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

Abstract

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 α-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.

Heterogeneity of Macrophage Populations and Myofibroblasts Appearing in Rat Renal Interstitial Fibrosis

“…ED1-positive cells may be responsible for production of TNF-α and TGF-β1 in the early stages, leading to the induction of myofibroblastic cells 25,56 . In fact, α-SMApositive myofibroblastic cell number begins to increase with increased number of ED1-positive cells in the acute and chronic models 6,25,26 . ED2 is used to detect resident macrophages 17,27,30,34 .…”

“…Compared with cisplatin-injected adult rats that develop extensive interstitial fibrosis in the corticomedullary junction, the formation of fibrotic lesions induced in neonatal rats by a single injection of cisplatin (4.5 mg/kg) is delayed, and the lesions are limited to the area around the affected nephrons 26 . In the neonatal lesions, ED1-, ED2-and OX6-positive cells also appear mainly around the dilated tubules.…”

“…In contrast to humans and mice, however, monoclonal antibodies available for rat macrophage detection are smaller in number. In this article, ED1, ED2, and OX6 will be introduced, because the author has used them to investigate the pathogenesis of chemically-induced rat renal lesions [25][26][27] . ED1 (rat CD68) is most popular to identify macrophages in rat pathological areas 23,24,27,28 .…”

“…The acute renal failure (acute model) can be induced in rats by an intraperitoneal, single injection of sublethal dose of cisplatin (6 mg/kg body weight) 7,26 . Two to 4 days after administration, in the corticomedullary junction epithelial cells in the damaged renal tubules have swollen cytoplasm; occasional cells undergo apoptosis.…”

Farnesoid X Receptor Ligand Prevents Cisplatin-Induced Kidney Injury by Enhancing Small Heterodimer Partner

“…We have demonstrated that cisplatin-induced nephrotoxicity is associated with the activation of apoptosis, inflammation and fibrosis pathways [2]. A single injection of cisplatin may induce renal epithelial cell damage, epithelial-to-mesenchymal transition (EMT), and progressive interstitial fibrosis, along with an upregulation of transforming growth factor-β1 (TGF-β1) [3], [4]. Cisplatin may activate pro-apoptotic genes and repress anti-apoptotic genes by transcriptional regulation [5].…”