Poricoic acid A suppresses renal fibroblast activation and interstitial fibrosis in UUO rats via upregulating Sirt3 and promoting ß-catenin K49 deacetylation.

Renal interstitial fibrosis is the common pathological process of various chronic kidney diseases to end-stage renal disease. Inhibition of fibroblast activation attenuates renal interstitial fibrosis. Our previous studies show that poricoic acid A (PAA) isolated from Poria cocos is a potent anti-fibrotic agent. In the present study we investigated the effects of PAA on renal fibroblast activation and interstitial fibrosis and the underlying mechanisms. Renal interstitial fibrosis was induced in rats or mice by unilateral ureteral obstruction (UUO). UUO rats were administered PAA (10 mg·kg-1·d-1, i.g.) for 1 or 2 weeks. An in vitro model of renal fibrosis was established in normal renal kidney fibroblasts (NRK-49F cells) treated with TGF-ß1. We showed that PAA treatment rescued Sirt3 expression, and significantly attenuated renal fibroblast activation and interstitial fibrosis in both the in vivo and in vitro models. In TGF-ß1-treated NRK-49F cells, we demonstrated that Sirt3 deacetylated ß-catenin (a key transcription factor of fibroblast activation) and then accelerated its ubiquitin-dependent degradation, thus suppressing the protein expression and promoter activity of pro-fibrotic downstream target genes (twist, snail1, MMP-7 and PAI-1) to alleviate fibroblast activation; the lysine-49 (K49) of ß-catenin was responsible for Sirt3-mediated ß-catenin deacetylation. In molecular docking analysis, we found the potential interaction of Sirt3 and PAA. In both in vivo and in vitro models, pharmacological activation of Sirt3 by PAA significantly suppressed renal fibroblast activation via facilitating ß-catenin K49 deacetylation. In UUO mice and NRK-49F cells, Sirt3 overexpression enhanced the anti-fibrotic effect of PAA, whereas Sirt3 knockdown weakened the effect. Taken together, PAA attenuates renal fibroblast activation and interstitial fibrosis by upregulating Sirt3 and inducing ß-catenin K49 deacetylation, highlighting Sirt3 functions as a promising therapeutic target of renal fibroblast activation and interstitial fibrosis.

Small molecules as modulators of regulated cell death against ischemia/reperfusion injury.

Ischemia/reperfusion (IR) injury contributes to disability and mortality worldwide. Due to the complicated mechanisms and lack of proper therapeutic targets, few interventions are available that specifically target the pathogenesis of IR injury. Regulated cell death (RCD) of endothelial and parenchymal cells is recognized as the promising intervening target. Recent advances in IR injury suggest that small molecules exhibit beneficial effects on various RCD against IR injury, including apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis, and parthanatos. Here, we describe the mechanisms behind these novel promising therapeutic targets and explain the machinery powering the small molecules. These small molecules exert protection by targeting endothelial or parenchymal cells to alleviate IR injury. Therapies of the ideal combination of small molecules targeting multiple cell types have shown potent synergetic therapeutic effects, laying the foundation for novel strategies to attenuate IR injury.

Intrarenal 1-methoxypyrene, an aryl hydrocarbon receptor agonist, mediates progressive tubulointerstitial fibrosis in mice.

Recent studies have shown that endogenous metabolites act via aryl hydrocarbon receptor (AhR) signalling pathway in tubulointerstitial fibrosis (TIF) pathogenesis. However, the mechanisms underlying endogenous metabolite-mediated AhR activation are poorly characterised. In this study, we conducted untargeted metabolomics analysis to identify the significantly altered intrarenal metabolites in a mouse model of unilateral ureteral obstruction (UUO). We found that the levels of the metabolite 1-methoxypyrene (MP) and the mRNA expression of AhR and its target genes CYP1A1, CYP1A2, CYP1B1 and COX-2 were progressively increased in the obstructed kidney at Weeks 1, 2 and 3. Furthermore, these changes were positively correlated with progressive TIF in UUO mice. In NRK-52E, RAW 264.7 and NRK-49F cells, MP dose-dependently upregulated the mRNA expression of AhR and its four target genes and the protein expression of nuclear AhR, accompanied by the upregulated protein expression of collagen I, α-SMA and fibronectin, as well as downregulated E-cadherin expression. Consistently, oral administration of MP in mice progressively enhanced AhR activity and upregulated profibrotic protein expression in the kidneys; these effects were partially inhibited by AhR knockdown in MP-treated mice and cell lines. In addition, we screened and identified erythro-guaiacylglycerol-ß-ferulic acid ether (GFA), which was isolated from Semen plantaginis, as a new AhR antagonist. GFA significantly attenuated TIF in MP-treated NRK-52E cells and mice by partially antagonising AhR activity. Our results suggest that MP activates AhR signalling, thus mediating TIF through epithelial-mesenchymal transition and macrophage-myofibroblast transition. MP is a crucial metabolite that contributes to TIF via AhR signalling pathway.

