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This study suggests a new optimized model for optimum identification of the unknown variables in a Solid Oxide (SO) fuel cell. The method is conditioned by designing an improved version of metaheuristics to improve the effectiveness of the original method and using it by the Sum of Squared Error (SSE) minimization between the model and the experimental data including output voltage. The metaheuristic is based on a new improved model of a new metaheuristic, called the Red Fox Optimization Algorithm (IRFO). To assess the method’s accuracy and its consistency, it is validated by various pressure and temperature functional conditions. The results showed that the error value of the produced power by different temperatures is lower than 0.0073 kW and the error value of the output voltage by different temperatures is lower than 0.16 V which is a promising result for stack identification. Also, the achievements of the algorithm are compared with several approaches from the literature. The final results show a satisfying verification between the empirical and the optimized technique

This study presents new soliton solutions for the nonlinear fractional twin-core couplers with Kerr law nonlinearity by employing the modifed extended tanh method with Riccati equation. The solutions are expressed in terms of some elementary functions including rational, trigonometric and hyperbolic types. Graphical demonstrations of the simulations are provided.

It has been shown that cyclooxygenase (COX)-2-dependent activation of renal (pro)renin receptor (PRR) contributes to angiotensin II (ANG II)-induced hypertension. However, less is known about the involvement of this mechanism in ANG II-independent hypertension. The goal of the present study was to test whether or not COX-2-dependent upregulation of PRR serves as a universal mechanism contributing to ANG II-dependent and -independent hypertension. Here, we examined the association between renal COX-2 and PRR during deoxycorticosterone acetate (DOCA)-salt hypertension in rats. By immunoblot analysis and immunofluorescence, renal protein expression of PRR was remarkably upregulated by DOCA-salt treatment. Surprisingly, this upregulation of renal PRR expression was unaffected by a COX-2 inhibitor, celecoxib. To address the role of renal PRR to the pathogenesis of DOCA-salt hypertension, a decoy PRR inhibitor, PRO20, was infused to the renal medulla of uninephrectomized Sprague-Dawley rats for 14 days. Radiotelemetry demonstrated effective attenuation of DOCA-salt hypertension by intramedullary infusion of a PRR inhibitor, PRO20. In parallel, DOCA-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied with blunted polydipsia and polyuria. In contrast, intravenous infusion of PRO20 was less effective in attenuating DOCA-salt hypertension and cardiorenal injury. Together, these results suggest that COX-2-independent activation of renal PRR contributes to DOCA-salt hypertension.

Crowdsensing exploits the sensing abilities offered by smart phones and users' mobility. Users can mutually help each other as a community with the aid of crowdsensing. The potential of crowdsensing has yet to be fully realized for improving public health. A protocol based on gamification to encourage data sharing and mutual assistance is proposed. The game is called “Lemmings,” which stands for location-based mutual and mobile information navigation system; it is based on a classical video game where a group of creatures have to work and win through the puzzle game together. This game includes an asynchronized messaging system where a player may proactively seek for answers or advice by depositing a question on the messaging server. The server will automatically disseminate the question, which is related to a specific location, to a group of users who are either within the proximity currently or have just recently been there. The users/players are encouraged to help each other in post-pandemic Corona virus period; karma scoring distinguishes the most helpful users in the community.

We have previously shown that activation of (pro)renin receptor (PRR) induces epithelial Na+channel (ENaC) activity in cultured collecting duct cells. Here, we examined the role of soluble PRR (sPRR), the cleavage product of PRR in ENaC regulation, and further tested its relevance to aldosterone signaling. In cultured mpkCCD cells, administration of recombinant histidine-tagged sPRR (sPRR-His) at 10 nM within minutes induced a significant and transient increase in the amiloride-sensitive short-circuit current as assessed using the Ussing chamber technique. The acute ENaC activation was blocked by the NADPH oxidase 1/4 inhibitor GKT137892 and siRNA against Nox4 but not the β-catenin inhibitor ICG-001. In primary rat inner medullary collecting duct cells, administration of sPRR-His at 10 nM for 24 h induced protein expression of the α-subunit but not β- or γ-subunits of ENaC, in parallel with upregulation of mRNA expression as well as promoter activity of the α-subunit. The transcriptional activation of α-ENaC was dependent on β-catenin signaling. Consistent results obtained by epithelial volt ohmmeter measurement of equivalent current and Ussing chamber determination of short-circuit current showed that aldosterone-induced transepithelial Na+transport was inhibited by the PRR decoy inhibitor PRO20 and PF-429242, an inhibitor of sPRR-generating enzyme site-1 protease, and the response was restored by the addition of sPRR-His. Medium sPRR was elevated by aldosterone and inhibited by PF-429242. Taken together, these results demonstrate that sPRR induces two phases of ENaC activation via distinct mechanisms and functions as a mediator of the natriferic action of aldosterone.

It is well demonstrated that activation of renal (pro)renin receptor (PRR) contributes to AngII-induced hypertension. Relatively, less is known about involvement of soluble PRR (sPRR), the extracellular domain of PRR, primarily generated by site-1 protease(S1P) and furin. Moreover, the relationship between PRR/sPRR and the renin-angiotensin system (RAS) has been debated. In the present study, we used CRISPR/Cas9 strategy to generate mice with mutagenesis of the overlapping cleavage site for both proteases in PRR (termed as PRR R279V/L282V ) to examine the phenotype during angiotensin II (AngII) infusion with particular emphasis on circulating and intrarenal renin status. PRR R279V/L282V mice exhibited a reduction of sPRR level in plasma by ~53% and in the kidney by ~82%, were fertile, and had no gross developmental abnormalities. At basal condition, PRR R279V/L282V mice had drastically suppressed renin levels from plasma (plasma total prorenin/renin content [ng/ml]: 9.3 ± 0.7 in PRR R279V/L282V mice vs. 12.8 ± 0.9 in WT mice, n = 5, p < 0.05), urine (urinary total prorenin/renin excretion [ng/24h]: 0.54 ± 0.11 in PRR R279V/L282V mice vs. 1.05 ± 0.15 in WT mice, n = 5, p < 0.05), and the kidney as compared to wild-type controls (WT). By telemetry, the hypertensive response of PRR R279V/L282V to AngII infusion (300 ng/min/kg) was blunted (MAP [mmHg] in Day 10: 125.9 ± 4.6 in PRR R279V/L282V mice vs. 138.5 ± 2.8 in WT mice, n = 8 for each group, p < 0.05) in parallel with attenuated response of intrarenal renin and renal medullary α-ENaC expression. We further examined the direct role of sPRR in renin regulation in As4.1 cells, a renin-expressing cell line isolated from mouse renal tumor and M-1 cells, a mouse cell line derived from the collecting duct. The exposure to sPRR-His in both cell types consistently elevated renin activity, and renin expression at both protein and mRNA levels, all of which were sensitive to inhibition by ICG-001, a β-catenin signaling inhibitor. Together, these results represent strong evidence favoring sPRR as a mediator of AngII-induced hypertension and a master regulator of renin expression at systemic and local levels. Therefore, PRR should be considered as an integrative member of the RAS.

