JOURNAL OF ETHNOPHARMACOLOGY
·
2023
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IF 5.4
Lei Zhao,Siyuan Han,Chengzhi Chai
Ethnopharmacological relevance Huangkui capsule (HKC), a Chinese patent medicine, has been widely used in China as adjuvant therapy for chronic kidney disease (CKD). It displays superior anti-proteinuria efficacy than losartan in patients with CKD at stages 1–2, however, the mechanism of HKC alleviating proteinuria has not been well elucidated. Aim of the study This study aims to confirm the therapeutic effect and investigate associated underlying mechanism of HKC against proteinuria by in vivo and in vitro experiments. Materials and methods We established a doxorubicin (DOX) induced proteinuria mouse model to evaluate kidney function by biochemical markers measurement and to observe histopathological alterations by hematoxylin and eosin (H&E), Masson's trichrome and Periodic Acid-Schiff (PAS)-stained sections of renal, respectively. Moreover, the expressions of Nephrin and Podocin were measured by immunohistochemistry (IHC) and western blotting analysis to investigate podocyte damage. Furthermore, we established Mouse Podocyte Clone-5 (MPC-5) injury model to identify the active components of HKC against podocyte damage by detecting the expressions of Nephrin, Podocin, and ZO-1 proteins. At last, the key protein levels of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were assessed by western blotting analysis to explore the underlying mechanism of HKC against proteinuria. Results Our results showed that HKC administration for three consecutive weeks dose-dependently ameliorated both renal function and histopathological damages, elevated the expressions of Nephrin and Podocin, the pivotal molecules maintaining filtration function of the podocyte, indicating the promising protective effect against podocyte injury under DOX exposure. Consistently, in vitro experiments showed HKC administration effectively reversed the abnormal expressions of Nephrin and Podocin in MPC-5 cells treated with DOX, suggesting its protective effect against podocyte injury to maintain filtration barrier integrity. In addition, Hibifolin was identified as the most active ingredients in HKC, which suppressed upstream JAK2/STAT3 and PI3K/Akt pathway phosphorylation to maintain the structural and functional integrity of podocyte filtration barrier. Of note, AG490 , a selective JAK2 inhibitor , was used to further affirm the role of Hibifolin involving in regulation JAK2/STAT3. Conclusions Our study suggested that HKC may protect podocytes via JAK2/STAT3 and PI3K/Akt pathway to display its effects of ameliorating proteinuria.
研究领域:
药理学
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肾病学
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民族药理学
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分子生物学
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
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IF 4.319
Nianxiu Tian,Yanbin Gao,Xiaolei Wang,Xiaoming Wu,Dawei Zou,Zhiyao Zhu,ZheJi Han,Tao Wang,Yimin Shi
Background Endoplasmic reticulum stress is associated with podocyte apoptosis in the pathogenesis of diabetic nephropathy (DN). A previous study has demonstrated that emodin has a protective effect in the kidney by suppressing proliferation of mesangial cells and inhibiting the renal tubular epithelial-to-mesenchymal transition. However, the effects of emodin on the podocyte apoptosis in DN and its mechanisms are unknown.Aim This study aimed to explore the effect of emodin on DN model KK-Ay mice and high glucose induced podocytes apoptosis via the PERK–eIF2α pathway.Methods KK-Ay mice model of DN were treated with emodin at dose of 40 and 80 mg/kg/day for 8 weeks. Urine albumin, serum creatinine, blood urea nitrogen levels and the renal histopathology in mice were performed. In vitro, conditionally immortalized mouse podocytes exposed to HG (30mM) were incubated with emodin. Cell viability was measured by CCK-8 assay. Additionally, we performed RNA interference and measured the apoptosis in cultured podocytes treated with emodin. Immunohistochemistry, immunofluorescence, western blot, and real-time PCR were used to detect gene and protein expression both in vivo and in vitro.Results The results showed that emodin treatment ameliorated urine albumin, serum creatinine, and blood urea nitrogen of DN mice. The pathological damage of kidney tissue was also improved after treatment with emodin. Moreover, emodin increased nephrin expression. Podocytes apoptosis and endoplasmic reticulum stress markers (GRP78) were significantly reduced upon emodin treatment. Furthermore, emodin treatment decreased the expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (P-PERK), phosphorylated P-eIF2α, ATF4, and CHOP. In vitro, emodin treatment was further found to decrease the GRP78 level induced by high glucose or tunicamycin (TM). Besides, emodin and PERK knockdown inhibited the apoptosis of podocytes cultured in high glucose by counteracting the upregulation of phosphorylated PERK, phosphorylated eIF2α, ATF4, and CHOP.Conclusion Overall, the findings indicate that emodin mitigates podocytes apoptosis by inhibiting the PERK-eIF2α signaling pathway in vivo and in vitro, and, therefore, exerts a protective action on podocytes in DN.