Small molecule inhibitors of epithelial-mesenchymal transition for the treatment of cancer and fibrosis.

Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial-mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc-finger E-box-binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor-ß1, RAC-α serine/threonine-protein kinase, Wnt, nuclear factor-kappa B, peroxisome proliferator-activated receptor, Notch, and RAS), RNA-binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.

Microbiome-metabolomics reveals gut microbiota associated with glycine-conjugated metabolites and polyamine metabolism in chronic kidney disease.

Dysbiosis of the gut microbiome and related metabolites in chronic kidney disease (CKD) have been intimately associated with the prevalence of cardiovascular diseases. Unfortunately, thus far, there is a paucity of sufficient knowledge of gut microbiome and related metabolites on CKD progression partly due to the severely limited investigations. Using a 5/6 nephrectomized (NX) rat model, we carried out 16S rRNA sequence and untargeted metabolomic analyses to explore the relationship between colon's microbiota and serum metabolites. Marked decline in microbial diversity and richness was accompanied by significant changes in 291 serum metabolites, which were mediated by altered enzymatic activities and dysregulations of lipids, amino acids, bile acids and polyamines metabolisms. Interestingly, CCr was directly associated with some microbial genera and polyamine metabolism. However, SBP was directly related to certain microbial genera and glycine-conjugated metabolites in CKD rats. Administration of poricoic acid A (PAA) and Poria cocos (PC) ameliorated microbial dysbiosis as well as attenuated hypertension and renal fibrosis. In addition, treatments with PAA and PC lowered serum levels of microbial-derived products including glycine-conjugated compounds and polyamine metabolites. Collectively, the present study confirmed the CKD-associated gut microbial dysbiosis and identified a novel dietary and therapeutic strategy to improve the gut microbial dysbiosis and the associated metabolomic disorders and retarded the progression of kidney disease in the rat model of CKD.

Microbiome-metabolome reveals the contribution of gut-kidney axis on kidney disease.

Dysbiosis represents changes in composition and structure of the gut microbiome community (microbiome), which may dictate the physiological phenotype (health or disease). Recent technological advances and efforts in metagenomic and metabolomic analyses have led to a dramatical growth in our understanding of microbiome, but still, the mechanisms underlying gut microbiome-host interactions in healthy or diseased state remain elusive and their elucidation is in infancy. Disruption of the normal gut microbiota may lead to intestinal dysbiosis, intestinal barrier dysfunction, and bacterial translocation. Excessive uremic toxins are produced as a result of gut microbiota alteration, including indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide, all implicated in the variant processes of kidney diseases development. This review focuses on the pathogenic association between gut microbiota and kidney diseases (the gut-kidney axis), covering CKD, IgA nephropathy, nephrolithiasis, hypertension, acute kidney injury, hemodialysis and peritoneal dialysis in clinic. Targeted interventions including probiotic, prebiotic and symbiotic measures are discussed for their potential of re-establishing symbiosis, and more effective strategies for the treatment of kidney diseases patients are suggested. The novel insights into the dysbiosis of the gut microbiota in kidney diseases are helpful to develop novel therapeutic strategies for preventing or attenuating kidney diseases and complications.

Combined Clinical Phenotype and Lipidomic Analysis Reveals the Impact of Chronic Kidney Disease on Lipid Metabolism.