A recently identified adipokine C1q/TNF-related protein 1 (CTRP1) displayed a potent beneficial effect in managing metabolic disorders during type 2 diabetes and obesity. However, little is known about a potential role of CTRP1 in regulation of renal function and blood pressure (BP) in the context of obesity. Therefore, the present study aimed to determine the effect of a recombinant CTRP1 protein (termed CTRP1-His) on blood pressure in mice with diet-induced obesity (DIO). 8-mo-old male C57/B6 mice were fed a high-fat diet (60 Kcal% fat) for eight weeks and were infused with vehicle or CTRP1-His (10 ng/min/kg) via subcutaneously implanted osmotic minipump for the last seven days. BP parameters were recorded using telemetry devices. Consistent with other groups’ studies, mice infused with CTRP1-His exhibited remarkably improved multiple metabolic parameters, including hyperglycemia and hyperinsulinemia. Compared to the vehicle group, BP responses to CTRP1-His treatment developed a modest but significant increase in BP (MAP on day 7 [mmHg]: 122.3 ± 2.2 vs. 109 ± 1.73, n = 3 per each group, p < 0.01) accompanied with decreased hematocrit (Hct [%]: 43.8 ± 1.3 vs. 49 ± 1.2 %, p < 0.05), an index of plasma volume expansion. The DIO mice infused with CTRP1-His demonstrated a reduced urinary sodium excretion (U Na /Creatinine [mmol/mg]: 0.17 ± 0.04 vs. 0.27 ± 0.06, p = 0.07). By immunoblotting CTRP1-His infusion induced significant upregulation of renal abundances of p-NHE3, V2R, and AQP2 but suppressed obesity-induced renal abundances of p-NCC/NCC, p-NKCC2/NKCC2, and cleaved α-ENaC protein. Interestingly, CTRP1-His infusion tends to decrease albuminuria (urine albumin/Creatinine [mg/g]: 78.8 ± 7.7 vs. 120.5 ± 14, p = 0.07) in the DIO mice. Overall, our results indicated that CTRP1-His exerted a pressor effect in DIO mice via stimulating sodium-water retention through activation of NHE3 and AQP2 associated with compensatory attenuation of Na+ transporters in the distal nephron.

Renal collecting duct (CD), an important site for fine-tuning urinary Na + and water excretion, is not traditionally thought to play a role in pathogenesis of chronic kidney disease. In the present study, we examined a profibrotic role of CD PRR in a mouse model of unilateral ureteral obstruction (UUO) and further defined the underlying mechanism involving soluble PRR (sPRR)-dependent activation of alternative macrophages activation. We subjected mice with CD-specific deletion of PRR (CD PRR KO) and their floxed controls to UUO or sham surgery. After 7 days of UUO, CD PRR KO decreased the fibronectin (28.6±6.8%) and α-SMA (39.2±7.8%) protein expression in obstructed kidneys. The Masson’s trichrome staining data also showed that CD PRR KO significantly attenuated UUO-induced collagen deposition and histological damage in the kidney. In parallel, CD PRR KO reduced TGF-β1 (56.7±3.2%) and TGF-β2 (53±1.2%) mRNA expression in obstructed kidneys. Moreover, in macrophages sorted from obstructed kidneys of CD PRR KO mice showed a significantly reduced of M2 macrophage markers such as mannose receptor ( MR ) (58.7±2.1%), arginase-1 ( Arg-1 ) (50±1.5%), chitinase-like lectins ( YM-1 ) (59.3±1.9%), inflammatory zone-1 ( Fizz1 ) (39.1±4.1%) mRNA expression and Yes-associated protein ( Yap ) (77±6.8%)/ transcriptional coactivator with PDZ-binding motif ( Taz ) (54.5±1.8%) mRNA expression compared with macrophages sorted from obstructed kidneys of floxed mice. Meanwhile, plasma sPRR was elevated in floxed mice by UUO and this elevation was blunted by CD PRR KO (23.7±0.4%). Administration of site-1 protease (S1P) inhibitor PF-429242 to C57BL/6 mice with UUO almost completely recapitulated the antifibrotic action as well as the inhibitory effect on M2 activation of CD PRR KO. In bone marrow-derived macrophages, sPRR-His treatment promoted macrophage M2 polarization, fibrosis and Yap/Taz expression. Overall, these results suggest that activation of CD PRR releases sPRR that activates M2 polarization via Yap/Taz axis, leading to renal fibrosis during UUO.

In the context of the implementation of the rural revitalization strategy, the development of the digital economy closely connects with it. The realization of rural revitalization needs to make full use of the advantages of the digital economy to promote the process of rural revitalization. The digital wave is a huge opportunity for the poor to bridge the gap between rich and poor, seize digital opportunities, share digital dividends, achieve sustainable poverty alleviation, and prevent intergenerational transmission of poverty. The article will focus on two aspects of rural e-commerce and mobile payment. Through the discussion of the aspects, this paper gives the suggestion to the government, platforms, enterprises and farmers to work together to promote agricultural development and realize industrial digitalization by using existing resources.

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II–induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II–induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II–induced hypertension through enhancement of intrarenal renin level and activation of ENaC.

This paper aims to investigate the development of Macao's gaming industry during the past decades. This topic has tracked tons of attention while little works has been done to measure the Macao's gaming industry from performance perspective. Based on the theory of linear programming, the mathematical model of Malmquist index has been implied to measure the performance of gaming sectors. Data are collected from six Macao main casino concessionaires in the year of 2007-2014, the analysis result reveal that on the average, the efficiency of Macao's gaming industry is 82.3% and total factor productivity growth improved 17.4% for the period 2007-2014.

