title: Naringenin ameliorates daunorubicin induced nephrotoxicity by mitigating AT1R, ERK1/2-NFκB p65 mediated inflammation.
abstract: Inflammation and oxidative stress play important roles in the progression of renal damage. The natural polyphenol naringenin is known to exert potent antioxidant and anti-inflammatory effects. In this study, we have investigated the effect of naringenin on kidney dysfunction, fibrosis, endoplasmic reticulum (ER) stress, angiotensin II type I receptor (AT1R) expression and inflammation in daunorubicin (DNR) induced nephrotoxicity model. Nephrotoxicity was induced in rats by intravenous injection of DNR at a cumulative dose of 9 mg/kg. After 1 week, naringenin (20mg/kg/day. p.o) was administered daily for 6 weeks. Biochemical studies were performed to evaluate renal function. Western blotting was performed to measure the protein levels of AT1R, endothelin (ET)1, ET receptor type A (ETAR), extracellular signal-regulated kinase (ERK)1/2, nuclear factor (NF)κB p65, peroxisome proliferator activated receptor (PPAR)γ, oxidative/ER stress, apoptosis, and inflammatory markers in the kidney of DNR treated rats. Histopathological analysis was done using hemotoxylin eosin and Masson trichrome stained renal sections to investigate the structural abnormalities and fibrosis. DNR treated rats suffered from nephrotoxicity as evidenced by worsened renal function, increased blood urea nitrogen, serum creatinine levels in renal tissues and histopathogical abnormalities. Treatment with naringenin mitigated these changes. Furthermore, naringenin up regulated PPARγ and down regulated AT1R, ET1, ETAR, p-ERK1/2, p-NFκB p65, ER stress, apoptosis, and inflammatory markers. Our results suggest that naringenin has an ability to improve renal function and attenuates AT1R, ERK1/2-NFκB p65 signaling pathway in DNR induced nephrotoxicity in rats.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Vengadeshprabhu
authors.initials: V
authors.lastname: Karuppagounder
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Arumugam
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan; Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Rajarajan Amirthalingam
authors.initials: RA
authors.lastname: Thandavarayan
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Vigneshwaran
authors.initials: V
authors.lastname: Pitchaimani
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Remya
authors.initials: R
authors.lastname: Sreedhar
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Rejina
authors.initials: R
authors.lastname: Afrin
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Meilei
authors.initials: M
authors.lastname: Harima
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Cardiology, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi Kofu, Yamanashi 400-8506, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Ueno
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan. Electronic address: watanabe@nupals.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D003630:Daunorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005355:Fibrosis; D044950:Flavanones / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D047495:PPAR gamma / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D012076:Renal Agents / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000903:Antibiotics, Antineoplastic; D044950:Flavanones; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D012076:Renal Agents; D051996:Transcription Factor RelA; C005273:naringenin; D003630:Daunorubicin
keywords: Angiotensin II type I receptor; Endoplasmic reticulum stress; Extracellular signal-regulated kinase; Inflammation; Nephrotoxicity