Chronic kidney disease (CKD) results in significant dyslipidemia and profound changes in lipid and lipoprotein metabolism. The associated dyslipidemia, in turn, contributes to progression of CKD and its cardiovascular complications. To gain an in-depth insight into the disorders of lipid metabolism in advanced CKD, we applied UPLC-HDMS-based lipidomics to measure serum lipid metabolites in 180 patients with advanced CKD and 120 age-matched healthy controls. We found significant increases in the levels of total free fatty acids, glycerolipids, and glycerophospholipids in patients with CKD. The levels of free fatty acids, glycerolipids, and glycerophospholipids directly correlated with the level of serum triglyceride and inversely correlated with the levels of total cholesterol and eGFR. A total of 126 lipid species were identified from positive and negative ion modes. Out of 126, 113 identified lipid species were significantly altered in patients with CKD based on the adjusted FDR method. These results pointed to profound disturbance of fatty acid and triglyceride metabolisms in patients with CKD. Logistic regression analysis showed strong correlations between serum methyl hexadecanoic acid, LPC(24:1), 3-oxooctadecanoic acid, and PC(20:2/24:1) levels with eGFR and serum creatinine levels (R > 0.8758). In conclusion, application of UPLC-HDMS-based lipidomic technique revealed profound changes in lipid metabolites in patients with CKD. The observed increases in serum total fatty acids, glycerolipids, and glycerophospholipids levels directly correlated with increased serum triglyceride level and inversely correlated with the eGFR and triglyceride levels.

The link between phenotype and fatty acid metabolism in advanced chronic kidney disease.

BACKGROUND: The kidney plays a central role in elimination of metabolic waste products and regulation of low-molecular weight metabolites via glomerular filtration, tubular secretion and reabsorption. Disruption of these processes results in profound changes in the biochemical milieu of the body fluids, which contribute to complications of chronic kidney disease (CKD) by inducing cytotoxicity and inflammation. Insight into the changes of the composition of metabolites and dysregulation of target genes and proteins enhances the understanding of the pathophysiology of CKD and its complications, and the development of novel therapeutic strategies. Chronic interstitial nephropathy is a common cause of CKD. The present study was designed to determine the effect of chronic interstitial nephropathy on the composition of serum metabolites and regulation of oxidative, inflammatory, fibrotic and cytoprotective pathways. METHODS: Male Sprague-Dawley rats were randomized to the CKD and control groups ( n = 8/group). CKD was induced by administration of adenine (200 mg/kg body weight/day) by oral gavage for 3 weeks. The control group was treated with the vehicle alone. The animals were then observed for an additional 3 weeks, at which point they were sacrificed and kidney and serum samples were collected. Serum metabolomic and lipidomic analyses were performed using ultra-performance liquid chromatography-quadrupole time-of-flight high-definition mass spectrometry. Kidney tissues were processed for histological and molecular biochemical analyses. RESULTS: CKD rats exhibited increased plasma urea and creatinine concentrations, renal interstitial fibrosis, tubular damage and up-regulation of pro-inflammatory, pro-oxidant and pro-fibrotic pathways. Comparison of serum from CKD and control rats revealed significant differences in concentrations of amino acids and lipids including 33 metabolites and 35 lipid species. This was associated with marked abnormalities of fatty acid oxidation, and γ-linolenic acid and linoleic acid metabolism in CKD rats. Logistic regression analysis identified tetracosanoic acid, docosatrienoic acid, PC(18:3/14:1) and l -aspartic acid, tetracosanoic acid and docosatrienoic acid as novel biomarkers of chronic interstitial nephropathy. CONCLUSIONS: Advanced CKD in rats with adenine-induced chronic interstitial nephropathy results in profound changes in the serum metabolome, activation of inflammatory, oxidative and fibrotic pathways, and suppression of cytoprotective and antioxidant pathways.

Urinary biomarker and treatment mechanism of Rhizoma Alismatis on hyperlipidemia.

Rhizoma Alismatis (RA), a diuretic in Asia and Europe, was found to possess anti-hyperlipidemic activity. Since the biomarkers and mechanisms of RA in the treatment of hyperlipidemia are inadequate, ultra-performance liquid chromatography coupled with quadrupole time-of-flight synapt high-definition mass spectrometry and multivariate data analysis were employed to investigate the urinary metabolomics of RA on hyperlipidemic rats induced by high-fat diet. The metabolic profile of RA-treated hyperlipidemic group located between control and diet-induced hyperlipidemic groups. Nineteen metabolites with significant fluctuations were identified as potential biomarkers related to the hyperlipidemia and anti-hyperlipidemia of RA using partial least-squares-discriminate analysis, heatmap analysis and correlation coefficient analysis. The fluctuations of these biomarkers represented disturbances in amino acid metabolism, purine metabolism, pyrimidine metabolism and energy metabolism. After RA treatment, these perturbed metabolites were restored to normal or nearly normal levels. RA can alleviate high-fat diet-induced dysfunctions in these metabolic pathways.

