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1 Pathology, UMC Utrecht, Utrecht, The Netherlands
* To whom correspondence should be addressed. E-mail: p.roestenberg{at}azu.nl.
CTGF is overexpressed in diabetic nephropathy (DN) and has therefore been implicated in its pathogenesis. The objective of the present study was to determine the tissue distribution of increased CTGF expression, and the relation of plasma, urinary, and renal CTGF levels with the development and severity of DN. We studied the relation between CTGF and renal pathology in Streptozotocin (STZ)-induced diabetes in C57Bl/6J mice. Diabetic and age-matched control mice were sacrificed after 1, 2, 4 and 9 weeks of diabetes. In addition, key parameters of diabetes and DN were analyzed in ten-month-old diabetic ob/ob mice and their ob/+ littermates. STZ-induced diabetic mice showed a significantly increased urinary albumin excretion after 1 wk and increased mesangial matrix score after 2 wks. Increased renal fibronectin, fibronectin ED-A and collagen IVa1 expression, as well as elevated plasma creatinine levels, were observed after 9 wks. After 2 wks, CTGF mRNA was 3-fold upregulated in renal cortex. By 9 wks, CTGF mRNA was increased also in heart and liver. In contrast, TGF-b1 mRNA content was significantly increased only in the kidney by 9 wks. Renal CTGF expression was mainly localized in podocytes and parietal glomerular epithelial cells, and less prominent in mesangial cells. In addition, plasma CTGF levels and urinary CTGF excretion were increased in diabetic mice. Moreover, albuminuria strongly correlated with urinary CTGF excretion (R=0.83, p<0.0001). Increased CTGF expression was also demonstrated in type 2 diabetic ob/ob mice, which points at a causal relation between diabetes and CTGF, and thus argues against a role of STZ in this process. The observed relation of podocyte-, and urinary CTGF with markers of DN, suggests a pathogenic role of CTGF in the development of DN.
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