Potential Application of Gambogic Acid for Retarding Renal Cyst Progression in Polycystic Kidney Disease.

Abnormal cell proliferation and accumulation of fluid-filled cysts along the nephrons in polycystic kidney disease (PKD) could lead to a decline in renal function and eventual end-stage renal disease (ESRD). Gambogic acid (GA), a xanthone compound extracted from the brownish resin of the Garcinia hanburyi tree, exhibits various pharmacological properties, including anti-inflammation, antioxidant, anti-proliferation, and anti-cancer activity. However, its effect on inhibiting cell proliferation in PKD is still unknown. This study aimed to determine the pharmacological effects and detailed mechanisms of GA in slowing an in vitro cyst growth model of PKD. The results showed that GA (0.25-2.5 µM) significantly retarded MDCK cyst growth and cyst formation in a dose-dependent manner, without cytotoxicity. Using the BrdU cell proliferation assay, it was found that GA (0.5-2.5 µM) suppressed MDCK and Pkd1 mutant cell proliferation. In addition, GA (0.5-2.5 µM) strongly inhibited phosphorylation of ERK1/2 and S6K expression and upregulated the activation of phosphorylation of AMPK, both in MDCK cells and Pkd1 mutant cells. Taken together, these findings suggested that GA could retard MDCK cyst enlargement, at least in part by inhibiting the cell proliferation pathway. GA could be a natural plant-based drug candidate for ADPKD intervention.

Chitosan oligosaccharide mitigates kidney injury in prediabetic rats by improving intestinal barrier and renal autophagy.

Consumption of a high-fat diet (HFD) not only increases the risk of metabolic syndrome but also initiates kidney injury. Lipid accumulation-induced systemic low-grade inflammation is an upstream mechanism of kidney injury associated with prediabetes. Chitosan oligosaccharide (COS) provides potent anti-obesity effects through several mechanisms including fecal lipid excretion. In this study, we investigated the effects of COS on the prevention of obesity-related complications and its ability to confer renoprotection in a prediabetic model. Rats fed on a HFD developed obesity, glucose intolerance and kidney dysfunction. COS intervention successfully ameliorated these conditions (p < 0.05) by attenuating intestinal lipid absorption and the renal inflammation-autophagy-apoptosis axis. A novel anti-inflammatory effect of COS had been demonstrated by the strengthening of intestinal barrier integrity via calcium-sensing receptor (p < 0.05). The use of COS as a supplement may be useful in reducing prediabetic complications especially renal injury and the risk of type 2 diabetes.

The combination of dapagliflozin and statins ameliorates renal injury through attenuating the activation of inflammasome-mediated autophagy in insulin-resistant rats.

Long-term use of a high-fat diet with high-fructose (HFF) intake could promote insulin resistance and induce lipid accumulation leading to kidney injury possibly via impairment of the autophagy process and enhancement of the inflammasome pathway. We investigated whether dapagliflozin as a monotherapy or combined with atorvastatin could restore kidney autophagy impairment and reduce inflammasome activation associated with kidney injury induced by HFF consumption. Male Wistar rats were given an HFF for 16 weeks and then treated with dapagliflozin with or without atorvastatin for 4 weeks. Impaired glucose tolerance, dyslipidemia, renal lipid accumulation along with impaired renal autophagy and activated inflammasome pathway promoted renal injury were exhibited in HFF rats. Dapagliflozin with or without atorvastatin treatment could partially restore disrupted metabolic parameters and reduce kidney injury. In particular, the combination treatment group showed significant amelioration of inflammasome activation and autophagy impairment. In conclusion, the combination therapy of dapagliflozin and atorvastatin has a positive effect on renal injury associated with autophagy and inflammasome activation induced by HFF in insulin-resistant rats. This study is the first report demonstrating the underlying mechanism associated with a combination treatment of dapagliflozin and atorvastatin on autophagy and inflammasome pathways in an insulin-resistant condition. Therefore, dapagliflozin in combination with atorvastatin may be a further preventive or therapeutic strategy for chronic kidney disease in an insulin-resistant or diabetic condition.

