Immunophenotypical Characterization of M1/M2 Macrophages and Lymphocytes in Cisplatin-Induced Rat Progressive Renal Fibrosis.

Minto Nakagawa,Mohammad Rabiul Karim,Jyoji Yamate,Mitsuru Kuwamura,Takeshi Izawa

doi:10.3390/cells10020257

Minto Nakagawa, Mohammad Rabiul Karim + Show 3 more

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https://doi.org/10.3390/cells10020257

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Abstract

Renal fibrosis is regarded as the common final pathway leading to chronic kidney diseases; macrophages and myofibroblasts play important roles in the development of fibrosis. F344 rats were injected once with cisplatin (CDDP; 6 mg/kg BW) for renal lesions. Here, immunophenotypical characteristics of macrophages and lymphocytes in CDDP-induced rat renal lesions were investigated histopathologically; the CDDP-induced renal lesions consisted of tissue damage at the early-stage, worsen the damage and commencement of interstitial fibrosis at the mid-stage, and progressive fibrosis at the late stage; the KIM-1 expression and α-SMA+ myofibroblast area reflected renal tubular damage/abnormal regeneration and renal interstitial fibrosis, respectively. CD68+ M1 macrophages began to increase at the mid-stage, with increased mRNA expressions of M1-related cytokines (INF-γ, TNF-α and IL-6), and then slightly decreased at the late-stage. CD163+ M2 macrophages showed a gradually increased number at the mid- and late-stages, accompanied by increased TGF-β1 mRNA expression (a fibrogenic factor). Double immunofluorescence using fibrotic samples at the late-stage revealed that 62.0–78.0% of CD68+ M1 macrophages co-expressed CD163, indicating that M1/M2 macrophages may contribute to progressive renal fibrosis in cooperation; further, MHC class II-expressing macrophages had a tendency towards M1 polarization, whereas CD204-expressing macrophages towards M2 polarization. In addition, CD4+ and CD8+ T cells were increased at the late-stage. Collectively, progressive renal interstitial fibrosis may be developed by complicated mechanisms that arose via interaction of M1/M2 macrophages (inflammatory for M1 and anti-inflammatory for M2) and T cells reacting to CD4 (for helper) and CD8 (for cytotoxicity). This study would provide some information on the pathogenesis of renal fibrosis based on inflammatory cells.

Highlights

Regardless of initial causes, renal fibrosis is regarded as the common final pathway leading to chronic kidney diseases (CKD)
The degrees and progression of interstitial fibrosis seen in the present rat renal failure were generally corresponding to those reported previously [16,20]
Renal fibrosis is characterized by the appearance of myofibroblasts [20]

Summary

Introduction

Regardless of initial causes, renal fibrosis is regarded as the common final pathway leading to chronic kidney diseases (CKD). The pathogenic mechanism of renal fibrosis should be clarified to prevent the progression. Macrophages and myofibroblasts play important roles in the development of fibrosis [1,2]. Myofibroblasts are mesenchymal cells capable of producing ECMs, and transforming growth factor-β1 (TGF-β1) is an important factor for the activation of myofibroblasts [3]. Macrophages produce TGF-β1 [4]. TGF-β1 may promote tubular epithelial cell transdifferentiation into myofibroblasts (epithelial-mesenchymal transition; EMT) and enhance interstitial deposition of ECMs produced by myofibroblasts [5,6]. Macrophages are crucial in the pathogenesis of renal fibrosis [1]

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