Effects of furosemide, acetazolamide and amiloride on renal cortical and medullary tissue oxygenation in non-anaesthetised healthy sheep.

It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ , and renal function were then monitored for up to 8 h post-treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.

Supplementation of amino acids and organic acids prevents the increase in blood pressure induced by high salt in Dahl salt-sensitive rats.

A high-salt (HS) diet leads to metabolic disorders in Dahl salt-sensitive (SS) rats, and promotes the development of hypertension. According to the changes in the metabolites of SS rats, a set of combined dietary supplements containing amino acids and organic acids (AO) were designed. The purpose of the present study was to evaluate the effect of AO supplementation on the blood pressure of SS rats after the HS diet and clarify the mechanism of AO by metabolomics and biochemical analyses. The results showed that AO supplementation avoided the elevation of blood pressure induced by the HS diet in SS rats, increased the renal antioxidant enzyme activities (catalase, superoxide dismutase, glutathione reductase, and glutathione S-transferase), reduced the H2O2 and MDA levels, and restored the normal antioxidant status of the serum and kidneys. AO also reversed the decrease in the nitric oxide (NO) levels and NO synthase activity induced by the HS feed, which involved the L-arginine/NO pathway. Metabolomics analysis showed that AO administration increased the levels of amino acids such as cysteine, glycine, hypotaurine, and lysine in the renal medulla and the levels of leucine, isoleucine, and serine in the renal cortex. Of note, lysine, hypotaurine and glycine had higher metabolic centrality in the metabolic correlation network of the renal medulla after AO administration. In conclusion, AO intervention could prevent HS diet-induced hypertension in SS rats by restoring the metabolic homeostasis of the kidneys. Hence, AO has the potential to become a functional food additive to improve salt-sensitive hypertension.

Systems biology and machine learning approaches identify drug targets in diabetic nephropathy.

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, has become a massive global health burden. Despite considerable efforts, the underlying mechanisms have not yet been comprehensively understood. In this study, a systematic approach was utilized to identify the microRNA signature in DN and to introduce novel drug targets (DTs) in DN. Using microarray profiling followed by qPCR confirmation, 13 and 6 differentially expressed (DE) microRNAs were identified in the kidney cortex and medulla, respectively. The microRNA-target interaction networks for each anatomical compartment were constructed and central nodes were identified. Moreover, enrichment analysis was performed to identify key signaling pathways. To develop a strategy for DT prediction, the human proteome was annotated with 65 biochemical characteristics and 23 network topology parameters. Furthermore, all proteins targeted by at least one FDA-approved drug were identified. Next, mGMDH-AFS, a high-performance machine learning algorithm capable of tolerating massive imbalanced size of the classes, was developed to classify DT and non-DT proteins. The sensitivity, specificity, accuracy, and precision of the proposed method were 90%, 86%, 88%, and 89%, respectively. Moreover, it significantly outperformed the state-of-the-art (P-value ≤ 0.05) and showed very good diagnostic accuracy and high agreement between predicted and observed class labels. The cortex and medulla networks were then analyzed with this validated machine to identify potential DTs. Among the high-rank DT candidates are Egfr, Prkce, clic5, Kit, and Agtr1a which is a current well-known target in DN. In conclusion, a combination of experimental and computational approaches was exploited to provide a holistic insight into the disorder for introducing novel therapeutic targets.

Astragaloside IV ameliorates diabetic nephropathy in db/db mice by inhibiting NLRP3 inflammasome­mediated inflammation.