Sodium-chloride cotransporter (NCC), uniquely located at the distal convoluted tubule (DCT), is the target of thiazide diuretics and critically involved in renal handling of both Na + and K + . However, the mechanism of how NCC activity is regulated is incompletely understood. Here we report a novel role of (pro)renin receptor (PRR) and its cleavage product soluble PRR (sPRR) via site-1 protease (S1P) as negative regulators of NCC during high-salt or high-K + loading. Mice with DCT-specific deletion of PRR (termed as DCT PRR KO) was generated by crossing PRR floxed mice with a transgenic mouse line expressing Cre under the control of the parvalbumin (PV) promoter. Radiotelemrty demonstrated that under basic condition, DCT PRR KO mice exhibited modest hypertension (~5 mmHg) associated with reduced urinary Na + (Floxed: 0.20±0.02, KO: 0.12±0.01 mmol/24h, p+ (Floxed: 0.29±0.02, KO: 0.18±0.03 mmol/24h, p- (Floxed: 0.30±0.03, KO: 0.21±0.02 mmol/24h, pin vivo NCC activity as assessed by hydrochlorothiazide (HCTN)-induced natriuresis ( by 61%). Renal protein abundance of pNCC-T53 (by 51%) but not total NCC was elevated in the null mice. Following a high salt diet, DCT PRR KO mice were salt sensitive as evidenced by a ~30 mm Hg increase of mean arterial pressure (MAP) which was sensitive to HCTN (ΔMAP, Floxed+HS: -2.05±1.50, KO+HS: -12.77±2.6 mmHg, p+ intake. This phenotype was recapitulated by treatment of C57/BL6 mice with S1P inhibitor PF429242. In cultured Flp-In T-REx 293 NCC cells, S1P-derived sPRR directly dephosphorylated NCC (by 40%) via activation of angiotensin II receptor type 1 (AT1R) independently of aldosterone. 1 / 2 Taken together, the present study has demonstrated that S1P-derived sPRR via AT1R negatively regulates NCC activity in the DCT to render salt resistance and to promote K + excretion. 2 / 2

We have previously shown that activation of (pro)renin receptor (PRR) induces epithelial Na + channel (ENaC) activity in cultured collecting duct cells. Here, we examined the role of soluble PRR (sPRR), generated by site-1 protease (S1P), a newly identified PRR cleavage protease, in ENaC regulation, and further tested its relevance to Aldo signaling. In cultured mpkCCD cells, administration of recombinant histidine-tagged sPRR (sPRR-His) at 10 nM for 24 h induced a significant increase in the amiloride-sensitive short-circuit current as assessed using the Ussing chamber technique ( I eq : 7.5 ± 0.7 μA/cm 2 in sPRR group vs. 3.5 ± 0.5 μA/cm 2 in vehicle group, n = 6, p < 0.01) . In primary cultured rat IMCD cells, the same sPRR-His treatment induced a 1.7 fold increase in protein expression of the α-subunit but not β- or γ-subunit of ENaC, in parallel with upregulation of mRNA expression as well as promoter activity of the α-subunit. The upregulation of α-ENaC transcription depended on β-catenin signaling. Consistent results obtained by epithelial volt ohmmeter measurement of equivalent current and Using chamber determination of short-circuit current showed that Aldo-induced ENaC activity was almost completely abolished by PF-429242 (PF), a S1P inhibitor, and the response was restored by supplement of sPRR-His ( I eq : 7.2 ± 0.7 μA/cm 2 in Aldo group vs. 5.0 ± 0.3 μA/cm 2 in Aldo/PF group vs. 6.8 ± 0.3 μA/cm 2 in Aldo/PF/sPRR-His group, n = 5, p < 0.05). Medium sPRR was elevated by Aldo and inhibited by PF. Male C57BL/6 mice were pretreated with PF (30 mg/kg/day) or vehicle via minipump, followed by 3 days of aldosterone (0.2 mg/kg/day via a second minipump). Amiloride-sensitive Na+ current in freshly isolated CCD as measured by using patch clamp lower in Aldo + PF group than in Aldo group. Together, these results support an essential role of S1P-derived sPRR in mediating Aldo-induced ENaC activation.

Soluble (pro)renin receptor (sPRR), the extracellular domain of PRR, is generated by multiple proteases, including furin or ADAM19, and recently site-1 protease (S1P). We have previously reported that the therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed as sPRR-His, in a mouse obesity model induced by high-fat diet (DIO) for management of obesity and hyperglycemia. Conversely, inhibition of endogenous sPRR production by PF429242, an inhibitor of S1P in DIO mice aggravated diabetes and insulin resistance (Wang F et al. JCI Insight In press). However, the existence of the multiple substrates for S1P may impose confounding influence on the function of sPRR. The goal of the present study was to employ CRISPR strategy to mutagenize the overlapping recognition site for S1P and furin in PRR (termed as mutant mice) to examine its impact on metabolism. Mutant mice were fertile and developed normally with a 50% reduction plasma and tissue sPRR. 12-wk-old male mutant mice fed chow diet exhibited increased body weight (45.6 ± 4.8 g vs. 34.8 ± 2.7 g, n = 9, p < 0.05) and fat mass percentage ( fat mass/ body weight: 26% ± 4% vs. 12% ± 3%, n =9, p < 0.01) accompanied by reduced energy expenditure (0.35 ± 0.02 Kcal/kg/h vs. 0.54 ± 0.04 Kcal/kg/h, n = 4, p < 0.05) as assessed by calorimetry. The mutant mice developed hyperglycemia (fasting blood glucose: 172 ± 6.8 in mutant vs. 118 ± 5.4 mg/dL in WT, n = 15, p < 0.01), hyperinsulinemia (serum insulin: 48.7 ± 12.9 ng/ml vs. 3.7 ± 0.4 ng/ml, n = 6, p < 0.01), and impaired GTT and ITT. Additionally, sPRR-His supplement in the mutant mice nearly normalized blood glucose (132.4 ± 12.2 mg/dL) and insulin level (14.1 ± 5.9 ng/ml). Overall, these results support sPRR as an essential regulator of energy metabolism.

