Curcumin alleviates renal dysfunction and suppresses inflammation by shifting from M1 to M2 macrophage polarization in daunorubicin induced nephrotoxicity in rats Vengadeshprabhu Karuppagounder a , Somasundaram Arumugam a , Rajarajan A. Thandavarayan b , Remya Sreedhar a , Vijayasree V. Giridharan c , Rejina Afrin a , Meilei Harima a , Shizuki Miyashita a , Masanori Hara d , Kenji Suzuki e , Masahiko Nakamura f , Kazuyuki Ueno g , Kenichi Watanabe a,⇑ a Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan b Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA c Department of Psychiatry and Behavioral Sciences, Translational Psychiatry Program, McGovern Medical School, Houston, TX 77054, USA d Niigata Prefectural Yoshida Hospital, 32-14 Daibo-cho, Yoshida, Tsubame City 956-0242, Niigata, Japan e Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan f Department of Cardiology, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi Kofu, Yamanashi 400-8506, Japan g Department of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan article info Article history: Received 12 January 2016 Received in revised form 26 April 2016 Accepted 2 May 2016 Keywords: Curcumin Macrophage Cluster of differentiation 163 Nuclear factor kappa B Cytokine abstract The molecular mechanism of curcumin in macrophage polarization remains unknown in renal failure. We examined, whether curcumin treatment is associated with the modulation of renal function and macro- phage phenotype switch in daunorubicin (DNR) induced nephrotoxicity model. Sprague-Dawley rats were treated with a cumulative dose of 9 mg/kg DNR (i.v). Followed by curcumin (100 mg/kg) administration orally every day for 6 weeks. DNR treated rats showed nephrotoxicity as evidenced by worsening renal function, which was assessed by measuring creatinine and blood urea nitrogen in serum. These changes were reversed by treatment with curcumin, which resulted in significant improvement in renal function. Furthermore, curcumin increased cluster of differentiation (CD)163 expression, and down-regulated renal expression of antigen II type I receptor (AT1R), endothelin (ET)1, ET receptor type A and B (ETAR and ETBR), CD68 and CD80. Renal protein expression of extracellular signal-regulated kinase (ERK)1/2 and nuclear factor (NF)jB p65 were increased in DNR treated rats, and treatment with curcumin atten- uated these increased expression. Curcumin mediated a further increase in the levels of interleukin (IL)- 10. In addition, the expression of M1 phenotype was increased in DNR treated rats, which were attenu- ated by curcumin. Taken together, our results demonstrated that polyphenol curcumin has an ability to improve renal function and might induce the phenotypic switching from M1 to M2 macrophage polariza- tion in DNR induced nephrotoxicity in rats. Ó 2016 Elsevier Ltd. All rights reserved. 1. Introduction Cancer patients may develop a variety of kidney lesions not only their immediate survival, but also limits the adequate treatment of the underlying malignant process [1]. Daunorubicin (DNR), an anthracyclin antibiotic, is an effective drug for the chemotherapy of myeloblastic and acute lymphoblastic leukemia [2]. Neverthe- less, its use in chemotherapy has been limited largely due to its diverse toxicities, including renal, hematological, testicular, and cardio toxicity [3]. Inflammatory or oxidative stress has been asso- ciated with DNR-induced renal impairment. Rats with DNR admin- istration showed increased glomerular capillary permeability, tubular necrosis, and intertubular hemorrhages [4]. Although the precise mechanism of DNR induced nephrotoxicity remains unknown, appropriate approaches to minimize these risks are still being explored. Macrophages are central regulators of the innate immune sys- tem and are needed for tissue homeostasis, immune regulation and injury resolution [5]. Macrophages show a range of pheno- types, a phenomenon that has been described as macrophage polarization or heterogeneity. This phenotype is divided into two http://dx.doi.org/10.1016/j.cyto.2016.05.001 1043-4666/Ó 2016 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha Ku, Niigata 956-8603, Japan. E-mail address: watanabe@nupals.ac.jp (K. Watanabe). Cytokine 84 (2016) 1–9 Contents lists available at ScienceDirect Cytokine journal homepage: www.journals.elsevier.com/cytokine