Diabetic nephropathy (DN) is a primary cause of end­stage renal disease. Despite the beneficial effects of astragaloside IV (AS)­IV on renal disease, the underlying mechanism of its protective effects against DN has not been fully determined. The aims of the present study were to assess the effects of AS­IV against DN in db/db mice and to explore the mechanism of AS­IV involving the NLR family pyrin domain containing 3 (NLRP3), caspase­1 and interleukin (IL)­1ß pathways. The 8­week­old db/db mice received 40 mg/kg AS­IV once a day for 12 weeks via intragastric administration. Cultured mouse podocytes were used to further confirm the underlying mechanism in vitro. AS­IV effectively reduced weight gain, hyperglycemia and the serum triacylglycerol concentration in db/db mice. AS­IV also reduced urinary albumin excretion, urinary albumin­to­creatinine ratio and creatinine clearance rate, as well as improved renal structural changes, accompanied by the upregulation of the podocyte markers podocin and synaptopodin. AS­IV significantly inhibited the expression levels of NLRP3, caspase­1 and IL­1ß in the renal cortex, and reduced the serum levels of tumor necrosis factor (TNF)­α and monocyte chemoattractant protein­1. In high glucose­induced podocytes, AS­IV significantly improved the expression levels of NLRP3, pro­caspase­1 and caspase­1, and inhibited the cell viability decrease in a dose­dependent manner, while NLRP3 overexpression eliminated the effect of AS­IV on podocyte injury and the inhibition of the NLRP3 and caspase­1 pathways. The data obtained from in vivo and in vitro experiments demonstrated that AS­IV ameliorated renal functions and podocyte injury and delayed the development of DN in db/db mice via anti­NLRP3 inflammasome­mediated inflammation.

Effects of Virgin Olive Oil on Blood Pressure and Renal Aminopeptidase Activities in Male Wistar Rats.

High saturated fat diets have been associated with the development of obesity and hypertension, along with other pathologies related to the metabolic syndrome. In contrast, the Mediterranean diet, characterized by its high content of monounsaturated fatty acids, has been proposed as a dietary factor capable of positively regulating cardiovascular function. These effects have been linked to changes in the local renal renin angiotensin system (RAS) and the activity of the sympathetic nervous system. The main goal of this study was to analyze the role of two dietary fat sources on aminopeptidases activities involved in local kidney RAS. Male Wistar rats (six months old) were fed during 24 weeks with three different diets: the standard diet (S), the standard diet supplemented with virgin olive oil (20%) (VOO), or the standard diet enriched with butter (20%) plus cholesterol (0.1%) (Bch). Kidney samples were separated in medulla and cortex for aminopeptidase activities (AP) assay. Urine samples were collected for routine analysis by chemical tests. Aminopeptidase activities were determined by fluorometric methods in soluble (sol) and membrane-bound (mb) fractions of renal tissue, using arylamide derivatives as substrates. After the experimental period, the systolic blood pressure (SBP) values were similar in standard and VOO animals, and significantly lower than in the Bch group. At the same time, a significant increase in GluAP and IRAP activities were found in renal medulla of Bch animals. However, in VOO group the increase of GluAP activity in renal medulla was lower, while AspAP activity decreased in the renal cortex. Furthermore, the VOO diet also affected other aminopeptidase activities, such as TyrAP and pGluAP, related to the regulation of the sympathetic nervous system and the metabolic rate. These results support the beneficial effect of VOO in the regulation of SBP through changes in local AP activities of the kidney.

Glutathione depletion induces oxidative injury and apoptosis via TRPM2 channel activation in renal collecting duct cells.

Oxidative stress (OS)-induced glutathione (GSH) depletion plays an essential role in several kidney diseases such as chronic kidney disease and nephrotoxicity. The OS-dependent activation of TRPM2 cation channel in several neurons and cells were modulated by the concentration of intracellular GSH. However, the effects of GSH alteration on TRPM2 activation, OS, and apoptosis in the cortical collecting duct (mpkCCDc14) cells still remain elusive. We investigated the effects of GSH supplementation on OS-induced TRPM2 activation, mitochondrial oxidative stress, and apoptosis in the human embryonic kidney 293 (HEK293) and mpkCCDc14 cells treated with buthionine-sulfoximine (BSO), a GSH synthase inhibitor. The HEK293 and mpkCCDc14 cells were divided into five groups as control, GSH (10 mM for 2 h), BSO (0.5 mM for 6 h), BSO + GSH, and BSO + TRPM2 channel blockers. Apoptosis, cell death, mitochondrial OS, caspase -3, caspase -9, cytosolic free Zn2+, and Ca2+ concentrations were increased in the BSO group of the TRPM2 expressing mpkCCDc14 cells, although they were diminished by the treatments of GSH, PARP-1 inhibitors (PJ34 and DPQ), and TRPM2 blockers (ACA and 2-APB). The BSO-induced decreases in the levels of cell viability and cytosolic GSH were increased by the treatments of GSH, ACA, and 2-APB. However, the effects of BSO and GSH were not observed in the non-TRPM2 expressing HEK293 cells. Current results show that maintaining GSH homeostasis is not only important for quenching OS in the cortical collecting duct cells but equally critical to modulate TRPM2 activation. Thus, suppressing apoptosis and mitochondrial OS responses elicited by oxidant action of GSH depletion.

