Angiogenic Protein Cyr61 is Expressed by Podocytes in Anti-Thy-1 Glomerulonephritis

Abstract

Abstract. Dynamic recovery of glomerular structure occurs after severe glomerular damage in anti-Thy-1 glomerulonephritis (Thy-1 GN), but its mechanism remains to be investigated. To identify candidate genes possibly involved in glomerular reconstruction, screening was performed for genes that are specifically expressed by podocytes and are upregulated in glomeruli of Thy-1 GN. Among them, cysteine-rich protein 61 (Cyr61 or CCN1), a soluble angiogenic protein belonging to the CCN family, was identified. By Northern blot analysis, Cyr61 mRNA was markedly upregulated in glomeruli of Thy-1 GN from day 3 through day 7, when mesangial cell migration was most prominent. By in situ hybridization and immunohistochemistry, Cyr61 mRNA and protein were expressed by proximal straight tubules and afferent and efferent arterioles in normal rat kidneys and were intensely upregulated at podocytes in Thy-1 GN. Platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-␤1 (TGF-␤1), of which the gene expression in the glomeruli of Thy-1 GN was upregulated in similar time course as Cyr61, induced Cyr61 mRNA expression in cultured podocytes. Furthermore, supernatant of Cyr61-overexpressing cells inhibited PDGF-induced mesangial cell migration. In conclusion, it is shown that Cyr61 is strongly upregulated at podocytes in Thy-1 GN possibly by PDGF and TGF-␤. Cyr61 may be involved in glomerular remodeling as a factor secreted from podocytes to inhibit mesangial cell migration.

CCN1 expression in interleukin-6 deficient mouse kidney in experimental model of heart failure

“…Moreover, contrary to rats, in mouse kidney we did not observe CCN1-positive staining in afferent and efferent arterioles, but in medium size arteries, while similarly as in rats we did not observe any reaction in large arteries. In addition, we detected CCN1-positive staining in mouse glomeruli, probably in podocytes, which supports earlier findings of Sawai et al [15,27] who detected CCN1 expression in cultured mouse podocytes.…”

“…At day 5 of experimental glomerulonephritis mRNA of CCN1 was detected on outer surfaces of glomerular basement membrane, which appeared to be podocytes. Similarly to the above studies performed on rats [14,15], in all groups of mice evaluated in the present study we observed CCN1-positive staining in proximal straight tubules, and contrary to studies performed on rats, we found the strongest reaction in distal convoluted tubules. Moreover, contrary to rats, in mouse kidney we did not observe CCN1-positive staining in afferent and efferent arterioles, but in medium size arteries, while similarly as in rats we did not observe any reaction in large arteries.…”

“…A second study, dealing with CCN1 expression in rat kidney, was performed in an experimental model of Thy-1 glomerulonephritis [15]. Contrary to the previous study, CCN1 protein expression, evaluated by in situ hybridization, was observed in normal rat kidney in the outer stripe of outer medulla, which corresponded to the proximal straight tubules.…”

“…CCN1 protein expression represents an immediate early gene response, therefore, regulation of this protein in the kidney and other organs was mainly described in experimental models of acute diseases [14,15,17]. Acute kidney ischemia/reperfusion upregulates CCN1 expression [14], so it may be hypothesized that early after myocardial infarction there is also transient induction of CCN1, which might have delayed alterations of kidney structure and function.…”

“…In rodent kidney the basal expression of CCN1 protein is rather low [14]. In rat kidney it was observed in the outer stripe of outer medulla and in some afferent and efferent arterioles, while experimental anti-Thy-1 glomerulonephritis induced CCN1 expression in podocytes [15]. In different tissues the expression of CCN1 can be regulated by over 30 factors [16].…”