Protective Effect of Low Molecular Weight Peptides from Solenocera crassicornis Head against Cyclophosphamide-Induced Nephrotoxicity in Mice via the Keap1/Nrf2 Pathway

Abstract

The major component of the Solenocera crassicornis head protein hydrolysates-fraction 1 (SCHPs-F1) are low molecular weight peptides (MW < 1 kDa). In this study, we investigated the potential renoprotective effects of SCHPs-F1 in a cyclophosphamide (CTX) toxicity mouse model. In brief, 40 male mice were randomly divided into 5 groups and received either saline or 80 mg/kg body weight (BW) CTX by intraperitoneal injection for 5 days, followed by either saline or SCHPs-F1 (100, 200, and 400 mg/kg BW) by intragastric administration for 15 days. SCHPs-F1 treatment significantly reversed the CTX-induced decreases in the levels of blood urea nitrogen (BUN), creatinine (CRE), and cytochrome P450 (CYP450), as well as the renal histological lesions. Furthermore, the results indicated that SCHPs-F1 potentially alleviated CTX-induced nephrotoxicity through mitigating inflammatory responses, oxidative stress, and apoptosis status of the kidneys, as evidenced by decreased levels of malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and increased levels of total antioxidant capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Moreover, overexpression of pro-apoptotic proteins pair B-cell lymphoma-2 (Bcl-2)-associated X (Bax)/Bcl-2, cysteinyl aspartate specific proteinase (caspase)-3 and caspase-9 in renal tissues were suppressed by treatment with SCHPs-F1. In addition, the protein levels of the antioxidant factor nuclear factor erythroid-2 related factor 2 (Nrf2) and the expression levels of its downstream target genes heme-oxygenase (HO-1), glutamate-cysteine ligase modifier subunit (GCLM) and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were stimulated by treatment with SCHPs-F1 in the CTX-induced renal injury model. Taken together, our data suggested that SCHPs-F1 could provide a novel potential strategy in mitigating the nephrotoxicity caused by CTX.

Effect of a Low Dose of Carvedilol on Cyclophosphamide-Induced Urinary Toxicity in Rats—A Comparison with Mesna

“…CPX, in contrast to ifosfamide, is not uptaken by kidney proximal tubules and the nephrotoxic action of CPX is rather due to the generation of ROS and peroxynitrite, activation of inflammatory pathways, cell membrane disruption, mitochondrial dysfunction and DNA or protein adducts formation by acrolein [73]. In the study we performed, cyclophosphamide caused a significant increase in kidney index which indicates that the edema of the renal tissue, and similar changes were described by Dobrek et al [11] in a rat model or by Jiang et al [74] in a mice model of chronic CPX administration. In the CPX group, we noticed a significant increase in serum potassium and creatinine levels which was reported by many other authors after CPX injection to rats [10,75,76] or mice [77][78][79] in both acute and chronic models of CPX administration.…”

Protective Effects of Shrimp Peptide on Dextran Sulfate Sodium-Induced Colitis in Mice

“…Shrimp peptide (SP) has biological activities such as hepatoprotective ( 14 ), antioxidant ( 15 , 16 ), anti-inflammatory ( 17 ), and antibacterial effects ( 18 , 19 ). However, it is not known whether Chinese pipe whip SP can protect dextran sulfate sodium (DSS)-induced mice with UC.…”

Keap1/Nrf2 Signaling Pathway

“…Therefore, investigations of the protective effects of Keap1/Nrf2 signaling that focus on specific tissues or organs are of great interest. Such studies have traditionally focused on tissues with detoxification functions such as the liver [ 6 , 7 ] but have also expanded to diverse tissues, including the kidney [ 8 , 9 ], skin [ 10 ], lung [ 11 ], colon [ 12 ], heart [ 13 ], nervous system [ 14 ], adipose tissue [ 15 ], pancreas [ 16 ] and thyroid [ 17 , 18 ], as evidenced by the respective tissue/organ-specific studies that are outlined below and comprise the majority of studies in the present Special Issue. Lastly, research on Nrf2 has expanded to encompass not only basic but also translational and clinical studies.…”

“…In a preclinical research study in mice, Jiang et al show that low-molecular weight peptides extracted from the head of a prawn ( Solenocera crassicornis ) have a protective effect against the renal toxicity of cyclophosphamide [ 9 ], which is used as a chemotherapeutic or immunosuppressive agent. Treatment of mice with the extract had beneficial effects on markers of inflammation, oxidative stress and apoptosis in the kidney, and this was accompanied by increased protein abundance of Nrf2 and increased mRNA expression levels of some of its target genes, including Hmox1 and Nqo1 [ 9 ]. However, like other studies, the data remain correlative because Nrf2 knock-out mice were not employed to demonstrate the mechanistic specificity and the magnitude of the Nrf2-attributable effect.…”