ABSTRACT
Renal interstitial fibrosis (RIF) is the crucial pathway in chronic kidney disease (CKD) leading to the end-stage renal failure. However, the underlying mechanism of Shen Qi Wan (SQW) on RIF is not fully understood. In the current study, we investigated the role of Aquaporin 1 (AQP1) in SQW on tubular epithelial-to-mesenchymal transition (EMT). A RIF mouse model induced by adenine and a TGF-ß1-stimulated HK-2 cell model were etablished to explore the involvement of AQP 1 in the protective effect of SQW on EMT in vitro and in vivo. Subsequently, the molecular mechanism of SQW on EMT was explored in HK-2 cells with AQP1 knockdown. The results indicated that SQW alleviated kidney injury and renal collagen deposition in the kidneys of mice induced by adenine, increased the protein expression of E-cadherin and AQP1 expression, and decreased the expression of vimentin and α-smooth muscle actin (α-SMA). Similarly, treatmement with SQW-containing serum significantly halted EMT process in TGF-ß1 stimulated HK-2 cells. The expression of snail and slug was significantly upregulated in HK-2 cells after knockdown of AQP1. AQP1 knockdown also increased the mRNA expression of vimentin and α-SMA, and decreased the expression of E-cadherin. The protein expression of vimentin increased, while the expression of E-cadherin and CK-18 significantly decreased after AQP1 knockdown in HK-2 cells. These results revealed that AQP1 knockdown promoted EMT. Furthermore, AQP1 knockdown abolished the protective effect of SQW-containing serum on EMT in HK-2 cells. In sum, SQW attentuates EMT process in RIF through upregulation of the expression of AQP1.
Subject(s)
Aquaporin 1 , Drugs, Chinese Herbal , Renal Insufficiency, Chronic , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/pharmacology , Humans , Animals , Mice , Male , Cell Line , Rats , Kidney/pathology , Kidney/physiology , Fibrosis/drug therapy , Renal Insufficiency, Chronic/drug therapy , Adenine , Epithelial-Mesenchymal Transition , Aquaporin 1/metabolismABSTRACT
BACKGROUND: Shi chang pu (Acorus tatarinowii Schott) is a herbal used in the treatment of Alzheimer's disease (AD) in China. The essential oil of Shi chang pu (SCP-oil) is the main active component. However, its effects on the neuroinflammation of AD have not been well studied. PURPOSE: Neuroinflammation mediated by the NLRP3 inflammasome plays a crucial role in AD. This study was designed to evaluate the effect of SCP-oil on cognitive impairment of AppSwe/PSEN1M146V/MAPTP301L triple transgenic (3 × Tg-AD) mice model and investigate the mechanism underlying its anti-inflammation effects. METHODS: Thirty-two 3 × Tg-AD mice at 12 months and 8 wild-type B6 mice were used for this experiment. The 3 × Tg-AD mice were administered with SCP-oil or donepezil hydrochloride for 8 weeks. Morris water maze test and step-down test were used to evaluate the cognitive ability of mice. The pathological changes, neuroinflammation, and the NLRP3 inflammasome related-protein of AD mice were detected by histomorphological examination, TUNEL staining, immunofluorescence, immunohistochemistry, qRT-PCR, Elisa, and western blot assays. RESULTS: SCP-oil treatment attenuated cognitive dysfunction of 3 × Tg-AD mice. Moreover, SCP-oil also ameliorated characteristics pathological of AD, such as pathological changes damage, deposition of Aß, phosphorylation of Tau, and neuronal loss. Additionally, SCP-oil treatment alleviated the neuroinflammation and inhibited phosphorylation of IKKß, NF-κB, and NLRP3 inflammasome related-protein NLRP3, ASC, Caspase-1, cleaved-Caspase-1, and GSDMD-N in the hippocampus of 3 × Tg-AD mice. CONCLUSION: Overall, SCP-oil contributed to neuroprotection in 3 × Tg-AD mice by reduced activation of NLRP3 inflammasome by inhibiting the NF-κB signaling pathway.
Subject(s)
Acorus , Alzheimer Disease , Oils, Volatile , Mice , Animals , Inflammasomes/metabolism , Alzheimer Disease/metabolism , Mice, Transgenic , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NF-kappa B/metabolism , Neuroinflammatory Diseases , Oils, Volatile/pharmacology , Oils, Volatile/therapeutic use , Caspase 1/metabolismABSTRACT
Alzheimer's disease is the most common form of neurodegenerative disease, and increasing evidence shows that insulin signaling has crucial roles in AD initiation and progression. In this study, we explored the effect and underlying mechanism of SQW, a representative formula for tonifying the kidney and promoting yang, on improving the cognitive function in a streptozotocin-induced model of AD rats. We investigated memory impairment in the AD rats by using the Morris water test. HE and Nissl staining were employed to observe the histomorphological changes in the hippocampal. Expression levels of NeuN and proteins related to Tau and apoptosis were measured using immunohistochemistry and Western blotting, respectively. Additionally, we performed RNA sequencing, and the selected hub genes were then validated by qRT-PCR. Furthermore, the protein expression levels of PI3K/AKT pathway-related proteins were detected by Western blot. We found that SQW treatment significantly alleviated learning and memory impairment, pathological damage, and apoptosis in rats, as evidenced by an increased level of NeuN and Bcl-2, and decreased phosphorylation of Tau, Bax, and Caspase-3 protein expression. SQW treatment reversed the expression of insulin resistance-related genes (Nr4a1, Lpar1, Bdnf, Atf2, and Ppp2r2b) and reduced the inhibition of the PI3K/AKT pathway. Our results demonstrate that SQW could contribute to neuroprotection against learning and memory impairment in rats induced by STZ through activation of the PI3K/AKT pathway.