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Cisplatin-Induced Renal Interstitial Fibrosis in Neonatal Rats, Developing as Solitary Nephron Unit Lesions

¹ Laboratory of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan
² Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc, Muya-cho, Naruto, Tokushima 772-8601, Japan
³ Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N 1G2W1, Canada

Correspondence: Address correspondence to: Jyoji Yamate, DVM., PhD., Laboratory of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan; e-mail:yamate{at}vet.osakafu-u.ac.jp

Cisplatin (CDDP)-induced renal lesions in rats prove a useful model for analysis of the pathogenesis of post-tubular injury-renal interstitial fibrosis. This study investigated the histopathological changes in 10-day-old neonatal rats induced by a single injection of CDDP (4.5 mg/kg). Compared with age-matched controls, on postinjection (PI) days 1 to 6, the number of apoptotic cells, demonstrable with TUNEL method, was significantly increased in CDDP-treated neonates, and there was no marked epithelial necrosis nor fibrotic lesions. Fibrotic lesions began to be developed solitarily around some nephrons with dilated ducts in the corticomedullary junction on PI day 10 and the lesions became more prominent until PI day 20. The -SMA-positive myofibroblastic cells were seen exclusively in the fibrotic lesions. Additionally, the numbers of macrophages reacting with ED1 (specific for exudate macrophages), ED2 (for resident macrophages), and OX6 (recognizing MHC class II antigens expressed in antigen-presenting macrophages/dendritic cells) were significantly increased around the affected renal tubules. A greater immunoreaction for TGF-β1 was seen mostly in the renal epithelial cells of CDDP-treated neonates. These findings indicated that macrophage populations and myofibrolastic cells as well as TGF-β1 may be responsible for the production of neonatal renal interstitial fibrosis. Compared with CDDP-injected adult rats that develop extensive interstitial fibrosis (Yamate et al., J Comp Pathol, 1995), the formation of fibrotic lesions was delayed, and the lesions were limited to the area around the affected nephrons; this could be attributable to differences in renal morphology between neonates and mature kidney of adult rats.

Key Words: Cisplatin-induced renal fibrosis • macrophages • nephrogenesis • nephron unit lesion • neonatal rat

Abbreviations: CDDP, cisplatin (cis-diamminedichloroplatinum) • -SMA, -smooth muscle actin • TGF-β1, transforming growth factor-β1 • ECMs, extracellular matrices • BUN, blood urea nitrogen • PBS, phosphate buffered saline • BrdU, bromodeoxyuridine • H&E, hematoxylin & eosin • DAB, 3,3'-diaminobenzidine • TUNEL, terminal deoxyribonucleotide transferase (TdT)-mediated dUTP nick end labeling • RT-PCR, reverse transcription-polymerase chain reaction • PDGF, platelet-derived growth factor • NGF, nerve growth factor

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