Huaiqihuang (HQH) granule alleviates cyclophosphamide-induced nephrotoxicity via suppressing the MAPK/NF-κB pathway and NLRP3 inflammasome activation

Abstract

Context Severe nephrotoxicity greatly limits the clinical use of the common effective chemotherapeutic agent cyclophosphamide (CYP). Huaiqihuang (HQH) is a Chinese herbal complex with various pharmacological activities, widely used for treating kidney disease. Objective This study estimates the protective effect of HQH against CYP-induced nephrotoxicity in rats. Materials and methods Four groups of 10 Sprague-Dawley rats were pre-treated with once-daily oral gavage of 3 and 6 mg/kg HQH for 5 days before receiving a single dose of CYP (200 mg/kg i.p.) on the 5th day; the control group received equivalent dose of saline. Renal function indices, morphological changes, oxidative stress, apoptosis and inflammatory mediators were measured. In addition, phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were analysed. Results Both doses of HQH reduced the levels of serum creatinine (31.27%, 43.61%), urea nitrogen (22.66%, 32.27%) and urine protein (12.87%, 15.98%) in the CYP-treated rats, and improved histopathological aberrations. Additionally, HQH decreased the production of MDA (37.02%, 46.18%) and increased the activities of antioxidant enzyme CAT (59.18%, 112.25%) and SOD (67.10%, 308.34%) after CYP treatment. HQH protected against CYP-induced nephrotoxicity by modulating apoptosis-related protein and suppressing the inflammatory responses. Furthermore, the phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were significantly boosted in CYP-treated rats, which was also abrogated by HQH treatment. Conclusions HQH effectively protected against CYP-induced nephrotoxicity, which was associated with regulating oxidative stress, apoptosis and inflammation, and so HQH may be a useful agent for treating nephrotoxicity caused by CYP.

Network Pharmacology and Molecular Docking Analysis to Explore the Mechanism of Huaiqihuang-Mediated Alleviation of Henoch–Schönlein Purpura Nephritis

“…In addition, conventional medicines, such as CYP, increase nephrotoxicity while treating HSPN [ 16 ]. Importantly, HQH has a protective effect against CYP-induced nephrotoxicity [ 11 ]. Therefore, HQH may be a special adjunctive drug in treating HSPN.…”

“…Oxidative stress pathologically aggravates kidney diseases. HQH can alleviate oxidative damage [ 11 ]. Moreover, HQH relieves CYP-induced kidney damage by suppressing the MAPK/NF- κ B pathway, which is associated with oxidative stress regulation.…”

“…HQH exhibits a significant therapeutic effect against kidney diseases by enhancing immune function and reducing proteinuria and hematuria [ 9 , 10 ]. Moreover, HQH compensates for the defects of cyclophosphamide (CYP) by reducing nephrotoxicity [ 11 ]. However, our understanding of HQH in HSPN treatment remains unclear.…”

Potential Protective Effects of Antioxidants against Cyclophosphamide-Induced Nephrotoxicity

“…A Chinese herbal complex Huaiqihuang, composed of Trametes robiniophila (Auriculariacaee), Lycium barbarum (Solanaceae), and Polygonatum sibiricum (Liliaceae) showed significant antioxidant, antiapoptosis, and anti-inflammatory activity and exhibits a therapeutic effect against renal diseases. Huaiqihuang showed protective effect against cyclophosphamide-induced nephrotoxicity in rats through decreasing the production of MDA, and increasing the activities of antioxidant enzymes including, CAT and SOD [ 92 , 93 ].…”

Anti-inflammatory and anti-apoptotic potential of beta-glucan on chemotherapy-induced nephrotoxicity in rats

“…However, the therapeutic use of CP is restricted due to the side effects it produces, such as nephrotoxicity, cardiotoxicity, and hepatotoxicity [3]. Renal damage induced by CP includes apoptosis and necrosis of tubular epithelial cells [3], inflammation [4], fibrosis [5], and decreased lysosomal enzyme activity [6]. The toxic mechanism of CP is attributed to its main metabolites, phosphoramide mustard and acrolein, which cause an increase in free radicals [7].…”