Adriamycin (ADR) administration in susceptible rodents such as the BALB/c mouse strain produces injury to the glomerulus mimicking human chronic kidney disease due to primary focal segmental glomerulosclerosis. The goal of the present study was to use this model to investigate antiproteinuric actions of the (pro)renin receptor decoy inhibitor PRO20. BALB/c mice were pretreated for 1 day with PRO20 at 500 μg·kg−1·day−1 via an osmotic minipump followed by a single injection of vehicle or ADR (10 mg/kg) via the tail vein. Albuminuria and renal function were analyzed at the fourth week post-ADR administration. ADR-treated mice exhibited severe proteinuria, hypoalbuminemia and hyperlipidemia, glomerulosclerosis, podocyte loss, tubulointerstitial fibrosis, and oxidative stress, accompanied by elevated urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, all of which were significantly attenuated by PRO20. Urinary and renal renin activity and angiotensin II were elevated by ADR and suppressed by PRO20. In parallel, urinary and renal H2O2 levels and renal NADPH oxidase 4 (Nox4) and transient receptor potential channel C6 (TRPC6) expression in response to ADR were all similarly suppressed. Taken together, the results of the present study provide the first evidence that PRO20 can protect against podocyte damage and interstitial fibrosis in ADR nephropathy by preventing activation of the intrarenal renin-angiotensin system and upregulation of Nox4 and TRPC6 expression. PRO20 may have a potential application in the treatment of ADR nephropathy.

As that large supermarkets combine cashier and weighing into one or use self-service all-in-one machine to alleviate the problem of customer queuing, this paper studies two queuing models: one is the queuing system with separate cashier and weighing, which can be represented by a mixed queuing system consisting of a two-stage series queuing and a single-stage queuing. The other is a queuing system combining the cashier and the weighing, which can be expressed as M/M/1. This paper fist analyzes the behavior of the customers, get the balance of the customer arrival rate in these two queueing systems. Further, this paper analyzes the optimal pricing problem of supermarket, and gets the average optimal price the supermarket shall set up. Finally, through comparing two kinds of queuing system, this paper gives the supermarket the determination when the cashier weighing mergers, and when to separate the two conditions.

How to manage inventory is becoming an increasingly crucial issue for most manufacturing companies. R&D, the pseudonymous case study considered here, is a foreign direct investment (FDI) company engaged in producing electronic components. As the prices of raw materials and operation costs increased, R&D was challenged to maintain a smooth relationship among several factors: level of inventory, customer satisfaction and production efficiency. This paper first discusses the key factors that affect R&D’s inventory level. It then combines recent supply chain management theories and quantitative data into a framework for identifying how R&D might determine optimal ordering policies and strategies to reduce overall costs, while at the same time satisfying customers in terms of service.

In view of the lack of image enhancement processing in the traditional methods in image preprocessing, which leads to a long detection time for internal cracks in the image and poor visual effects, an intelligent detection method for internal cracks in aircraft landing gear images under multimedia processing is proposed. A spatial index structure is established based on the multimedia database, and the aircraft landing gear images in the structure are enhanced and denoised. Image segmentation is performed according to the preprocessing results, the crack foreground and the road surface background in the image are separated, and the threshold value of each image is calculated. The threshold segmentation result is used to distinguish which pixels are the areas where the cracks may exist and which pixels belong to the image background, and the judgment result realizes crack detection. The experimental results show that the crack detection time of the proposed method is shorter, the visual effect of the detection results is better, and the average of the expert score reaches 93.6 points, which verifies the effectiveness of the proposed method from both the subjective and objective aspects.

Endoplasmic reticulum (ER) stress has been implicated in some types of glomerular and tubular disorders. The objectives of this study were to elucidate the role of ER stress in lithium-induced nephrogenic diabetes insipidus (NDI) and to investigate whether attenuation of ER stress by 4-phenylbutyric acid (4-PBA) improves urinary concentrating defect in lithium-treated rats. Wistar rats received lithium (40 mmol/kg food), 4-PBA (320 mg/kg body wt by gavage every day), or no treatment (control) for 2 wk, and they were dehydrated for 24 h before euthanasia. Lithium treatment resulted in increased urine output and decreased urinary osmolality, which was significantly improved by 4-PBA. 4-PBA also prevented reduced protein expression of aquaporin-2 (AQP2), pS256-AQP2, and pS261-AQP2 in the inner medulla of kidneys from lithium-treated rats after 24-h dehydration. Lithium treatment resulted in increased expression of ER stress markers in the inner medulla, which was associated with dilated cisternae and expansion of ER in the inner medullary collecting duct (IMCD) principal cells. Confocal immunofluorescence studies showed colocalization of a molecular chaperone, binding IgG protein (BiP), with AQP2 in principal cells. Immunohistochemistry demonstrated increased intracellular expression of BiP and decreased AQP2 expression in IMCD principal cells of kidneys from lithium-treated rats. 4-PBA attenuated expression of ER stress markers and recovered ER morphology. In IMCD suspensions isolated from lithium-treated rats, 4-PBA incubation was also associated with increased AQP2 expression and ameliorated ER stress. In conclusion, in experimental lithium-induced NDI, 4-PBA improved the urinary concentrating defect and increased AQP2 expression, likely via attenuating ER stress in IMCD principal cells.

We have previously shown that systemic administration of (pro)renin receptor (PRR) decoy inhibitor PRO20 impaired kaliuretic response to high K + (HK) intake (5% KCl in diet). The present study extends this observation by examining the phenotype of inducible renal tubule-specific PRR knockout (RT PRR KO) mice fed a HK diet. The null mice were generated by breeding Floxed PRR mice with mice transgenic for Pax8-rtTA and LC-1 transgene. To induce RT PRR KO, mice with homozygous for Floxed PRR gene and hemizygous for the Pax8-rtTA and the LC-1 transgene were given 2 mg/ml doxycycline in 5% sucrose drinking water for 14 days followed by 4-wk off doxycycline. Following 1-wk HK intake, RT PRR KO mice had decreased urinary K + (by 33.6%) excretion and elevated plasma K + level (KO+HK: 5.38 ± 0.21 vs. Floxed+HK: 3.98 ± 0.03 mM, P + -K + -ATPase (160.3%), β-ENaC (130.2%), and cleaved-γ-ENaC (542.0%), and downregulated phosphorylated NCC-T53 (pNCC-T53) protein expression, all of which were significantly blunted in RT PRR KO mice (by 25-80%). In Flp-In T-REX 293 NCC cell line (stably expressing NCC), PRR siRNA significantly increased pNCC-T53 (by 72.3%) and partially reversed prorenin (100 nM)-induced inhibition of pNCC-T53 (by 38.2%). sPRR-His (10 nM) inhibited pNCC-T53 (by 48.9%), which were significantly reversed by losartan or angiotensin II receptor type 1 (AT1R) siRNA, without affecting total NCC expression. Together, these results suggest that PRR/sPRR contributes to the kaliuretic response through an impact on the intrarenal RAAS and the K + secretory machinery in the distal nephron.