A chalcone derivative retards renal cyst enlargement by inhibiting fluid secretion and cell proliferation in an in vitro model of polycystic kidney disease.

BACKGROUND: Renal bilateral fluid filled-cyst in polycystic kidney disease (PKD) is associated with abnormal epithelial cell proliferation and transepithelial fluid secretion which leads to end-stage renal disease (ESRD). A chalcone derivative, isoliquiritigenin (ISLQ), has been shown to have various pharmacological properties. Since several studies have shown that ISLQ could inhibit CFTR channel activity, it is interesting to see whether it can inhibit renal cyst enlargement. The present study was aimed to determine an inhibitory effect and the mechanism of chalcone derivatives on MDCK cyst progression and Pkd1 mutant cells. METHODS: MDCK cyst growth and cyst formation experiments, MTT assay, Ussing chamber experiment, BrdU cell proliferation assay and western blot analysis were performed in this study. RESULTS: Among four compounds of chalcone derivatives tested, CHAL-005 (100 µM) was found to inhibit MDCK cyst growth in a dose-dependent manner without cytotoxicity. It inhibited short-circuit current of chloride secretion as well as CFTR protein expression in MDCK cells. CHAL-005 significantly suppressed cell proliferation. In addition, CHAL-005 strongly reduced phosphorylation ERK1/2 and phosphorylation S6 kinase in MDCK and Pkd1 mutant cells. Interestingly, CHAL-005 activated phosphorylation of AMP kinase protein expression in MDCK and Pkd1 mutant cells. CONCLUSION: CHAL-005 slowed MDCK cyst progression by inhibiting CFTR expression and reducing ERK1/2 and mTOR/S6K signaling pathways as well as activating AMPK expression. Therefore, a chalcone derivative could represent as a promising drug candidate for polycystic kidney disease intervention.

Farnesoid X Receptor Activation Stimulates Organic Cations Transport in Human Renal Proximal Tubular Cells.

Farnesoid X receptor (FXR) is a ligand-activated transcription factor highly expressed in the liver and kidneys. Activation of FXR decreases organic cation transporter (OCT) 1-mediated clearance of organic cation compounds in hepatocytes. The present study investigated FXR regulation of renal clearance of organic cations by OCT2 modulation and multidrug and toxin extrusion proteins (MATEs). The role of FXR in OCT2 and MATEs functions was investigated by monitoring the flux of 3H-MPP+, a substrate of OCT2 and MATEs. FXR agonists chenodeoxycholic acid (CDCA) and GW4064 stimulated OCT2-mediated 3H-MPP+ uptake in human renal proximal tubular cells (RPTEC/TERT1 cells) and OCT2-CHO-K1 cells. The stimulatory effect of CDCA (20 µM) was abolished by an FXR antagonist, Z-guggulsterone, indicating an FXR-dependent mechanism. CDCA increased OCT2 transport activity via an increased maximal transport rate of MPP+. Additionally, 24 h CDCA treatment increased MATEs-mediated 3H-MPP+ uptake. Moreover, CDCA treatment increased the expression of OCT2, MATE1, and MATE2-K mRNA compared with that of the control. OCT2 protein expression was also increased following CDCA treatment. FXR activation stimulates renal OCT2- and MATE1/2-K-mediated cation transports in proximal tubules, demonstrating that FXR plays a role in the regulation of OCT2 and MATEs in renal proximal tubular cells.

Mitigation of renal inflammation and endoplasmic reticulum stress by vildagliptin and statins in high-fat high-fructose diet-induced insulin resistance and renal injury in rats.

