Pharmacological potential of Astragali Radix for the treatment of kidney diseases.

BACKGROUND: With the increasing prevalence of hypertension, diabetes, and obesity, the incidence of kidney diseases is also increasing, resulting in a serious public burden. Conventional treatments for kidney diseases have unsatisfactory effects and are associated with adverse reactions. Traditional Chinese medicines have good curative effects and advantages over conventional treatments for preventing and treating kidney diseases. Astragali Radix is a Chinese herbal medicine widely used to treat kidney diseases. PURPOSE: To review the potential applications and molecular mechanisms underlying the renal protective effects of Astragali Radix and its components and to provide direction and reference for new therapeutic strategies and future research and development of Astragali Radix. STUDY DESIGN AND METHODS: PubMed, Google Scholar, and Web of Science were searched using keywords, including "Astragali Radix," "Astragalus," "Astragaloside IV" (AS-IV), "Astragali Radix polysaccharide" (APS), and "kidney diseases." Reports on the effects of Astragali Radix and its components on kidney diseases were identified and reviewed. RESULTS: The main components of Astragali Radix with kidney-protective properties include AS-IV, APS, calycosin, formononetin, and hederagenin. Astragali Radix and its active components have potential pharmacological effects for the treatment of kidney diseases, including acute kidney injury, diabetic nephropathy, hypertensive renal damage, chronic glomerulonephritis, and kidney stones. The pharmacological effects of Astragali Radix are manifested through the inhibition of inflammation, oxidative stress, fibrosis, endoplasmic reticulum stress, apoptosis, and ferroptosis, as well as the regulation of autophagy. CONCLUSION: Astragali Radix is a promising drug candidate for treating kidney diseases. However, current research is limited to animal and cell studies, underscoring the need for further verifications using high-quality clinical data.

Ameliorative effects of Modified Huangqi Chifeng decoction on podocyte injury via autophagy mediated by PI3K/AKT/mTOR and AMPK/mTOR pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Proteinuria is recognized as a risk factor for the exacerbation of chronic kidney disease. Modified Huangqi Chifeng decoction (MHCD) has distinct advantages in reducing proteinuria. Our previous experimental results have shown that MHCD can inhibit excessive autophagy. However, the specific mechanism by which MHCD regulates autophagy needs to be further explored. AIM OF THE STUDY: In this study, in vivo and in vitro experiments were conducted to further clarify the protective mechanism of MHCD on the kidney and podocytes by regulating autophagy based on phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK)/mTOR signaling pathways. MATERIALS AND METHODS: By a single injection via the tail vein, Sprague-Dawley rats received Adriamycin (5 mg/kg) to establish a model of proteinuria nephropathy. They were divided into control, model, MHCD, 3-methyladenine (3 MA), 3 MA + MHCD, and telmisartan groups and were administered continuously for 6 weeks. The MHCD-containing serum was prepared, and a model of podocyte injury induced by Adriamycin (0.2 µg/mL) was established. RESULTS: MHCD reduced the 24-h urine protein levels and relieved pathological kidney damage. During autophagy in the kidneys of rats with Adriamycin-induced nephropathy, the PI3K/AKT/mTOR signaling pathway is inhibited, while the AMPK/mTOR signaling pathway is activated. MHCD antagonized these effects, thereby inhibiting excessive autophagy. MHCD alleviated Adriamycin-induced podocyte autophagy, as demonstrated using Pik3r1 siRNA and an overexpression plasmid for Prkaa1/Prkaa2. Furthermore, MHCD could activate the PI3K/AKT/mTOR signaling pathway while suppressing the AMPK/mTOR signaling pathway. CONCLUSIONS: This study demonstrated that MHCD can activate the interaction between the PI3K/AKT/mTOR and the AMPK/mTOR signaling pathways to maintain autophagy balance, inhibit excessive autophagy, and play a role in protecting the kidneys and podocytes.