Thiazolidinediones, the PPARgamma agonists, represent a unique class of insulin sensitizers for management of hyperglycemia in type 2 diabetes but are limited by the side effect of fluid retention. Here we report therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed as sPRR-His, in a mouse obesity model induced by 9-month high fat diet (DIO) for management of glucose dysregulation. In the DIO mice, a 2-wk administration of sPRR-His lowered body weight (47.0 ± 1.4 vs. 52.8 ± 1.2 g) and remarkably improved multiple metabolic parameters including hyperglycemia (serum glucose: 148.8 ± 19.1 vs. 224.8 ± 12.5 mg/dL), hyperinsulinemia (serum insulin: 3.7 ± 0.4 vs. 10.9 ± 0.9 ng/ml), glucose intolerance, albuminuria (urine albumin/ Creatinine: 63.4 ± 3.5 vs. 97.7 ± 10.2 mg/g), and glomerular hyperfiltration (GFR: 264.7 ± 12.2 vs. 521.3 ± 18.2 μl/min) in the absence of fluid retention (plasma volume: 28.7 ± 1.2 vs. 27.8 ± 0.9 μl/g). GFR and plasma volume were measured by using FITC-sinistrin (7.5mg/100g i.v.) and FITC-dextran (2 mg/100 g i.v.) respectively. Conversely, inhibition of endogenous sPRR production by PF429242, an inhibitor of site-1 protease induced diabetes and insulin resistance which were reversed by sPRR-His supplement. At cellular level, sPRR-His enhanced insulin-induced increases in glucose uptake via upregulation of phosphorylated AKT and protein abundance of Glut4. Promoter and gene expression analysis revealed PRR as a direct target gene of PPARγ. Adipocyte-specific PPARγ deletion induced severe diabetes (blood glucose: 243.6 ± 39.8 vs. 108.4 ± 2.1 mg/dL) and insulin resistance (plasma insulin: 48.9 ± 4 vs. 1.5 ± 0.2 ng/ml) associated with reduced adipose PRR expression and circulating sPRR (plasma sPRR: 265.7 ± 14 vs. 893.0 ± 86.8 pg/ml). sPRR-His supplement in the null mice nearly normalized blood glucose (142.4 ± 12.2 mg/dL) and insulin level (14.3 ± 7.9 ng/ml). Additionally, sPRR-His treatment suppressed DIO-induced renal sodium-glucose cotransporter-2 (SGLT2) expression. Overall, sPRR-His exerts potent hypoglycemic action via serving as a mediator of insulin-sensitizing action of thiazolidinedione as well as a negative regulator of renal SGLT2 in the absence of fluid retention side effect.

The therapies available for management of obesity and associated conditions are limited, because they are often directed toward an individual component of metabolic syndrome and are associated with adverse effects. Here, we report the multifaceted therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed sPRR-His, in a mouse model of diet-induced obesity (DIO). In the DIO model, 2-week administration of sPRR-His lowered body weight and remarkably improved multiple metabolic parameters in the absence of fluid retention. Conversely, inhibition of endogenous sPRR production by PF429242 induced diabetes and insulin resistance, both of which were reversed by the sPRR-His supplement. At the cellular level, sPRR-His enhanced insulin-induced increases in glucose uptake via upregulation of phosphorylated AKT and protein abundance of glucose transporter 4. Promoter and gene expression analysis revealed PRR as a direct target gene of PPARγ. Adipocyte-specific PPARγ deletion induced severe diabetes and insulin resistance associated with reduced adipose PRR expression and circulating sPRR. The sPRR-His supplement in the null mice nearly normalized blood glucose and insulin levels. Additionally, sPRR-His treatment suppressed DIO-induced renal sodium-glucose cotransporter-2 (SGLT2) expression. Overall, sPRR-His exhibits a therapeutic potential in management of metabolic syndrome via interaction with PPARγ.

Dahl salt-sensitive (SS) hypertensive rats exhibit increased expression of renal (pro)renin receptor (PRR) and aberrant activation of the intrarenal renin-angiotensin system (RAS) with unclear functional implication. Recent evidence demonstrates that soluble PRR (sPRR) serves as a potential regulator of tubular transport via activating Wnt/ β-catenin pathway in the distal nephron and is derived from the cleavage by site-1 protease (S1P). The present study attempted to define the role of sPRR during salt-sensitive hypertension in SS rats. The effect of S1P inhibitor PF-429242 (PF at 20 mg/kg/d via mini-pump) on blood pressure, proteinuria, and urinary renin were tested in SS rats during high salt loading. In a separate group, a recombinant sPRR (sPRR-His at 20 μg/kg/d) was infused via catheterization of jugular vein to SS rats during PF treatment. In High sodium (HS)-loaded SS rats, administration of PF attenuated the hypertension development (MAP on day 10, HS+PF group: 124.5 ± 4.6 mmHg vs. HS group: 144.1 ± 8.2 mmHg) as assessed by radiotelemetry and proteinuria (HS+PF group: 50.9 ± 5.5 μg/24h vs. HS group: 105.3 ± 7.4 μg/24h). PF treatment reduced HS-stimulated urinary sPRR excretion by 65% in SS rats. Supplement of sPRR restored HS-induced hypertension during PF treatment (MAP on day 10, HS+PF+sPRR-His group: 138.7 ± 6.1 vs. HS+PF group: 124.5 ± 4.6 mmHg) and proteinuria (HS+PF+sPRR-His group: 79.0 ± 5.8 μg/24h vs. HS+PF group: 50.9 ± 5.5 μg/24h) in SS rats. Concurrently, PF treatment reduced HS-stimulated urinary renin activity (by 80%), aldosterone excretion (by 36%) and renal medullary prorenin and renin (by 60%), which were all restored by sPRR-His infusion (1.5- to 3-fold). Indices of Wnt/β-catenin pathway including protein levels of renal cytosolic Axin-2 and nuclear β-catenin as assessed by immunoblotting were elevated by HS (3.4-fold, 2.2-fold respectively) in SS but not SR rats, which were all suppressed by S1P inhibition (by 80% and 50% respectively) and restored by sPRR-His infusion. Given β-catenin signaling as a known regulator of intrarenal RAS, our results suggest that S1P-derived sPRR plays a pathogenic role in salt-sensitive hypertension in SS rats via β-catenin/intrarenal RAS pathway.