Dyslipidemia and insulin resistance in obesity can lead to lipotoxicity and cellular damage. Renal lipotoxicity in association with an impairment of lipid metabolism induces renal damage through the activation of inflammation, ER stress, fibrosis and apoptosis. We investigated the effects of a combination treatment of the DPP-4 inhibitor vildagliptin and atorvastatin on renal lipotoxicity related to renal dysfunction and injury in a high-fat high-fructose diet (HFF)-induced insulin resistant condition. Male Wistar rats were fed on a high-fat diet and were given drinking water with 10% fructose for 16 weeks. After that, rats were divided into: no treatment (HFF), treatment with vildagliptin, atorvastatin and vildagliptin plus atorvastatin for 4 weeks. The results demonstrated that the combination treatment prominently improved insulin resistance, dyslipidemia and kidney morphological changes induced by HFF. These changes correlated well with the increased expression of nephrin and podocin and decreased urine protein. Notably, the combined treatment produced greater improvement in renal lipid metabolism through increasing fatty acid oxidation with the decreases in fatty acid transporters and fatty acid synthesis, thereby reducing renal lipid accumulation in HFF rats. The reduction in renal lipotoxicity via diminishing renal inflammation, ER stress, fibrosis and apoptosis was also more significant in the combined treatment group than in the other groups in which the drug was used as a monotherapy. In conclusion, the combination therapy produced synergistic beneficial effects on metabolic parameters, lipid metabolism and accumulation related to renal lipid accumulation-induced lipotoxicity and kidney injury in the HFF-induced insulin resistant model with improved outcomes.

Effects of dapagliflozin and statins attenuate renal injury and liver steatosis in high-fat/high-fructose diet-induced insulin resistant rats.

High-fat high-fructose diet (HFF) in obesity can induce dyslipidemia and lipid accumulation both in kidney and liver which related to insulin resistance and lipotoxicity-induced cellular damage. We investigated whether dapagliflozin with or without atorvastatin could improve lipid accumulation-induced kidney and liver injury in HFF-induced insulin resistant rats. Male Wistar rats were fed with HFF for 16 weeks and then received drug treatments for 4 weeks; vehicle, dapagliflozin, atorvastatin and dapagliflozin plus atorvastatin treatment groups. HFF rats demonstrated insulin resistance, dyslipidemia, liver injury and renal dysfunction associated with impaired renal lipid metabolism and lipid accumulation. Dapagliflozin and combination treatment could improve HFF-induced insulin resistance, lipogenesis and lipotoxicity-related renal oxidative stress, inflammation, fibrosis and apoptosis leading to kidney dysfunction recovery. Liver injury-associated inflammation was also improved by these two regimens. Notably, the reduced lipid accumulation in liver and kidney that linked to an improvement of lipid oxidation was prominent in the combination treatment. Therefore, dapagliflozin combined with atorvastatin treatment exert the beneficial effects on lipid metabolism and lipotoxicity in liver and kidney injury via the attenuation of oxidative stress, fibrosis and apoptosis in insulin resistant model.

Atorvastatin attenuates obese-induced kidney injury and impaired renal organic anion transporter 3 function through inhibition of oxidative stress and inflammation.

An excessive consumption of high-fat diet can lead to the alterations of glucose and lipid metabolism, impaired insulin signaling and increased ectopic lipid accumulation resulting in renal lipotoxicity and subsequent renal dysfunction. Atorvastatin is a lipid-lowering drug in clinical treatment. Several studies have reported that atorvastatin has several significant pleiotropic effects including anti-inflammatory, antioxidant, and anti-apoptotic effects. However, the effects of atorvastatin on metabolic disturbance and renal lipotoxicity in obesity are not fully understood. In this study, obesity in rat was developed by high-fat diet (HFD) feeding for 16 weeks. After that, the HFD-fed rats were received either a vehicle (HF), atorvastatin (HFA) or vildagliptin (HFVIL), by oral gavage for 4 weeks. We found that HF rats showed insulin resistance, visceral fat expansion and renal lipid accumulation. Impaired renal function and renal organic anion transporter 3 (Oat3) function and expression were also observed in HF rats. The marked increases in MDA level, renal injury and NF-κB, TGF-ß, NOX-4, PKC-α expression were demonstrated in HF rats. Atorvastatin or vildagliptin treatment attenuated insulin resistance and renal lipid accumulation-induced lipotoxicity in HFA and HFVIL rats. Moreover, the proteins involved in renal inflammation, fibrosis, oxidative stress and apoptosis were attenuated leading to improved renal Oat3 function and renal function in the treated groups. Interestingly, atorvastatin showed higher efficacy than vildagliptin in improving insulin resistance, renal lipid accumulation and in exerting renoprotective effects in obesity-induced renal injury and impaired renal Oat3 function.