Effects and mechanisms of Chinese herbal medicine on IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN), is the main cause of end-stage renal disease, that causes serious physical and psychological burden to patients worldwide. Some traditional treatment measures, such as blocking the renin-angiotensin-aldosterone system, controlling blood pressure, and following a low-protein diet, may not achieve satisfactory results. Therefore, more effective and safe therapies for IgAN are urgently needed. PURPOSE: The aim of this review is to summarize the clinical efficacy of Chinese herbal medicines (CHMs) and their active ingredients in the treatment and management of IgAN based on the results of clinical trials, systematic reviews, and meta-analyses, to fully understand the advantages and perspectives of CHMs in the treatment of IgAN. STUDY DESIGN AND METHODS: For this review, the following electronic databases were consulted: PubMed, ResearchGate, Science Direct, Web of Science, Chinese National Knowledge Infrastructure and Wanfang Data, "IgA nephropathy," "traditional Chinese medicine," "Chinese herbal medicine," "herb," "mechanism," "Meta-analysis," "systematic review," "RCT" and their combinations were the keywords to search the relevant literature. Data were collected from 1990 to 2022. RESULTS: This review found that the active ingredients of CHMs commonly act on multiple signaling pathways in the clinical treatment of IgAN, mainly with antioxidant, anti-inflammatory and anti-fibrosis effects, and regulation of autophagy. CONCLUSION: Compared with the single-target therapy of modern medicine, CHMs can regulate the corresponding pathways from the aspects of anti-inflammation, anti-oxidation, anti-fibrosis and autophagy to play a multi-target treatment of IgAN through syndrome differentiation and treatment, which has good clinical efficacy and can be used as the first choice or alternative therapy for IgAN treatment. This review provides evidence and research direction for a comprehensive clinical understanding of the protective effect of Chinese herbal medicine on IgAN.

Ferroptosis: A new mechanism of traditional Chinese medicine compounds for treating acute kidney injury.

Acute kidney injury (AKI) is a major health concern owing to its high morbidity and mortality rates, to which there are no drugs or treatment methods, except for renal replacement therapy. Therefore, identifying novel therapeutic targets and drugs for treating AKI is urgent. Ferroptosis is an iron-dependent and lipid-peroxidation-driven regulatory form of cell death and is closely associated with the occurrence and development of AKI. Traditional Chinese medicine (TCM) has unique advantages in treating AKI due to its natural origin and efficacy. In this review, we summarize the mechanisms underlying ferroptosis and its role in AKI, and TCM compounds that play essential roles in the prevention and treatment of AKI by inhibiting ferroptosis. This review suggests ferroptosis as a potential therapeutic target for AKI, and that TCM compounds show broad prospects in the treatment of AKI by targeting ferroptosis.

Clinical efficacy of supplementing qi dispelling wind and activating blood circulation method in the treatment of IgA nephropathy: A meta-analysis.

BACKGROUND: IgA nephropathy (IgAN) is a common primary glomerular disease, and supplementing qi dispelling wind and activating blood is commonly used as a treatment method in Chinese medicine. However, the existing studies have small sample sizes. This study aimed to use a meta-analysis to explore the clinical efficacy of this method and to systematically introduce this effective treatment. METHODS: We searched for randomized controlled trial studies on supplementing qi dispelling wind and activating blood circulation methods for IgAN indexed in the China National Knowledge Infrastructure, Wanfang Data, Chongqing VIP, SinoMed, PubMed, EMBASE, and Web of Science databases, which were interrogated from database inception to January 2022. Combining the inclusion and exclusion criteria to screen the literature, we included a total of 15 eligible studies; the quality of the included studies was evaluated using the risk of bias assessment tool of the Cochrane System Revies Manual 5.4. The outcome indexes were extracted, and a meta-analysis was performed using Review Manager 5.4 software. RESULTS: Fifteen articles were included in this review. A meta-analysis of the results led to the conclusion that supplementing qi dispelling wind and activating blood circulation prescription has beneficial effects on the total effective rate [odds ratios = 3.95, 95% confidence interval (CI) 2.76-5.67], and can reduce 24-hour urinary protein quantity (mean deviation = -0.35, 95% CI -0.54 to -0.16) and serum creatinine (mean deviation = -15.41,95% CI -28.39 to -2.44) without impact normal level of alanine transaminase, hemoglobin, and serum albumin. CONCLUSIONS: Supplementing qi dispelling wind and activating blood can significantly improve renal function and reduce 24-hour urinary protein quantity levels in patients with IgAN compared to the use of non-Chinese medicine treatment. This finding provides a rationale for using this method in the clinical treatment of IgAN.

Traditional Chinese medicine compounds ameliorating glomerular diseases via autophagy: A mechanism review.