[Research progress on pharmacology, pharmacokinetics and determination of ergosta-4,6,8 (14),22-tetraen-3-one].

Ergosta-4,6,8(14),22-tetraen-3-one (ergone) is one of main components in many medicinal fungi. Ergone has been reported to possess the activities of diuresis, cytotoxicity, antitumor, immunosuppression, as well as treatment of chronic kidney disease. According to reported literatures, an overview of spectroscopy characteristics, content determination, pharmacological activity and pharmacokinetics, etc. for ergone is presented in this review. Furthermore, the present review can provide a certain reference value for the further study and development of ergone.

Targeting pyruvate kinase M2 for the treatment of kidney disease.

Pyruvate kinase M2 (PKM2), a rate limiting enzyme in glycolysis, is a cellular regulator that has received extensive attention and regards as a metabolic regulator of cellular metabolism and energy. Kidney is a highly metabolically active organ, and glycolysis is the important energy resource for kidney. The accumulated evidences indicates that the enzymatic activity of PKM2 is disturbed in kidney disease progression and treatment, especially diabetic kidney disease and acute kidney injury. Modulating PKM2 post-translational modification determines its enzymatic activity and nuclear translocation that serves as an important interventional approach to regulate PKM2. Emerging evidences show that PKM2 and its post-translational modification participate in kidney disease progression and treatment through modulating metabolism regulation, podocyte injury, fibroblast activation and proliferation, macrophage polarization, and T cell regulation. Interestingly, PKM2 activators (TEPP-46, DASA-58, mitapivat, and TP-1454) and PKM2 inhibitors (shikonin, alkannin, compound 3k and compound 3h) have exhibited potential therapeutic property in kidney disease, which indicates the pleiotropic effects of PKM2 in kidney. In the future, the deep investigation of PKM2 pleiotropic effects in kidney is urgently needed to determine the therapeutic effect of PKM2 activator/inhibitor to benefit patients. The information in this review highlights that PKM2 functions as a potential biomarker and therapeutic target for kidney diseases.

Tangshen Formula alleviates inflammatory injury against aged diabetic kidney disease through modulating gut microbiota composition and related amino acid metabolism.

Diabetic kidney disease (DKD) is leading causes and one of the fastest growing causes of chronic kidney disease worldwide, and leads to high morbidity and mortality. Emerging evidences have revealed gut microbiota dysbiosis and related metabolism dysfunction play a dominant role in DKD progression and treatment through modulating inflammation. Our previous studies showed that Tangshen Formula (TSF), a Chinese herbal prescription, exhibited anti-inflammatory effect on DKD, but underlying mechanism that involved gut microbiota and related metabolism in aged model remained obscure. Here, BTBR ob/ob mice were used to establish aged DKD model, and 16S rRNA sequence and untargeted metabolomic analyses were employed to investigate the correlation between colonic microbiota and serum metabolism. The aged ob/ob mice exhibited obvious glomerular and renal tubule injury and kidney function decline in kidney, while TSF treatment significantly attenuated these abnormalities. TSF also exhibited potent anti-inflammatory effect in aged ob/ob mice indicating by reduced proinflammatory factor IL-6 and TNF-α, MCP-1 and COX-2 in serum, kidney and intestine, which suggested the involvement of gut microbiota with TSF effect. The 16S rDNA sequencing of the colonic microbiome and untargeted serum metabolomics analysis revealed significant differences in gut microbiota structure and serum metabolomic profiles between WT and ob/ob mice. Notably, TSF treatment reshaped the structure of gut microbiota and corrected the disorder of metabolism especially tryptophan metabolism and arginine biosynthesis. TSF increased Anaeroplasma and Barnesiella genera and decreased Romboutsia, Akkermansia, and Collinsella genera, and further elevated tryptophan, 5-hydroxyindoleacetate, glutamic acid, aspartate and reduced 4-hydroxy-2-quinolinecarboxylic acid, indole-3-acetic acid, xanthurenic acid, glutamine. Further correlation analysis indicated that disturbed gut microbiota was linked to tryptophan metabolism and arginine biosynthesis to regulate inflammation in aged DKD. Our data revealed that TSF attenuated renal inflammation by modulating gut microbiota and related amino acid metabolism in aged DKD model, highlighting gut microbiota and related metabolism functioned as potential therapeutic target for DKD in elderly patients.