Dapagliflozin attenuates renal gluconeogenic enzyme expression in obese rats.

The kidneys release glucose into the systemic circulation through glucose reabsorption and renal gluconeogenesis. Currently, the significance of renal glucose release in pathological conditions has become a subject of interest. We examined the effect of sodium-dependent glucose cotransporter 2 inhibitor (SGLT2i) on renal gluconeogenic enzyme expression in obese rats. Male Wistar rats (180-200 g) were fed either a normal diet (ND, n = 6) or a high-fat diet. At 16 weeks, after confirming the degree of glucose intolerance, high-fat diet-fed rats were randomly subdivided into three groups (n = 6/group): untreated group (HF), treated with dapagliflozin 1 mg/kg/day (HFSG) and treated with metformin 30 mg/kg/day (HFM). The treatment was continued for 4 weeks. We observed that dapagliflozin or metformin mitigated the enhanced expression of renal gluconeogenic enzymes, PEPCK, G6Pase and FBPase, as well as improved glucose tolerance and renal function in obese rats. Dapagliflozin downregulated the elevated expression of gluconeogenic transcription factors p-GSK3ß, p-CREB and coactivator PGC1α in the renal cortical tissue. Metformin reduced the expression levels of renal cortical FOXO1 and CREB. Furthermore, reduced renal insulin signaling was improved and renal oxidative stress was attenuated by either dapagliflozin or metformin treatment in obese rats. We concluded that glucose tolerance was improved by dapagliflozin in obese prediabetic rats by suppressing renal glucose release from not only glucose reabsorption but also renal gluconeogenesis through improving renal cortical insulin signaling and oxidative stress. The efficacy of dapagliflozin in improving renal insulin signaling, oxidative stress and renal function was greater than that of metformin.

High affinity of 4-(4-(dimethylamino)styryl)-N-methylpyridinium transport for assessing organic cation drugs in hepatocellular carcinoma cells.

Human organic cation transporter 1 (hOCT1) and human organic cation transporter 3 (hOCT3) are highly expressed in hepatocytes and play important roles in cationic drug absorption, distribution, and elimination. A previous study demonstrated that downregulation of hOCT1 and hOCT3 mRNA was related to hepatocellular carcinoma (HepG2) prognosis and severity. Whether these transporters expressed in HepG2 cells serve for cationic drug delivery has not been investigated. Besides radioactive transport, options for assessing hOCTs in hepatocytes are limited. This study clarified the significant roles of hOCTs in HepG2 by comparing cationic fluorescent 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+ ) with traditional [3 H]-1-methyl-4-phenylpyridinium (MPP+ ). The results showed ASP+ was preferably transported into HepG2 compared to [3 H]-MPP+ with high affinity and a high maximal transport rate. Selective transport of ASP+ mediated by hOCTs was influenced by extracellular pH, temperature, and membrane depolarization, corresponding to hOCT1 and hOCT3 expressions. Furthermore, transport of cationic drugs, metformin, and paclitaxel in HepG2 cells was blunted by OCT inhibitors, suggesting that hOCT1 and hOCT3 expressed in HepG2 cells exhibit notable impacts on cationic drug actions. The fluorescent ASP+ -based in vitro model may also provide a rapid and powerful analytical tool for further screening of cationic drug actions and interactions with hOCTs, particularly hOCT1 and hOCT3 in hepatocellular carcinoma.

Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats.

BACKGROUND: With an increasing prevalence of obesity and metabolic syndrome, exploring the effects and delineating the mechanisms of possible therapeutic agents are of critical importance. We examined the effects of SGLT2 inhibitor-dapagliflozin on insulin resistance, hepatic gluconeogenesis, hepatic injury and pancreatic ER stress in high-fat diet-induced obese rats. MATERIALS AND METHODS: Male Wistar rats were fed with normal diet (ND) or high-fat diet for 16 weeks. Then high-fat rats were given vehicle (HF) or dapagliflozin (1 mg/kg/day; HFDapa) or metformin (30 mg/kg/day; HFMet) for another 4 weeks. RESULTS: We found that dapagliflozin ameliorated high-fat diet-induced insulin resistance. The fasting plasma glucose level was comparable among groups, although dapagliflozin treatment led to substantial glycosuria. Hepatic gluconeogenic enzymes, PEPCK, G6Pase and FBPase, expression was not different in HF rats compared with ND rats. Meanwhile, dapagliflozin-treated group exhibited the elevation of these enzymes in parallel with the rise of transcription factor CREB, co-factor PGC1α and upstream regulator SIRT1. Hepatic oxidative stress, inflammation and NAFLD activity score as well as hepatic and pancreatic ER stress and apoptosis in obese rats were attenuated by dapagliflozin. CONCLUSION: We conclude that dapagliflozin improved obesity-related insulin resistance, hepatic and pancreatic injury independent of fasting plasma glucose level. Of note, dapagliflozin-induced glycosuria apparently triggered the up-regulation of hepatic gluconeogenic enzymes to prevent hypoglycemia.

Impaired renal organic anion transport 1 (SLC22A6) and its regulation following acute myocardial infarction and reperfusion injury in rats.

Acute kidney injury (AKI) is a high frequent and common complication following acute myocardial infarction (AMI). This study examined and identified the effect of AMI-induced AKI on organic anion transporter 1 (Oat1) and Oat3 transport using clinical setting of pre-renal AKI in vivo. Cardiac ischaemia (CI) and cardiac ischaemia and reperfusion (CIR) were induced in rats by 30-min left anterior descending coronary artery occlusion and 30-min occlusion followed by 120-min reperfusion, respectively. Renal hemodynamic parameters, mitochondrial function and Oat1/Oat3 expression and function were determined along with biochemical markers. Results showed that CI markedly reduced renal blood flow and pressure by approximately 40%, while these parameters were recovered during reperfusion. CI and CIR progressively attenuated renal function and induced oxidative stress by increasing plasma BUN, creatinine and malondialdehyde levels. Correspondingly, SOD, GPx, CAT mRNAs were decreased, while TNFα, IL1ß, COX2, iNOS, NOX2, NOX4, and xanthine oxidase were increased. Mitochondrial dysfunction as indicated by increasing ROS, membrane depolarisation, swelling and caspase3 activation were shown. Early significant detection of AKI; KIM1, IL18, was found. All of which deteriorated para-aminohippurate transport by down-regulating Oat1 during sudden ischaemia. This consequent blunted the trafficking rate of Oat1/Oat3 transport via down-regulating PKCζ/Akt and up-regulating PKCα/NFκB during CI and CIR. Thus, this promising study indicates that CI and CIR abruptly impaired renal Oat1 and regulatory proteins of Oat1/Oat3, which supports dysregulation of remote sensing and signalling and inter-organ/organismal communication. Oat1, therefore, could potentially worsen AKI and might be a potential therapeutic target for early reversal of such injury.

Activation of constitutive androstane receptor inhibits intestinal CFTR-mediated chloride transport.

