Modified Huangqi Chifeng decoction inhibits excessive autophagy to protect against Doxorubicin‑induced nephrotic syndrome in rats via the PI3K/mTOR signaling pathway

Abstract

The aim of the present study was to investigate whether modified Huangqi Chifeng decoction (MHCD) could be an effective treatment against Doxorubicin-induced nephrosis in rats and whether it regulates autophagy via the phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathway. A total of 40 male Sprague-Dawley rats were randomly divided into blank, model, telmisartan and MHCD groups. The rat model of nephrosis was induced by intragastric administration of Doxorubicin for 8 weeks. Rats were housed in metabolic cages and urine was collected once every 2 weeks to measure 24-h protein levels. Blood samples were obtained from the abdominal aorta and levels of albumin (ALB), total cholesterol (TCH), triacylglyceride (TG) and serum creatinine (Scr) were assessed. Renal pathological changes were examined using hematoxylin-eosin, Masson's trichome and periodic acid-Schiff staining. Podocytes and autophagosomes were observed using an electron microscope. The expression and distribution of microtubule-associated proteins 1A/1B light chain 3B (LC3), LC3-I, LC3-II, beclin-1, PI3K and mTOR were determined using immunohistochemistry and western blotting. At weeks 6 and 8, 24-h proteinuria significantly decreased in the MHCD group compared with the model group (P<0.05). Compared with the model group, the MHCD group exhibited significantly reduced levels of TG, TCH and Scr, as well as significantly increased ALB levels (P<0.05). MHCD was demonstrated to prevent glomerular and podocyte injury. The number of autophagosomes was significantly decreased and the expression of beclin-1, LC3, LC3-I and LC3-II was inhibited following MHCD treatment compared with the model group (P<0.05). MHCD treatment significantly increased the expression of PI3K and mTOR in Doxorubicin nephrotic rats compared with the model group (P<0.05). In conclusion, MHCD was demonstrated to ameliorate proteinuria and protect against glomerular and podocyte injury by inhibiting excessive autophagy via the PI3K/mTOR signaling pathway.

Morroniside Inhibits H2O2-Induced Podocyte Apoptosis by Down-Regulating NOX4 Expression Controlled by Autophagy In Vitro

“…The autophagy activity of podocytes has a bidirectional change under different injury conditions. For example, in patients with diabetes (Wu et al, 2018;Zhao et al, 2018;Li et al, 2020) and IgA nephropathy (Liang et al, 2018), decreased podocyte autophagy activity is observed; while in systemic lupus erythematosus (SLE) (Jin et al, 2018) or adriamycin-induced models of nephrotic syndrome (Yu et al, 2018), podocyte autophagy activity is found to be increased. Yu et al (2019) observed an increase in the number of autophagosomes and the expression of autophagy-related proteins such as LC3B-II and Beclin-1 in podocytes stimulated by lupus autoantibodies.…”

Bioinformatic Analysis Reveals VEGFA&nbsp;Promotes the Occurrence of PLA2R-associated Idiopathic Membranous Nephropathy by Angiogenesis via PI3K/AKT&nbsp;Signaling Pathway

“…Study reported that SNARE proteins mediate fusion of autophagosomes with endolysosomal vesicles, which mediates autophagosome maturation, resulting in autophagy [25]. And inhibiting autophagosomes induced excessive autophagy ameliorates proteinuria and protect against glomerular and podocyte injury in nephrotic syndrome rats [26].Moreover, with accumulation of autophagosomes, cell viability altered, which directly induces cellular toxicity [27]. In our report, we found that genes, including STX6, STX3, VAMP1, VAMP3, VAMP4, STX1B, and SEC22B, encoding SNARE proteins are highly expressed in kidney biopsies from IMN patients, which means inhibitor of SNARE interaction may provide a new therapeutic strategy in treating IMN,however, it needs to be veri ed experimentally.…”

Pharmacokinetic interference of doxorubicin with tolbutamide due to reduced metabolic clearance with increased serum unbound fraction in rats

“…Possibly due to its hepatotoxicity or nephrotoxicity, hypoalbuminaemia is believed to be a common event in patients treated with doxorubicin. A reduction in the serum albumin level by doxorubicin has been established using experimental animals (Kabel, Alzahrani, Bawazir, Khawtani, & Arab, ; Yu et al, ). The serum albumin level was confirmed to be significantly lower in the DOX group compared with the control group, lending support to our finding that the f u of intravenously administered tolbutamide was significantly increased by exposure to doxorubicin.…”