Glomerular diseases are major components of kidney disease, mainly manifested as podocyte disease, immune complex-associated glomerulonephritis, and renal autoimmune disease. They are the third leading cause of end-stage renal disease, especially in younger populations. Podocyte death or shedding is a key factor in the progression of glomerular diseases, and autophagy plays an important role in maintaining podocyte homeostasis. Dysfunction of autophagy has been associated with the progression of various glomerular diseases. Modulation of autophagy has been shown to play a protective role in experimental models of glomerular diseases, suggesting that autophagy is a potential therapeutic target for glomerular diseases. Traditional Chinese medicine (TCM) has unique advantages in the treatment of kidney disease. In vivo and in vitro studies have shown that TCM compounds can reduce podocyte apoptosis, inhibit inflammation, improve endoplasmic reticulum stress and oxidative stress responses, and play an active role via autophagy. This review summarizes the roles of autophagy in glomerular diseases and provides evidence that TCM compounds can regulate autophagy through different signaling pathways to ameliorate glomerular diseases.

Ginkgo Biloba Extract EGB761 Ameliorates the Extracellular Matrix Accumulation and Mesenchymal Transformation of Renal Tubules in Diabetic Kidney Disease by Inhibiting Endoplasmic Reticulum Stress.

The study is aimed at investigating the effects of Ginkgo biloba extract EGB761 on renal tubular damage and endoplasmic reticulum stress (ERS) in diabetic kidney disease (DKD). A total of 50 C57BL/6 N mice were randomly divided into the normal group, DKD group, DKD+EGB761 group (36 mg/kg), and DKD+4-phenylbutyrate (4-PBA) group (1 g/kg). The DKD model was replicated by high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). Renal tubular epithelial cells (HK-2) were divided into the control group, high-glucose group (30 mmol/L), EGB761 group (40 mg/L, 20 mg/L, 10 mg/L), TM group, and TM+4-PBA group. After 8 weeks of administration, expressions of serum creatinine (Scr), blood urea nitrogen (BUN), 24 h urinary protein (24 h Pro), fasting blood glucose (FBG), ß 2-microglobulin (ß 2-MG), and retinol binding protein 4 (RBP4) of mice were tested. The pathological changes of renal tissue were observed. The expressions of extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) markers α-smooth muscle actin (α-SMA), E-cadherin, fibronectin, and collagen IV, as well as the ERS markers GRP78 and ATF6, were tested by Western blot, qPCR, immunohistochemistry, or immunofluorescence. EGB761 could decrease the Scr, BUN, 24 h Pro, and FBG levels in the DKD group, alleviate renal pathological injury, decrease urine ß 2-MG, RBP4 levels, and decrease the expression of α-SMA, collagen IV, fibronectin, and GRP78, as well as ATF6, while increase the expression of E-cadherin. These findings demonstrate that EGB761 can improve renal function, reduce tubular injury, and ameliorate ECM accumulation and EMT in DKD kidney tubules, and the mechanism may be related to the inhibition of ERS.

Tongluo Digui decoction treats renal injury in diabetic rats by promoting autophagy of podocytes.

OBJECTIVE: To investigate the effects of Tongluo Digui decoction on renal injury and streptozotocin-induced podocyte autophagy in diabetic rats. METHODS: Male Sprague-Dawley rats were randomly divided into six groups: normal, model, Tongluo Digui decoction (high, medium, and low dose) and valsartan. Streptozotocin was injected intraperitoneally to replicate the diabetic animal model. After 8 weeks, proteinuria was evaluated to establish the diabetic nephropathy model. Treatments were administered daily via the intragastric route. At 16 weeks after gavage, we determined 24 h urine protein concentration, and blood glucose, serum creatinine, and urea nitrogen concentrations. Then, rats were sacrificed, and kidneys were harvested and stained with periodic acid-Schiff to evaluate the pathological changes in glomeruli, including glomerular podocytes by transmission electron microscopy. Western blot analysis was used to determine the expression of nephrin, podocin, p62, beclin-1, LC3Ⅱ/Ⅰ, and p-mTOR/mTOR protein in kidney tissues. RESULTS: Compared with the model group, Tongluo Digui decoction was associated with decreases in 24 h urine protein concentration, and blood glucose, hemoglobin A1c, serum creatinine, urea nitrogen concentrations, total serum protein and albumin. Concurrently, mesangial mesenteric broadening and fusion of foot processes were reduced, the glomerular basement membrane was not significantly thickened, and the number of podocytes and the number of autophagosomes in the podocytes was increased. Further, expression of nephrin, podocin, LC3Ⅱ, and beclin-1 protein in kidney tissue was up-regulated, while expression of p62 protein was down-regulated and mTOR phosphorylation was inhibited. CONCLUSION: Tongluo Digui decoction may inhibit the progression of diabetic nephropathy by inhibiting mTOR phosphorylation, thereby increasing autophagy to protect podocytes and reducing proteinuria.