Combinational Use of Antiplatelet Medication Sarpogrelate with Therapeutic Drug Rosuvastatin in Treating High-Cholesterol Diet-Induced Chronic Kidney Disease in ApoE-Deficient Mice.

A number of metabolic disorders, including hyperlipidemia, potentially cause chronic kidney disease (CKD), one of their major chronic complications and comorbidities. Rosuvastatin is one of the widely used antiatherogenic drugs among hyperlipidemic patients. Meanwhile, sarpogrelate is not only a 5-hydroxytryptamine receptor antagonist but also an antiplatelet agent, inhibiting platelet-stimulated blood coagulation and improving peripheral circulation. In this study, a combination of sarpogrelate and/or rosuvastatin was used on CKD mice induced by a high-fat diet for 8 weeks. The mice were tested for pathological changes using histological evaluation. Tremendous alterations were found, including a remarked increase in total cholesterol and low-density lipoprotein cholesterol levels, glomerular endothelial proliferation, and mesangial expansion. Also, tubular damage and extracellular matrix accumulation occurred, namely, a marked increase in the macula densa, scattered and apoptotic loss of the apical brush border with vacuolated basophilic cytoplasm and heavily stained nuclei, and expanded Bowman's space, which were at least partially ameliorated by sarpogrelate and/or rosuvastatin treatment. The analysis of expression profiles at both the RNA and protein levels, using real-time quantitative polymerase chain reaction and Western blot analysis, indicated that LDL-R/CD68/LOX-1-positive monocyte/macrophage-mediated enhanced proinflammatory activation, including the significant upregulation of tumor necrosis factor-α and interleukin-6, was actually attenuated by sarpogrelate and/or rosuvastatin treatment. The findings indicated that sarpogrelate and/or rosuvastatin treatment potentially ameliorates CKD progression in patients with the aforementioned comorbid metabolic disorders.

Contribution of Monocarboxylate Transporter 6 to the Pharmacokinetics and Pharmacodynamics of Bumetanide in Mice.

Bumetanide, a sulfamyl loop diuretic, is used for the treatment of edema in association with congestive heart failure. Being a polar, anionic compound at physiologic pH, bumetanide uptake and efflux into different tissues is largely transporter-mediated. Of note, organic anion transporters (SLC22A) have been extensively studied in terms of their importance in transporting bumetanide to its primary site of action in the kidney. The contribution of one of the less-studied bumetanide transporters, monocarboxylate transporter 6 (MCT6; SLC16A5), to bumetanide pharmacokinetics (PK) and pharmacodynamics (PD) has yet to be characterized. The affinity of bumetanide for murine Mct6 was evaluated using Mct6-transfected Xenopus laevis oocytes. Furthermore, bumetanide was intravenously and orally administered to wild-type mice (Mct6+/+) and homozygous Mct6 knockout mice (Mct6-/-) to elucidate the contribution of Mct6 to bumetanide PK/PD in vivo. We demonstrated that murine Mct6 transports bumetanide at a similar affinity compared with human MCT6 (78 and 84 µM, respectively, at pH 7.4). After bumetanide administration, there were no significant differences in plasma PK. Additionally, diuresis was significantly decreased by ∼55% after intravenous bumetanide administration in Mct6-/- mice. Kidney cortex concentrations of bumetanide were decreased, suggesting decreased Mct6-mediated bumetanide transport to its site of action in the kidney. Overall, these results suggest that Mct6 does not play a major role in the plasma PK of bumetanide in mice; however, it significantly contributes to bumetanide's pharmacodynamics due to changes in kidney concentrations. SIGNIFICANCE STATEMENT: Previous evidence suggested that MCT6 transports bumetanide in vitro; however, no studies to date have evaluated the in vivo contribution of this transporter. In vitro studies indicated that mouse and human MCT6 transport bumetanide with similar affinities. Using Mct6 knockout mice, we demonstrated that murine Mct6 does not play a major role in the plasma pharmacokinetics of bumetanide; however, the pharmacodynamic effect of diuresis was attenuated in the knockout mice, likely because of the decreased bumetanide concentrations in the kidney.

