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Cyclophosphamide (CP) is one of the most extensively used antineoplastic drug, but the nephrotoxicity caused by this drug is a major limiting factor for its use. Nerolidol (NERO) is a natural bioactive compound with diverse pharmacological actions. In Vitro and in vivo study was performed using HK-2 renal cells and Swiss Albino mice. Cell lines and animals were treated with NERO 25 and 50 µM + 30 µM CP ( in vitro ), 200 and 400 mg/kg, p.o. NERO from day 1 to day 15 + 200 mg/kg, i.p. CP on day 17 as single intraperitoneal injection ( in vivo ). The makers of oxidative stress, renal-specific injury markers, inflammation, apoptosis, fibrosis, and histopathological changes were studied. The study's outcome showed a significant reduction in the level of malonaldehyde and interleukin-6 (p < 0.01), tumor necrosis factor-α, IL-1β (p < 0.001), and an increase in the superoxide dismutase, catalase, glutathione and interleukin-10 level (p < 0.01), in the in vivo study when treated with NERO 400 and compared with CP 200. In Vitro study showed reduced expression of nuclear factor kappa light chain enhancer of activated B cells, cleaved caspase-3, kidney injury molecule-1 and transforming growth factor-β-1 (p < 0.001), when treated with NERO 50 µM whereas NERO 25 µM only reduced the level of cleaved caspase-3 (p < 0.05) when compared with 30 µM. NERO 400 also reduced uric acid (p < 0.05), urea (p < 0.01), blood urea nitrogen, and serum creatinine levels (p < 0.001) and increased the level of blood-urea-nitrogen/creatinine ratio (p < 0.001). Additionally, the level of fibrosis-specific markers such as transforming growth factor-β1, hyaluronic acid (p < 0.01), 4-hydroxyproline, a collagen-rich area in Masson's' trichome stain, and Smad3 expression was also significantly reduced (p < 0.001). Furthermore, the outcome of multiple renal staining showed structural reversal aberrations, reduction of the thick basement membrane, and glycogen level toward normal when treated with NERO 400. Thus, the study showed a novel mechanistic modality of NERO against cyclophosphamide-induced renal toxicity. The outcome of this study can be considered a step closer to the development of an adjuvant to mitigate cyclophosphamide-induced renal toxicity among patients treated with cyclophosphamide.

Renal fibrosis and inflammation are common underlying processes of progressive kidney diseases. Elongator protein 2 (Elp2), identical to signal transducer and activator of transcription-3 (STAT-3)-interacting protein-1 (Stip1), is a component of the Elongator complex that regulates RNA polymerase II. Elp2 regulates STAT-3 activation to control various cellular processes. The mechanisms of Elp2 prevention in renal interstitial fibrosis and inflammation remain unknown. In the study, Elp2 transgenic knockout (KO) and wild type (WT) mice were employed to investigate the effects of Elp2 on renal fibrosis and inflammation development after unilateral ureter obstruction (UUO) surgery. The results indicted that Elp2 was significantly expressed in renal tissues of WT/UUO mice. Elp2-KO mice exhibited attenuated histological changes of kidney, as well as collagen and fibrosis accumulation. Lower expressions of transforming growth factor (TGF)-β1, α-smooth muscle actin (α-SMA), fibronectin, vimentin, and phospho-Smad2/3 were observed in kidney of Elp2-KO mice than that of WT mice after UUO. Elp2-KO mice showed less inflammation, as evidenced by the decrease of circulating or renal pro-inflammatory cytokines, as well as the reduction of phospho-nuclear factor (NF)-κB. Additionally, Elp2-KO apparently led to a decrease in phospho-STAT3 in kidney of UUO mice. In vitro, we found that TGF-β1- and LPS-induced fibrosis and inflammation were abrogated by Elp2 knockdown, which were intriguingly abolished by activating STAT3 phosphorylation using its activator of colivelin (Col). Together, our findings supplied that Elp2 might be a potential therapeutic target to prevent the progression of renal fibrosis and inflammation., (Copyright © 2018. Published by Elsevier Inc.)