Constitutive androstane receptor (CAR) belonging to the nuclear receptor superfamily plays an important role in the xenobiotic metabolism and disposition. It has been reported that CAR regulates the expression of the ATP-binding cassette (ABC) transporters in the intestine, such as multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 2/3 (MRP2 and MRP3). In this study, we investigated the role of CAR in the regulation of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride transport in T84 human colonic epithelial cells and mouse intestinal tissues. Treatments of T84 cell monolayers with specific CAR agonists (CITCO and phenytoin at concentrations of 1 µM and 5 µM, respectively) for 24 h decreased transepithelial Cl- secretion in response to cAMP-dependent agonist. This inhibition was abolished by coincubation of CITCO with a CAR antagonist, CINPA1. We confirmed that an inhibitory effect of CAR agonists was not due to their cytotoxicity. Basolateral membrane permeabilization experiments also revealed that activation of CAR decreased apical Cl- current stimulated by both CPT-cAMP and genistein (a direct CFTR activator). Such activation also reduced both mRNA and protein expression of CFTR. Furthermore, CITCO decreased cholera toxin (CT)-induced Cl- secretion across T84 cell monolayers. In ICR mice, administration of TCPOBOP (3 mg/kgBW), a murine-specific CAR agonist, for 7 days produced significant decreases in CFTR mRNA and protein expressions in intestinal tissues. Interestingly, TCPOBOP also inhibited CT-induced intestinal fluid accumulation in mice. This is the first evidence showing that CFTR was downregulated by CAR activation in the intestine. Our findings suggest that CAR has potential as a new drug target for treatment of condition with hyperactivity/ hyperfunction of CFTR especially secretory diarrheas.

Exhaustive exercise decreases renal organic anion transporter 3 function.

This study aimed to investigate the effects of various types of exercise on organic anion transporter 3 (Oat3) function, a major transporter that plays a role in the secretion of a variety of drugs and endogenous compounds. Male Wistar rats were randomly allocated to non-exercise, exhaustive, acute and training exercise groups. The function of Oat3 was assessed by the uptake of [3H]-estrone sulfate ([3H]-ES) into rat renal cortical slices. Acute and training exercises had no effect on [3H]-ES uptake whereas a marked reduction in [3H]-ES uptake occurred immediately after exhaustive exercise. However, the reduction in Oat3 function was gradually recovered at 6 and 24 h after the exercise session. Importantly, the impairment of Oat3 function was associated with a decrease in renal Oat3 protein expression. Our results indicate that exhaustive exercise produces a significant impact on renal organic anion transport function, which in turn could alter the plasma level of drugs and compounds in the body.

An agonist of a zinc-sensing receptor GPR39 enhances tight junction assembly in intestinal epithelial cells via an AMPK-dependent mechanism.

Intestinal barrier function depends on integrity of tight junctions, which serve as barriers to transepithelial influx of noxious substances/microorganisms from gut lumen. The G-protein coupled receptor 39 (GPR39) is a zinc-sensing receptor, which is expressed in several cell types including intestinal epithelial cells (IECs). The main objective of this study was to investigate the effect of GPR39 activation on tight junction assembly in IECs. Treatment with TC-G 1008 (1 µM -10 µM), a GPR39 agonist, and zinc (10 µM -100 µM) increased tight junction assembly in T84 cells. This effect was suppressed by pretreatment with compound C, an inhibitor of AMP-activated protein kinase (AMPK). In addition, western blot analysis revealed that treatment with TC-G 1008 induced AMPK activation in time- and concentration-dependent manners. Interestingly, inhibitors of phospholipase C (PLC) and calcium/calmodulin-dependent protein kinase kinase ß (CaMKKß) abrogated the effect of TC-G 1008 on inducing AMPK activation, tight junction assembly and zonula occludens-1 re-organization. Collectively, this study reveals a novel role of GPR39 in enhancing tight junction assembly in IECs via PLC-CaMKKß-AMPK pathways. GPR39 agonists may be beneficial in the treatment of diseases associated impaired intestinal barrier function.