RNA-seq reveals altered gene expression levels in proximal tubular cell cultures compared to renal cortex but not during early glucotoxicity.

Cell cultures are often used to study physiological processes in health and disease. It is well-known that cells change their gene expression in vitro compared to in vivo, but it is rarely experimentally addressed. High glucose is a known trigger of apoptosis in proximal tubular cells (PTC). Here we used RNA-seq to detect differentially expressed genes in cultures of primary rat PTC, 3 days old, compared to cells retrieved directly from rat outer renal cortex and between PTC exposed to 15 mM glucose and control for 8 h. The expression of 6,174 genes was significantly up- or downregulated in the cultures of PTC compared to the cells in the outer renal cortex. Most altered were mitochondrial and metabolism related genes. Gene expression of proapoptotic proteins were upregulated and gene expression of antiapoptotic proteins were downregulated in PTC. Expression of transporter related genes were generally downregulated. After 8 h, high glucose had not altered the gene expression in PTC. The current study provides evidence that cells alter their gene expression in vitro compared to in vivo and suggests that short-term high glucose exposure can trigger apoptosis in PTC without changing the gene expression levels of apoptotic proteins.

Low doses of folic acid can reduce hyperhomocysteinemia-induced glomerular injury in spontaneously hypertensive rats.

Hypertension associated with hyperhomocysteinemia (HHcy) is associated with a high risk of vascular diseases. However, the mechanisms of HHcy-associated hypertensive renal damage and the efficacy of folic acid (FA) as a treatment have not been fully elucidated. The aim of the present study was to evaluate whether lowering the plasma homocysteine (Hcy) level using different doses of FA can reduce HHcy-associated glomerular injury in spontaneously hypertensive rats (SHRs) and to clarify the potential mechanisms of such effects. SHRs were randomized into a control group, HHcy group, HHcy + low-dose FA (LFA) group, and HHcy + high-dose FA (HFA) group. Compared with the control group, the HHcy group had reduced serum superoxide dismutase and GFR levels and elevated serum malondialdehyde and urinary albumin creatinine ratio levels. Increased extracellular matrix of the glomerulus and an increased glomerular sclerosis index, podocyte foot process effacement and fusion, as well as increased podocyte apoptosis, were observed in the HHcy group compared with the control group; these effects were associated with increased expression of NOX2 and NOX4 and decreased nephrin expression in renal tissue from SHRs with HHcy. HHcy-induced changes were counteracted by LFA and HFA treatment. Apart from lower levels of NOX2 in the HHcy + HFA group, there were no significant differences in other indicators between the HHcy + LFA and HHcy + HFA groups. These results suggest that even at a low dose, FA can reduce plasma Hcy and attenuate HHcy-induced glomerular injury by inhibiting oxidative stress and apoptosis.

[Insulin promotes BAMBI expression and inhibits inflammation in renal cortex of diabetic rats].

Objective To explore the expression of renal cortex bone morphogenetic protein and activating protein membrane binding inhibitor (BAMBI), NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck like protein containing a CARD-2 (ASC-2), caspase-1, inflammatory mediators and related fibrosis markers in renal cortex of diabetic mellitus (DM) rats treated with insulin. Methods SD rats were randomly divided into 3 groups: a normal control group, a DM group and an insulin treatment group. Each group included 8 rats. The DM rat model was established by streptozotocin (STZ). Four weeks after STZ injection, the rats in the insulin treatment group was subcutaneously injected with insulin at the dose of 8 U/kg once, three times each day for successive 6 weeks, and then sacrificed finally. The expression of BAMBI, NLRP3 and epithelial cadherin (E-cadherin) in the renal cortex were detected by immunohistochemistry. The expression of BAMBI, NLRP3, ASC-2, caspase-1, α-smooth muscle actin (α-SMA), fibronectin (FN) and type IV collagen (Col4) in the renal cortex were detected by Western blot analysis. The mRNA levels of BAMBI and NLRP3 in the renal cortex were measured by real-time quantitative PCR, and the levels of interleukin-1ß (IL-1ß) and IL-18 in the renal cortex were tested by ELISA. The correlation between BAMBI and NLRP3 was analyzed by Spearman method. Results Compared with the normal control group, the expression of NLRP3, ASC-2, caspase-1, α-SMA, FN and Col4 significantly increased, but BAMBI and E-cadherin significantly decreased in the renal cortex of DM group. However, the expression of NLRP3, ASC-2, caspase-1, α-SMA, FN, Col4, IL-1ß and IL-18 in the insulin-treated group were lower than those in the DM group, but the expression of BAMBI and E-cadherin were higher. According to the correlation analysis, there was a negative correlation between the expression of BAMBI and NLRP3 in the DM group and insulin treatment group. Conclusion Insulin can restore the expression of BAMBI in the renal cortex of DM rats, and then inhibit the activation of NLRP3, thus reducing the renal inflammatory response in the kidney of DM rats and preventing or delaying the progression of diabetic nephropathy.