We previously reported that (pro)renin receptor is activated by K + loading and is responsible for local generation of aldosterone (Aldo), contributing to the kaliuretic response. Furthermore, site-1 protease (S1P) but not furin or ADMA19 is the predominant PPR cleavage enzyme, and a recombinant sPRR, sPRR-His, stimulated Aldo synthase CYP11B2 expression and released Aldo in primary rat IMCD cells. The present study examined a potential role of renal S1P during high K + (HK) loading. In normal C57BL/6 mice, a 3-day HK intake (5% KCl in diet) induced renal protein expression of S1P (Cortical: 172.5%, Medullary: 380.5%). Administration of a S1P inhibitor PF429242 (PF) via mini pump infusion at 25 mg/kg/day for 3 days, to K + -loaded animals elevated plasma K + level (HK+vehicle: 4.12 ± 0.13 vs. HK+PF: 4.52± 0.23 mM, P + excretion (by 33%), accompanied with a reduction of urinary prorenin/renin content (by 63.2%), urinary renin activity (by 63.8%), urinary free and total Aldo excretion (by 53.6% and 58.6%, respectively), and kidney cortical and medullary Aldo (by 36.5% and 59.1%, respectively), without affecting plasma Aldo or renin levels. HK upregulated renal protein expression of sPRR (Cortical: 145.5%, Medullary: 211.6%), prorenin (Cortical: 184%, Medullary: 325.8%), CYP11B2 (cortical: 184.9%, medullary: 331.5%), renal outer medullary K + channel (ROMK) (139.1%), calcium-activated potassium channel subunit alpha-1 (α-BK) (147.8%), α-Na + -K + -ATPase (151.6%), β-ENaC (150%), and cleaved-γ-ENaC (622.3%), and downregulated total NCC and phosphorylated NCC (T53) protein expression (by 33.1% and 35.1%, respectively) as well as in vivo NCC activity response to hydrochlorothiazide (by 37.3% decrease in 6-h urine volume and UNaV), all of which were significantly blunted by PF (by 30-70%). In cultured CD-derived M1 cells, exposure to 10 mM KCl for 24 h augmented sPRR (155.6%) and Prorenin (154.4%) protein expression, which were both attenuated by PF (by 45.7% and 86.8%, respectively). Additionally, sPRR-His (10 nM) stimulated prorenin protein expression (165.2%). Together, these results suggest that S1P-derived sPRR contributes to K + secretion through activation of intrarenal RAAS.

The kalliuric action of the renin-angiotensin-aldosterone system (RAAS) is well established as highlighted by hyperkaliemia side effect of RAAS inhibitors but such action is usually ascribed to systemic RAAS. The present study attempted to address the involvement of intrarenal RAAS in K + homeostasis with emphasis on locally generated renin and aldosterone (Aldo) within the collecting duct (CD). In normal C57BL/6 mice, a 1-wk high K + (HK) intake (5% KCl in diet) induced parallel increases in renal prorenin (cortex: 298.8%; medulla: 323.8%) assessed by immunoblotting, and urinary prorenin/renin content (URC) (2.5-fold) assessed by ELISA, and urinary renin activity (URA) (1.5-fold), contrasting to suppressed plasma prorenin/renin concentration (by 25.6%) and renin activity (by 61.6%). Following 1-wk HK loading, mice lacking renin in the CD (CD renin KO) had decreased urinary K + excretion (by 20.2%) and elevated plasma K + level (KO+HK: 4.35 ± 0.14 vs. Floxed+HK: 3.89 ± 0.04 mM, P + channel (ROMK) (146.4%), calcium-activated potassium channel subunit alpha-1 (α-BK) (160.9%), α-Na + -K + -ATPase (155.8%), β-ENaC (165.1%), and cleaved-γ-ENaC (1800%), all of which were significantly blunted in CD renin KO mice (by 25-75%). We have developed an inducible renal tubule-wide CYP11B2 KO using the Pax8/LC1 transgenes (termed as RT CYP11B2 KO). While the homozygous deletion is lethal, the heterozygous mice exhibited normal development and were subjected to 3-day HK. K + -loaded RT CYP11B2 KO mice had decreased urinary K + excretion (by 30.5%) and hyperkalemia (KO+HK: 4.63 ± 0.05 vs . Floxed+HK: 3.98 ± 0.09 mM, P Aldo excretion (by 20.4% and 34.4%, respectively) without affecting plasma Aldo levels. Taken together, these results support a local action of CD renin and Aldo in regulation of K + homeostasis.