Pharmacokinetics of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside in rat using ultra-performance LC-quadrupole TOF-MS.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG) from Polygoni multiflori has been demonstrated to possess a variety of pharmacological activities, including antioxidant, anti-inflammatory and hepatoprotective activities. Ultra-performance LC-quadrupole TOF-MS with MS Elevated Energy data collection technique and rapid resolution LC with diode array detection and ESI multistage MS(n) methods were developed for the pharmacokinetics, tissue distribution, metabolism, and excretion studies of THSG in rats following a single intravenous or oral dose. The three metabolites were identified by rapid resolution LC-MS(n). The concentrations of the THSG in rat plasma, bile, urine, feces, or tissue samples were determined by ultra-performance LC-MS. The results showed that THSG was rapidly distributed and eliminated from rat plasma. After the intravenous administration, THSG was mainly distributing in the liver, heart, and lung. For the rat, the major distribution tissues after oral administration were heart, kidney, liver, and lung. There was no long-term storage of THSG in rat tissues. Total recoveries of THSG within 24 h were low (0.1% in bile, 0.007% in urine, and 0.063% in feces) and THSG was excreted mainly in the forms of metabolites, which may resulted from biotransformation in the liver.

[Chemical constituents of surface layer of Poria cocos and their pharmacological properties (I)].

The surface layer of the sclerotia of Poria cocos, named Fu-Ling-Pi, is used as a diuretic in traditional Chinese medicine to treat edema and urinary dysfunction. Recent studies have showed that the triterpenes (lanostane and 3,4-secolanostane skeletons) and polysaccharides (beta-pachyman) are the main components of Fu-Ling-Pi and they exhibited various biological activities, such as anti-tumor, antibacterial and antioxidant, etc. This review was focused on the chemistry, pharmacology, and clinical uses of this drug and it may provide scientific foundation for further development and utilization of Fulingpi.

Therapeutic mechanism and clinical application of Chinese herbal medicine against diabetic kidney disease.

Diabetic kidney disease (DKD) is the major complications of type 1 and 2 diabetes, and is the predominant cause of chronic kidney disease and end-stage renal disease. The treatment of DKD normally consists of controlling blood glucose and improving kidney function. The blockade of renin-angiotensin-aldosterone system and the inhibition of sodium glucose cotransporter 2 (SGLT2) have become the first-line therapy of DKD, but such treatments have been difficult to effectively block continuous kidney function decline, eventually resulting in kidney failure and cardiovascular comorbidities. The complex mechanism of DKD highlights the importance of multiple therapeutic targets in treatment. Chinese herbal medicine (active compound, extract and formula) synergistically improves metabolism regulation, suppresses oxidative stress and inflammation, inhibits mitochondrial dysfunction, and regulates gut microbiota and related metabolism via modulating GLP-receptor, SGLT2, Sirt1/AMPK, AGE/RAGE, NF-κB, Nrf2, NLRP3, PGC-1α, and PINK1/Parkin pathways. Clinical trials prove the reliable evidences for Chinese herbal medicine against DKD, but more efforts are still needed to ensure the efficacy and safety of Chinese herbal medicine. Additionally, the ideal combined therapy of Chinese herbal medicine and conventional medicine normally yields more favorable benefits on DKD treatment, laying the foundation for novel strategies to treat DKD.

Serum Metabolites Associated with Blood Pressure in Chronic Kidney Disease Patients.

Blood pressure is one of the most basic health screenings and it has a complex relationship with chronic kidney disease (CKD). Controlling blood pressure for CKD patients is crucial for curbing kidney function decline and reducing the risk of cardiovascular disease. Two independent CKD cohorts, including matched controls (discovery n = 824; validation n = 552), were recruited. High-throughput metabolomics was conducted with the patients' serum samples using mass spectrometry. After controlling for CKD severity and other clinical hypertension risk factors, we identified ten metabolites that have significant associations with blood pressure. The quantitative importance of these metabolites was verified in a fully connected neural network model. Of the ten metabolites, seven have not previously been associated with blood pressure. The metabolites that had the strongest positive association with blood pressure were aspartylglycosamine (p = 4.58 × 10-5), fructose-1,6-diphosphate (p = 1.19 × 10-4) and N-Acetylserine (p = 3.27 × 10-4). Three metabolites that were negatively associated with blood pressure (phosphocreatine, p = 6.39 × 10-3; dodecanedioic acid, p = 0.01; phosphate, p = 0.04) have been reported previously to have beneficial effects on hypertension. These results suggest that intake of metabolites as supplements may help to control blood pressure in CKD patients.