Effect of rosmarinic acid on potassium bromate induced renal cortical oxidative stress and apoptosis in adult male albino rat

Potassium bromate (KBrO3) is widely used as a food additive and is a major water disinfection by-product, in spite of its well-known oxidative cell and tissue damage. Therefore, the therapeutic efficacy of rosmarinic acid is examined to alleviate KBrO3 mediated renal oxidative damage. For this purpose, 24 adult male albino rats were categorized into four groups; group 1 (control); group 2: received 50 mg/Kg/day rosmarinic acid orally for 4 weeks; group 3: received 20 mg/Kg/dose KBrO3 orally twice weekly for 4 weeks, and group 4: received both KBrO3 and rosmarinic acid. After 4 weeks, serum was collected for analysis of kidney functions and kidneys were sampled for histopathological and biochemical analysis. The results indicated that treatment with rosmarinic acid significantly abated most of the indices and biomarkers of the renal toxicity caused by KBrO3. It significantly ameliorated histopathological changes and the changes in the immunoexpression of proapoptotic protein (Bax), antiapoptotic protein (Bcl2) and inducible nitric oxide synthase (iNOS) induced by KBrO3. Taken together, it could be concluded that the rosmarinic

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High-dose nitrate therapy recovers the expression of subtypes α1 and ß-adrenoceptors and Ang II receptors of the renal cortex in rats with myocardial infarction-induced heart failures.

BACKGROUND: Few studies examined the effect of long-acting nitrates on renal function in chronic heart failure (CHF). Thus, we aimed to investigate the effect of long-acting nitrate on the expression of adrenoceptors (AR) and angiotensin II receptor (ATR) subtypes of the renal cortex, in rats with myocardial infarction-induced CHF. METHODS: Rats were randomly divided into the following groups: control, sham-operated, CHF, low- and high-dose nitrate, positive drug control (olmesartan), and high-dose of long-acting nitrate + olmesartan. Ultrasound echocardiography markers were compared, and the levels of AR subtypes, AT1R, and AT2R were measured using reverse transcription-polymerase chain reaction and western blot analysis. Histopathology of the kidney was determined on hematoxylin and eosin-stained sections. RESULTS: CHF significantly increased plasma renin activity (PRA) and angiotensin II levels, upregulated AT1R expression and downregulated α1A-, ß1-, ß2-AR, and AT2R expression compared to the sham control. High-dose nitrate or olmesartan alone, and especially in combination, decreased the levels of PRA and angiotensin II and downregulated the CHF-induced expression of AT1R, α1A-, ß1-, and ß2-AR, and AT2R. CHF resulted in significant impairment of the renal tissue, including inflammatory cells infiltration to the tubular interstitium and surrounding the renal glomerulus, and tubular necrosis, which was alleviated in all treatment groups to different degrees. CONCLUSIONS: Long-acting nitrates could reverse CHF-induced changes in AR and ATR subtypes in the kidney, and improve cardiac function to protect renal function. Compared with monotherapy, the combination of nitrates and olmesartan shows more significant benefits in regulating AR and ATR subtypes.

Rotten to the Cortex: Ceramide-Mediated Lipotoxicity in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a prevalent and progressive comorbidity of diabetes mellitus that increases one's risk of developing renal failure. Progress toward development of better DKD therapeutics is limited by an incomplete understanding of forces driving and connecting the various features of DKD, which include renal steatosis, fibrosis, and microvascular dysfunction. Herein we review the literature supporting roles for bioactive ceramides as inducers of local and systemic DKD pathology. In rodent models of DKD, renal ceramides are elevated, and genetic and pharmacological ceramide-lowering interventions improve kidney function and ameliorate DKD histopathology. In humans, circulating sphingolipid profiles distinguish human DKD patients from diabetic controls. These studies highlight the potential for ceramide to serve as a central and therapeutically tractable lipid mediator of DKD.

