Cisplatin-induced renal interstitial fibrosis in neonatal rats, developing as solitary nephron unit lesions

• Published in: Toxicologic pathology Vol. 33; no. 2; p. 207
• Main Authors: Yamate, Jyoji, Machida, Yuuko, Ide, Mika, Kuwamura, Mitsuru, Kotani, Takao, Sawamoto, Osamu, LaMarre, Jonathan
• Format: Journal Article
• Language: English
• Published: United States 01.01.2005
• Subjects: Actins - metabolism; Animals; Animals, Newborn; Antineoplastic Agents - toxicity; Apoptosis - drug effects; Biomarkers - metabolism; Body Weight - drug effects; Cisplatin - toxicity; Disease Models, Animal; Fibrosis; In Situ Nick-End Labeling; Macrophages - drug effects; Macrophages - metabolism; Nephritis, Interstitial - chemically induced; Nephritis, Interstitial - metabolism; Nephritis, Interstitial - pathology; Nephrons - drug effects; Nephrons - metabolism; Nephrons - pathology; Rats; Rats, Inbred F344; RNA, Messenger - metabolism; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1
• ISSN: 0192-6233
• DOI: 10.1080/01926230490523978

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 alpha-SMA-positive myofibroblastic cells were seen exclusively in the fibrotic lesions. Additionally, the numbers of macrophages reacting with EDI (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-beta1 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-beta1 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.