Molecular signaling mechanisms of renal gluconeogenesis in nondiabetic and diabetic conditions.

The kidneys are as involved as the liver in gluconeogenesis which can significantly contribute to hyperglycemia in the diabetic condition. Substantial evidence has demonstrated the overexpression of rate-limiting gluconeogenic enzymes, especially phosphoenolpyruvate carboxykinase and glucose 6 phosphatase, and the accelerated glucose release both in the isolated proximal tubular cells and in the kidneys of diabetic animal models and diabetic patients. The aim of this review is to provide an insight into the mechanisms that accelerate renal gluconeogenesis in the diabetic conditions and the therapeutic approaches that could affect this process in the kidney. Increase in gluconeogenic substrates, reduced insulin concentration or insulin resistance, downregulation of insulin receptors and insulin signaling, oxidative stress, and inappropriate activation of the renin-angiotensin system are likely to participate in enhancing renal gluconeogenesis in the diabetic milieu. Several studies have suggested that controlling glucose metabolism at the renal level favors effective overall glycemic control in both type 1 and type 2 diabetes. Therefore, renal gluconeogenesis may be a promising target for effective glycemic control as a therapeutic strategy in diabetes.

Probiotic Lactobacillus paracasei HII01 protects rats against obese-insulin resistance-induced kidney injury and impaired renal organic anion transporter 3 function.

The relationship between gut dysbiosis and obesity is currently acknowledged to be a health topic which causes low-grade systemic inflammation and insulin resistance and may damage the kidney. Organic anion transporter 3 (Oat3) has been shown as a transporter responsible for renal handling of gut microbiota products which are involved in the progression of metabolic disorder. The present study investigated the effect of probiotic supplementation on kidney function, renal Oat3 function, inflammation, endoplasmic reticulum (ER) stress, and apoptosis in obese, insulin-resistant rats. After 12 weeks of being provided with either a normal or a high-fat diet (HF), rats were divided into normal diet (ND); ND treated with probiotics (NDL); HF; and HF treated with probiotic (HFL). Lactobacillus paracasei HII01 1 × 108 colony forming unit (CFU)/ml was administered to the rats daily by oral gavage for 12 weeks. Obese rats showed significant increases in serum lipopolysaccharide (LPS), plasma lipid profiles, and insulin resistance. Renal Oat 3 function was decreased along with kidney dysfunction in HF-fed rats. Obese rats also demonstrated the increases in inflammation, ER stress, apoptosis, and gluconeogenesis in the kidneys. These alterations were improved by Lactobacillus paracasei HII01 treatment. In conclusion, probiotic supplementation alleviated kidney inflammation, ER stress, and apoptosis, leading to improved kidney function and renal Oat3 function in obese rats. These benefits involve the attenuation of hyperlipidemia, systemic inflammation, and insulin resistance. The present study also suggested the idea of remote sensing and signaling system between gut and kidney by which probiotic might facilitate renal handling of gut microbiota products through the improvement of Oat3 function.

Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, slows the progression of renal complications through the suppression of renal inflammation, endoplasmic reticulum stress and apoptosis in prediabetic rats.