Inverse Regulation of Lipocalin-2/24p3 Receptor/SLC22A17 and Lipocalin-2 Expression by Tonicity, NFAT5/TonEBP and Arginine Vasopressin in Mouse Cortical Collecting Duct Cells mCCD(cl.1): Implications for Osmotolerance.

The rodent collecting duct (CD) expresses a 24p3/NGAL/lipocalin-2 (LCN2) receptor (SLC22A17) apically, possibly to mediate high-affinity reabsorption of filtered proteins by endocytosis, although its functions remain uncertain. Recently, we showed that hyperosmolarity/-tonicity upregulates SLC22A17 in cultured mouse inner-medullary CD cells, whereas activation of toll-like receptor 4 (TLR4), via bacterial lipopolysaccharides (LPS), downregulates SLC22A17. This is similar to the upregulation of Aqp2 by hyperosmolarity/-tonicity and arginine vasopressin (AVP), and downregulation by TLR4 signaling, which occur via the transcription factors NFAT5 (TonEBP or OREBP), cAMP-responsive element binding protein (CREB), and nuclear factor-kappa B, respectively. The aim of the study was to determine the effects of osmolarity/tonicity and AVP, and their associated signaling pathways, on the expression of SLC22A17 and its ligand, LCN2, in the mouse (m) cortical collecting duct cell line mCCD(cl.1). Normosmolarity/-tonicity corresponded to 300 mosmol/L, whereas the addition of 50-100 mmol/L NaCl for up to 72 h induced hyperosmolarity/-tonicity (400-500 mosmol/L). RT-PCR, qPCR, immunoblotting and immunofluorescence microscopy detected Slc22a17/SLC22A17 and Lcn2/LCN2 expression. RNAi silenced Nfat5, and the pharmacological agent 666-15 blocked CREB. Activation of TLR4 was induced with LPS. Similar to Aqp2, hyperosmotic/-tonic media and AVP upregulated Slc22a17/SLC22A17, via activation of NFAT5 and CREB, respectively, and LPS/TLR4 signaling downregulated Slc22a17/SLC22A17. Conversely, though NFAT5 mediated the hyperosmolarity/-tonicity induced downregulation of Lcn2/LCN2 expression, AVP reduced Lcn2/LCN2 expression and predominantly apical LCN2 secretion, evoked by LPS, through a posttranslational mode of action that was independent of CREB signaling. In conclusion, the hyperosmotic/-tonic upregulation of SLC22A17 in mCCD(cl.1) cells, via NFAT5, and by AVP, via CREB, suggests that SLC22A17 contributes to adaptive osmotolerance, whereas LCN2 downregulation could counteract increased proliferation and permanent damage of osmotically stressed cells.

Green tea extract protects the renal cortex against bisphenol A-induced nephrotoxicity in the adult male albino rat: a histological andimmunohistochemical study

Bisphenol A is a chemical used in the production of the plastic lining of food and beverage containers. As plastics are used extensively in modern life, bisphenol A is liberated into the surrounding environment. The goal of this study was to illustrate the histopathological effects of bisphenol A on the renal cortex with referral to the possible ameliorative effect of green tea extract and to throw more light on some underlying mechanisms, for the first time up to our knowledge, by which green tea extract exerted its effects against bisphenol A-induced nephrotoxicity. Forty adult male Sprague-Dawley rats were classified into four groups: Group I (control group); Group II (bisphenol A-treated group), received bisphenol by gavage 125 μg/kg once daily for 35 days; Group III (bisphenol A and green tea extract treated group), received bisphenol by gavage 125 μg/kg simultaneously with 200 mg/kg/day green tea extract once daily for 35 days; and Group IV (green tea extract treated group), received 200 mg/kg/day green tea extract for 35 days by gavage. At the end of the study, rats were anesthetized and the kidney from all groups were extracted and examined histologically and immunohistochemically. Deterioration of kidney structure was greatest in group II as compa-red to control group. Some of the renal corpuscles showed widening of the Bowman's capsule, shrunken degenerated glomerular tuft and dilated congested glomerular capillaries. Interstitial and intra-tubular hemorrhage was also observed. Moreover, there was a significant increase in the collagen deposition in bisphenol A-treated group in addition to up-regulation of inducible nitric oxide synthase (iNOS), Fas Ligand (Fas L), alpha smooth muscle actin (alfa-SMA) and desmin immunoreaction. The co-administration of green tea extract greatly reduced these nephrotoxic effects of bisphenol A exposure through its antioxidant