研究领域:
药理学
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肾病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Shuhui Zhou,Liping Zheng,Tingxuan Zheng,Haiyan Zhan,Qiuyuan Lin,Jiaoao Wei,Yong Huang
Background: Nephrotic syndrome has a significant impact on global health, often leading to cardiovascular disease and high mortality due to limited effective treatments. This study investigates the efficacy of Shensu IV in a puromycin aminonucleoside (PAN)-induced rat model of nephropathy.Methods: Rat models and in vitro podocyte PAN nephropathy models were established with PAN and treated with Shensu IV. Renal function was evaluated by measuring urine output and protein content, while hydrogen sulfide (H2S) and oxidative stress markers were quantified in serum and podocyte lysates. We conducted histological examination on kidney tissues and analyzed molecular markers (CD2AP, nephrin, and PI3K/AKT pathway) using RT-qPCR and Western blot.Results: Shensu IV significantly improved urine output and proteinuria, and attenuated glomerular damage, fibrosis, and mitochondrial swelling in PAN-treated rats. Mechanistically, Shensu IV enhanced endogenous H2S production, reducing oxidative stress and activating the PI3K/AKT pathway in vivo and in vitro. This facilitated the upregulation of the target genes CD2AP and nephrin, which are critical for maintaining glomerular integrity and improving renal function in PAN nephropathy models.Conclusion: Shensu IV and NaHS confer renal protection primarily by modulating oxidative stress and restoring the integrity of the glomerular filtration barrier through mechanisms involving the enhancement of the PI3K/AKT pathway and modulation of H2S levels. These findings suggest a promising therapeutic potential for these metabolites in the treatment of nephrotic syndrome.
研究领域:
药理学
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肾病学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF NUTRITION
·
2025
·Vol. 64
·期 6
·1-17
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IF 4.3
Chen Huihui,Lin Hongzhou,Qian Rengcheng,Tang Guoqi,Ding Yinjuan,Jiang Yalan,Guo Xiaoling,Wang Dexuan
Purpose Nephrotic syndrome (NS) is the main cause of the increasing end-stage renal disease (ESRD) patients worldwide. Podocytes are considered the crucial cells involved in the progression of NS, and their damage can directly lead to proteinuria. The objective of this study was to explore the protective effects of xanthohumol (XN) on podocyte injury. Methods Adriamycin (ADR)-induced podocyte injury in vivo and in vitro models were established to explore the effects of XN on adriamycin nephropathy (AN) by urine and serum biochemical assay, periodic acid-schiff (PAS) staining, immunohistochemistry, immunofluorescence, western blot, and real-time quantitative PCR (RT-qPCR). Results The results showed that XN could upregulate the expressions of podocyte specific marker Wilms’ tumor protein 1 (Wt1), and glomerular filtration related functional proteins such as Nephrin, Synaptopodin, Zonula occludens 1 (ZO-1), and Crumbs2 (Crb2) as well as downregulate the expression of podocyte injury marker Desmin in ADR-treated podocytes to restrain the podocyte actin cytoskeleton disruption. Conclusion Our study showed that XN treatment significantly attenuated ADR-induced podocyte injury, suggesting that XN may be a potential therapy option for patients with NS.
研究领域:
肾脏病学
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分子生物学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2018
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IF 3.457
YingHui Zhang,Bing Wang,Feng Guo,ZhiZhen Li,GuiJun Qin
Diabetic nephropathy is one of the manifestations of systemic microangiopathy in diabetes. Hesperetin , a natural flavanone glycoside compound in citrus fruits, has been demonstrated to exert hypoglycemic effects and protect kidney in experimental diabetic animals. The current study was aimed to investigate the mechanisms underlying the hypoglycemic effects of hesperetin in high-fat/streptozocin (STZ)–induced diabetic nephropathy. The results showed that mice in whom hesperetin was administered for 4 weeks attenuated the increased fasting blood glucose and impaired glucose tolerance ability that was observed in high-fat/STZ mice. In addition, we found that hesperetin ameliorated the abnormalities of biochemical parameters in serum, liver, and kidney of mice with diabetic nephropathy. Hesperetin also rescued the irregular distortions in glomerular basement membrane and expanded mesangial regions. Moreover, hesperetin repaired the function of podocyte by increasing renal nephrin expression and decreasing renal alpha-smooth muscle actin expression. Furthermore, hesperetin inhibited the expression of transforming growth factor-β1 (TGF-β1) and its downstream effectors integrin-linked kinase (ILK) and Akt. In conclusion, our study implies that hesperetin produced protective effects in diabetic nephropathy possibly by suppressing TGF-β1-ILK-Akt signaling.
研究领域:
药理学
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内分泌学
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肾病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aging-US
·
2023
·
IF 5.2
Huahua Li,Jin Zheng,Yacen Wu,Hong Zhou,Suli Zeng,Quanqing Li
Backgrounds: High glucose (HG) caused oxidative stress and mitochondrial dysfunction, resulting in insulin resistance in podocytes, a key mechanism of diabetic nephropathy. Dendrobium officinale polysaccharide (DOP) was able to improve insulin resistance and antioxidant capability. Objective: The purpose of this study is to explore the mechanism by which DOP decreases the podocyte injury induced by HG. Methods: MPC5 cells were treated with HG, DOP, and IRS-1/2 inhibitor NT157. Afterwards, glucose consumption, generations of ROS and MDA were measured using the detection kits. Mitophagy was monitored using both MtphagTracyker and LysoTracker. The mitochondrial membrane potential was evaluated by JC-1 staining. DOP was also used in a mouse model of diabetes, with the measurements of urine albumin, blood creatinine and blood urea nitrogen. Results: Treatment with DOP suppressed the HG-induced reduction of glucose consumption, the phosphorylation of IRS-1 (phospho Y632), AKT (phospho Ser473 and Thr308) and Nephrin. In addition, HG-induced augment of ROS and MDA, formation of γ-H2A.X foci and translocation of AKT to nucleus were inhibited by DOP. DOP enhanced mitophagy, which was associated with decreased mitochondrial membrane potential and ROS production. DOP conferred protective effect on podocyte in the diabetic mouse by reducing the albumin/creatinine ratio and blood urea nitrogen, and restoring Nephrin expression in podocytes. Conclusions: DOP alleviates HG-induced podocyte injuryby regulating IRS-1/AKT signal and promoting mitophagy.
研究领域:
药理学
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细胞生物学
·
糖尿病
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肾病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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