AIM: To evaluate the renoprotective roles of dapagliflozin in prediabetic rats in order to elucidate the effects of this sodium-glucose co-transporter-2 (SGLT2) inhibitor on the renal complications associated with metabolic dysfunction in diet-induced obesity. METHODS: Obesity was induced by feeding a high-fat diet (HFD) to male Wistar rats for 16 weeks. HFD-fed rats were treated with dapagliflozin (1 mg/kg/d) or metformin (30 mg/kg/d) by oral gavage for 4 weeks after insulin resistance had been established. The metabolic characteristics and renal function associated with lipid accumulation, inflammation, fibrosis, endoplasmic reticulum (ER) stress and apoptosis in the renal tissue were examined. RESULTS: The results showed that HFD-fed rats developed both obesity and impaired renal function, along with increased renal triglyceride accumulation. Importantly, dapagliflozin had greater efficacy in improving renal function and reducing both body weight and visceral fat accumulation than metformin treatment. Dapagliflozin and metformin were found to have similar effects regarding the suppression of renal triglycerides, superoxide dismutase (SOD) expression and malondialdehyde (MDA) levels, subsequently leading to a decrease in renal inflammation and fibrosis. Renal ER stress and apoptosis were increased in HFD-fed rats and were effectively reduced after administration of dapagliflozin. The expression of renal SGLT2 was not affected by administration of dapagliflozin or metformin. CONCLUSION: Collectively, these findings indicate that dapagliflozin exerts renoprotective effects by alleviating obesity-induced renal inflammation, fibrosis, ER stress, apoptosis and lipid accumulation in the prediabetic condition.

GPR40 receptor activation promotes tight junction assembly in airway epithelial cells via AMPK-dependent mechanisms.

Tight junctions play key roles in the regulation of airway epithelial barrier function and promotion of tight junction integrity is beneficial to lung health. G-protein coupled receptor (GPR) 40 has been identified as a receptor of polyunsaturated fatty acids. This study aimed to investigate the function of GPR40 in regulating tight junction assembly in human airway epithelial cells (Calu-3 cells) using GW9508, a GPR40 agonist. Immunoblotting and immunofluorescence analyses showed that Calu-3 cells expressed both types of polyunsaturated fatty acid receptors including GPR40 and GPR120. Intracellular Ca2+ measurements confirmed that GW9508 stimulated GPR40, but not GPR120. In Ca2+ switch assays, GW9508 promoted the recovery of transepithelial electrical resistance and re-localization of zonula occludens (ZO)-1 to intercellular areas. These effects were suppressed by inhibitors of GPR40 and phospholipase C (PLC). Interestingly, GW9508 enhanced tight junction assembly in an AMP-activated protein kinase (AMPK)-dependent manner. The effect of GW9508 on inducing tight junction assembly was also confirmed in 16HBE14o- cells. Our results indicate that GPR40 stimulation by GW9508 leads to AMPK activation via calcium/calmodulin-dependent protein kinase kinase ß (CaMKKß). Collectively, this study reveals an unprecedented role of GPR40 in facilitating airway epithelial tight junction assembly via PLC-CaMKKß-AMPK pathways. GPR40 represents a novel regulator of airway epithelial integrity and its stimulation may be beneficial in the treatment of airway diseases.

Lansoprazole reduces renal cyst in polycystic kidney disease via inhibition of cell proliferation and fluid secretion.

Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) is mediated by abnormal cyst-ling cell proliferation and fluid accumulation. Liver X receptor (LXR)-activating ligands suppresses renal cyst enlargement by modulation of cysticfibrosis transmembrane conductance regulator (CFTR)-mediated fluid accumulation. Lansoprazole has been reported as agonist of LXR, and shows an anti-proliferative effect in cancer cells. Here, lansoprazole's pharmacological effect and underlying mechanism on renal cyst development and expansion in in vitro; human ADPKD cyst-lining epithelial cell line and Type I Mardin Darby Canine Kidney (MDCK) cells, and in vivo models was investigated. Lansoprazole inhibited cyst development via inhibition of cell proliferation. In renal cells, lansoprazole's anti-proliferative effect was mediated by inhibition of mTOR/S6K and extracellular signal-regulated kinase (ERK) signaling proteins. In addition, lansoprazole inhibited CFTR-mediated fluid secretion via reduction of CFTR protein expression. In PCK rats, administering lansoprazole (50 mg/kgBW) for 4 weeks produced significant decreases in the cystic area and improved renal function by reduction of plasma creatinine and blood urea nitrogen. Inhibition of mTOR/S6K, ERK, and CFTR protein expression was observed in PCK rat kidney following lansoprazole treatment. The findings point to potential therapeutic application of lansoprazole in ADPKD.