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MiR-143-3p directly targets GLUT9 to reduce uric acid reabsorption and inflammatory response of renal tubular epithelial cells.

GLUT9 is generally considered to be associated with the uric acid transport, which plays an important role in the regulation of serum uric acid level. In this study, the expression level of miR-143-3p was significantly decreased in hyperuricemia mice model group compared with the normal control by miRNA microarray, the same results were confirmed in the hyperuricemia patients and the healthy control group. It is predicted that GLUT9 may be the target gene of miR-143-3p by target scan and other net-software. GLUT9 as the downstream target gene of miR-143-3p was determinated by fluorescence enzyme activity assay. Western blotting and qRT-PCR indicated that the expression of GLUT9 in human renal tubular epithelial cells transfected with miR-143-3p mimics was significantly reduced. Meanwhile inflammatory factors IL-1ß and MCP-1 significantly decreased. In conclusion, miR-143-3p can reduce uric acid reabsorption by inhibiting its downstream target gene GLUT9.

Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation.

Tolvaptan, a vasopressin type 2 receptor antagonist initially developed to increase free-water diuresis, has been approved for the treatment of autosomal dominant polycystic kidney disease in multiple countries. Furthermore, tolvaptan has been shown to improve the renal functions in rodent models of chronic kidney disease (CKD); however, the underlying molecular mechanisms remain unknown. CKD is characterized by increased levels of oxidative stress, and an antioxidant transcription factor-nuclear factor erythroid 2-related factor 2 (Nrf2)-has been gaining attention as a therapeutic target. Therefore, we investigated the effects of tolvaptan and a well-known Nrf2 activator, bardoxolone methyl (BARD) on Nrf2. To determine the role of tolvaptan, we used a renal cortical collecting duct (mpkCCD) cell line and mouse kidneys. Tolvaptan activated Nrf2 and increased mRNA and protein expression of antioxidant enzyme heme oxygenase-1 (HO-1) in mpkCCD cells and the outer medulla of mouse kidneys. In contrast to BARD, tolvaptan regulated the antioxidant systems via a unique mechanism. Tolvaptan activated the Nrf2/HO-1 antioxidant pathway through phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, tolvaptan and BARD could successfully generate synergistic activating effects on Nrf2/HO-1 antioxidant pathway, suggesting that this combination therapy can contribute to the treatment of CKD.

Understanding the effect of repeated administration of meloxicam on feline renal cortex and medulla: A lipidomics and metabolomics approach.

Repeated administration of meloxicam can cause kidney damage in cats by mechanisms that remain unclear. Metabolomics and lipidomics are powerful, noninvasive approaches used to investigate tissue response to drug exposure. Thus, the objective of this study was to assess the effects of meloxicam on the feline kidney using untargeted metabolomics and lipidomics approaches. Female young-adult purpose-breed cats were allocated into the control (n = 4) and meloxicam (n = 4) groups. Cats in the control and meloxicam groups were treated daily with saline and meloxicam at 0.3 mg/kg subcutaneously for 17 days, respectively. Renal cortices and medullas were collected at the end of the treatment period. Random forest and metabolic pathway analyses were used to identify metabolites that discriminate meloxicam-treated from saline-treated cats and to identify disturbed metabolic pathways in renal tissue. Our results revealed that the repeated administration of meloxicam to cats altered the kidney metabolome and lipidome and suggest that at least 40 metabolic pathways were altered in the renal cortex and medulla. These metabolic pathways included lipid, amino acid, carbohydrate, nucleotide and energy metabolisms, and metabolism of cofactors and vitamins. This is the first study using a pharmacometabonomics approach for studying the molecular effects of meloxicam on feline kidneys.