Natural Products Against Renal Fibrosis via Modulation of SUMOylation.

Renal fibrosis is the common and final pathological process of kidney diseases. As a dynamic and reversible post-translational modification, SUMOylation and deSUMOylation of transcriptional factors and key mediators significantly affect the development of renal fibrosis. Recent advances suggest that SUMOylation functions as the promising intervening target against renal fibrosis, and natural products prevent renal fibrosis via modulating SUMOylation. Here, we introduce the mechanism of SUMOylation in renal fibrosis and therapeutic effects of natural products. This process starts by summarizing the key mediators and enzymes during SUMOylation and deSUMOylation and its regulation role in transcriptional factors and key mediators in renal fibrosis, then linking the mechanism findings of SUMOylation and natural products to develop novel therapeutic candidates for treating renal fibrosis, and concludes by commenting on promising therapeutic targets and candidate natural products in renal fibrosis via modulating SUMOylation, which highlights modulating SUMOylation as a promising strategy for natural products against renal fibrosis.

1-Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway.

BACKGROUND AND PURPOSE: In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal transplant. Evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of 1-hydroxypyrene in mediating renal fibrosis. EXPERIMENTAL APPROACH: We analysed 5406 urine and serum samples from patients with Stage 1-5 CKD using metabolomics, and 1-hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine-induced rats. KEY RESULTS: We identified correlations between the urine and serum levels of 1-hydroxypyrene and the estimated GFR in patients with CKD onset and progression. Moreover, increased 1-hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Up-regulated mRNA expression of aryl hydrocarbon receptor and its target genes, including CYP1A1, CYP1A2 and CYP1B1, were observed in patients and rats with progressive CKD. Further we showed up-regulated mRNA expression of aryl hydrocarbon receptor and its three target genes, plus up-regulated nuclear aryl hydrocarbon receptor protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Treatment with aryl hydrocarbon receptor short hairpin RNA or flavonoids inhibited mRNA expression of aryl hydrocarbon receptor and its target genes in 1-hydroxypyrene-induced HK-2 cells and mice. CONCLUSION AND IMPLICATIONS: Metabolite 1-hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the aryl hydrocarbon receptor signalling pathway. Targeting aryl hydrocarbon receptor may be an alternative therapeutic strategy for CKD progression.

A Review of Traditional Chinese Medicine in Treating Renal Interstitial Fibrosis via Endoplasmic Reticulum Stress-Mediated Apoptosis.

Renal interstitial fibrosis (RIF) is the main pathological manifestation of end-stage renal disease. Recent studies have shown that endoplasmic reticulum (ER) stress is involved in the pathogenesis and development of RIF. Traditional Chinese medicine (TCM), as an effective treatment for kidney diseases, can improve kidney damage by affecting the apoptotic signaling pathway mediated by ER stress. This article reviews the apoptotic pathways mediated by ER stress, including the three major signaling pathways of unfolded protein response, the main functions of the transcription factor C/EBP homologous protein. We also present current research on TCM treatment of RIF, focusing on medicines that regulate ER stress. A new understanding of using TCM to treat kidney disease by regulating ER stress will promote clinical application of Chinese medicine and discovery of new drugs for the treatment of RIF.

The Active Compounds and Therapeutic Target of Tripterygium wilfordii Hook. f. in Attenuating Proteinuria in Diabetic Nephropathy: A Review.

Tripterygium wilfordii Hook. f. (TWHF) is a traditional Chinese herbal medicine and widely used to treat diabetic kidney disease in China. Emerging evidences have revealed its ability to attenuate diabetic nephropathy (DN). Tripterygium wilfordii polyglycosides (TWPs), triptolide (TP), and celastrol are predominantly active compounds isolated from TWHF. The effects and molecular mechanisms of TWHF and its active compounds have been investigated in recent years. Currently, it is becoming clearer that the effects of TWHF and its active compounds involve in anti-inflammation, anti-oxidative stress, anti-fibrosis, regulating autophagy, apoptosis, and protecting podocytes effect. This review presents an overview of the current findings related to the effects and mechanisms of TWHF and its active compounds in therapies of DN, thus providing a systematic understanding of the mechanisms and therapeutic targets by which TWHF and its active compounds affect cells and tissues in vitro and in vivo.