fold with stimulation by TGF-β1, and this increase was abolished with antisense CTGF treatment. Thus CTGF plays a crucial role in fibronectin synthesis induced by TGF-β, suggesting that CTGF blockade could be a possible therapeutic target against tubulointerstitial fibrosis.

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Abstract. Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-␤ (TGF-␤) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-␤ and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.