Emerging evidence has demonstrated that (pro)renin receptor (PRR)-mediated activation of intrarenal renin-angiotensin system (RAS) plays an essential role in renal handling of Na + and water balance and blood pressure. The present study tested the possibility that the intrarenal RAS served as a molecular target for the protective action of ELABELA (ELA, also known as Toddler/Apela), a novel endogenous ligand of APJ receptor (also known as APLNR) in the distal nephron. By RNAscope and immunofluorescence, mRNA and protein expression of endogenous ELA was consistently localized to the collecting duct (CD). In cultured CD-derived M1 cells, exogenous ELA induced parallel decreases of fPRR (by 31.6%), soluble PRR (sPRR) (by 46.5%), and prorenin (by 45.7%) protein expression as assessed by immunoblotting, and medium sPRR (by 66.7%) and prorenin/renin (by 60%) levels by ELISA. Conversely, deletion of PRR in the CD in mice elevated ELA mRNA levels (1.5-fold), and urinary ELA excretion (2.0-fold), supporting the antagonistic relationship between the two systems. Administration of exogenous ELA (5 mg/kg/day, minipump) to high salt (HS)-loaded Dahl salt-sensitive (SS) rats significantly lowered mean arterial pressure (113.0 ± 1.7 vs . 133.8 ± 1.5 mmHg, P vs . 142.9 ± 2.6 mmHg, P vs . 127.4 ± 0.9 mmHg, P vs . 394.1 ± 5.3 bpm, P vs . 5.1 ± 1.1 mg/24h, P

The antidiuretic hormone vasopressin (AVP), acting through its type 2 receptor (V(2)R) in the collecting duct (CD), critically controls urine concentrating capability. Here, we report that site-1 protease–derived (S1P-derived) soluble (pro)renin receptor (sPRR) participates in regulation of fluid homeostasis via targeting V(2)R. In cultured inner medullary collecting duct (IMCD) cells, AVP-induced V(2)R expression was blunted by a PRR antagonist, PRO20; a PRR-neutralizing antibody; or a S1P inhibitor, PF-429242. In parallel, sPRR release was increased by AVP and reduced by PF-429242. Administration of histidine-tagged sPRR, sPRR-His, stimulated V(2)R expression and also reversed the inhibitory effect of PF-429242 on the expression induced by AVP. PF-429242 treatment in C57/BL6 mice impaired urine concentrating capability, which was rescued by sPRR-His. This observation was recapitulated in mice with renal tubule–specific deletion of S1P. During the pharmacological or genetic manipulation of S1P alone or in combination with sPRR-His, the changes in urine concentration were paralleled with renal expression of V(2)R and aquaporin-2 (AQP2). Together, these results support that S1P-derived sPRR exerts a key role in determining renal V(2)R expression and, thus, urine concentrating capability.

Increasing evidence supports the important role of H(2)S in renal physiology and the pathogenesis of kidney injury. Whether H(2)S regulates water metabolism in the kidney and the potential mechanism are still unknown. The present study was conducted to determine the role of H(2)S in urine concentration. Inhibition of both cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), 2 major enzymes for endogenous H(2)S production, with propargylglycine (PPG) and amino-oxyacetate (AOAA), respectively, caused increased urine output and reduced urine osmolality in mice that was associated with decreased expression of aquaporin (AQP)-2 in the renal inner medulla. Mice treated with both PPG and AOAA developed a urine concentration defect in response to dehydration that was accompanied by reduced AQP-2 protein expression. Inhibition of CSE alone was associated with a mild decrease in AQP-2 protein level in the renal medulla of heterozygous CBS mice. GYY4137, a slow H(2)S donor, markedly improved urine concentration and prevented the down-regulation of renal AQP-2 protein expression in mice with lithium-induced nephrogenic diabetes insipidus (NDI). GYY4137 significantly increased cAMP levels in cell lysates prepared from inner medullary collecting duct (IMCD) suspensions. AQP-2 protein expression was also upregulated, but was significantly inhibited by the adenyl cyclase inhibitor MDL12330A or the PKA inhibitor H89, but not the vasopressin 2 receptor (V(2)R) antagonist tolvaptan. Inhibition of endogenous H(2)S production impaired urine concentration in mice, whereas an exogenous H(2)S donor improved urine concentration in lithium-induced NDI by increasing AQP-2 expression in the collecting duct principal cells. H(2)S upregulated AQP-2 protein expression, probably via the cAMP-PKA pathway.—Luo, R., Hu, S., Liu, Q., Han, M., Wang, F., Qiu, M., Li, S., Li, X., Yang, T., Fu, X., Wang, W., Li, C. Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.

The molecular mechanisms of melamine-induced renal toxicity have not been fully understood. The purpose of the study aimed to investigate whether melamine and cyanuric acid induced NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in the kidney, which may contribute to abnormal water and sodium handling in a rat model. Wistar rats received melamine (Mel; 200 mg·kg body wt−1·day−1), cyanuric acid (CA; 200 mg·kg body wt−1·day−1), or Mel plus CA (Mel + CA; 100 mg·kg body wt−1·day−1, each) for 2 wk. Mel + CA caused damaged tubular epithelial structure and organelles, dilated tubular lumen, and inflammatory responses. Crystals were observed in urine and serum specimen, also in the lumen of dilated distal renal tubules. The combined ingestion of Mel and CA in rats caused a markedly impaired urinary concentration, which was associated with reduced protein expression of aquaporin (AQP)1, 2, and 3 in inner medulla and α-Na-K-ATPase and Na-K-2Cl transporters in cortex and outer medulla. Mel + CA treatment was associated with increased protein expression of CD3 and mRNA levels of CD68 and F4/80 as well as phosphorylation of NF-κB in the kidney. Mel + CA treatment increased protein and mRNA expression of NLRP3 inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1β in the inner medulla of rats. NF-κB inhibitor Bay 11-7082 reduced IL-1β expression induced by Mel + CA and prevented downregulation of AQP2 in inner medullary collecting duct cell suspensions. In conclusion, Mel + CA treatment caused urinary-concentrating defects and reduced expression of renal AQPs and key sodium transporters, which is likely due to the inflammatory responses and activation of NLRP3 inflammasome induced by crystals formed in the kidney.

We consider a supply chain system involved in a perishable product with a fixed lifetime. The retailer is using a periodical reviewed (s, S) policy to manage the inventory and sell the products with backlogs. The supplier and the retailer coordinate the system using a revenue-sharing contract in order to improve the channel performance and maximize the total profit of the system. We show that coordination between supplier and retailer with revenue-sharing contract is possible to improve the performance of the system. Considering the risk of product expiration, the optimal coordination contract is different for system selling perishable product compared with normal long lifetime product.

Microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme that converts prostaglandin H2 to prostaglandin E2 (PGE2), plays an important role in a variety of inflammatory diseases. We investigated the contribution of mPGES-1 to renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) for 7 days using wild-type (WT) and mPGES-1 knockout (KO) mice. UUO induced increased mRNA and protein expression of mPGES-1 and cyclooxygenase-2 in WT mice. UUO was associated with increased renal PGE2 content and upregulated PGE2 receptor (EP) 4 expression in obstructed kidneys of both WT and mPGES-1 KO mice; EP4 expression levels were higher in KO mice with UUO than those in WT mice. Protein expression of NLRP3 inflammasome components ASC and interleukin-1β was significantly increased in obstructed kidneys of KO mice compared with that in WT mice. mRNA expression levels of fibronectin, collagen III, and transforming growth factor-β1 (TGF-β1) were significantly higher in obstructed kidneys of KO mice than that in WT mice. In KO mice, protein expression of fibronectin and collagen III was markedly increased in obstructed kidneys compared with WT mice, which was associated with increased phosphorylation of protein kinase B (AKT). EP4 agonist CAY10598 attenuated increased expression of collagen I and fibronectin induced by TGF-β1 in inner medullary collecting duct 3 cells. Moreover, CAY10598 prevented the activation of NLRP3 inflammasomes induced by angiotensin II in human proximal tubule cells (HK2). In conclusion, these findings suggested that mPGES-1 exerts a potentially protective effect against renal fibrosis and inflammation induced by UUO in mice.

Evidence supports an important role of Ca2+ release-activated Ca2+ channel protein 1 (Orai1)-mediated Ca2+ entry in the development of renal fibrosis, a common pathologic feature of CKDs that lead to ESRD, but the molecular mechanisms remain unclear. We determined the role of Orai1 calcium channel in renal fibrosis induced by high-fat diet and by unilateral ureteral obstruction. Mouse kidneys with fibrosis had higher levels of Orai1 protein expression than did kidneys without fibrosis. In vivo knockdown of Orai1 with adenovirus harboring Orai1-short hairpin RNA or inhibition of Orai1 with SKF96365 dramatically prevented renal fibrosis and significantly decreased protein expression of fibronectin, α‑smooth muscle actin, and TGF‑β1 in the kidney cortex of ApoE-/- mice on a high-fat diet and in the obstructed kidneys of mice with unilateral ureteral obstruction. Compared with kidney biopsy specimens of patients with glomerular minimal change disease, those of patients with fibrotic nephropathy had higher expression levels of Orai1. In cultured human proximal tubule epithelial cells (HK2), knockdown of Orai1 Ca2+ channel with adenovirus-Orai1-short hairpin RNA markedly inhibited TGF-β1-induced intracellular Ca2+ influx and phosphorylation of smad2/3. Knockdown or blockade of the Orai1 Ca2+ channel in HK2 cells also prevented epithelial-to-mesenchymal transition induced by TGF‑β1. In conclusion, blockade of the Orai1 Ca2+ channel prevented progression of renal fibrosis in mice, likely by suppressing smad2/3 phosphorylation and TGF-β1-induced epithelial-to-mesenchymal transition. These results render the Orai1 Ca2+ channel a potential therapeutic target against renal fibrosis.

Obesity-related kidney disease is related to caloric excess promoting deleterious cellular responses. Accumulation of saturated free fatty acids in tubular cells produces lipotoxicity involving significant cellular dysfunction and injury. The objectives of this study were to elucidate the role of renin-angiotensin system (RAS) activation in saturated fatty acid-induced endoplasmic reticulum (ER) stress in cultured human proximal tubule epithelial cells (HK2) and in mice fed with a high-fat diet. Treatment with saturated fatty acid palmitic acid (PA; 0.8 mM) for 24 h induced ER stress in HK2, leading to an unfolded protein response as reflected by increased expressions of the ER chaperone binding immunoglobulin protein (BiP) and proapoptotic transcription factor C/EBP homologous protein (CHOP) protein as evaluated by immunoblotting. PA treatment also induced increased protein expression of inositol requiring protein 1α (IRE1α), phosphorylated eukaryotic initiation factor-α (eIF2α), and activating transcription factor 4 (ATF4) as well as activation of caspase-3. PA treatment was associated with increased angiotensin II levels in cultured medium. The angiotensin II type 1 receptor (AT1R) blocker valsartan or renin inhibitor aliskiren dramatically suppressed PA-induced upregulation of BiP, CHOP, IRE1α, p-eIF2α, and ATF4 in HK2 cells. In contrast, valsartan or aliskiren did not prevent ER stress induced by tunicamycin. C57BL/6 mice fed with a high-fat diet for 14 wk exhibited increased protein expressions of BiP and CHOP compared with control mice, which were significantly attenuated by the valsartan treatment. Increased angiotensin II levels in serum and urine were observed in mice fed with a high-fat diet when compared with controls. It is suggested that the intrarenal RAS activation may play an important role in diabetic kidney injury via mediating ER stress induced by saturated fatty acid.

Ureteral obstruction is associated with reduced expression of renal aquaporins (AQPs), urinary concentrating defects, and an enhanced inflammatory response, in which the renin-angiotensin system (RAS) may play an important role. We evaluated whether RAS blockade by a direct renin inhibitor, aliskiren, would prevent the decreased renal protein expression of AQPs in a unilateral ureteral obstruction (UUO) model and what potential mechanisms may be involved. UUO was performed for 3 days (3UUO) and 7 days (7UUO) in C57BL/6 mice with or without aliskiren injection. In 3UUO and 7UUO mice, aliskiren abolished the reduction of AQP2 protein expression but not AQP1, AQP3, and AQP4. mRNA levels of renal AQP2 and vasopressin type 2 receptor were decreased in obstructed kidneys of 7UUO mice, which were prevented by aliskiren treatment. Aliskiren treatment was also associated with a reduced inflammatory response in obstructed kidneys of UUO mice. Aliskiren significantly decreased mRNA levels of several proinflammatory factors, such as transforming growth factor-β and tumor necrosis factor-α, seen in obstructed kidneys of UUO mice. Interestingly, mRNA and protein levels of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1β were dramatically increased in obstructed kidneys of 7UUO mice, which were significantly suppressed by aliskiren. In primary cultured inner medullary collecting duct cells, IL-1β significantly decreased AQP2 expression. In conclusions, RAS blockade with the direct renin inhibitor aliskiren increased water channel AQP2 expression in obstructed kidneys of UUO mice, at least partially by preventing NLRP3 inflammasome activation in association with ureteral obstruction.

In this paper, the design of an asynchronized messaging system where a user may proactively seek for answers or advice by depositing a question on the messaging system is presented. The messaging system will automatically disseminate the question which is related to a specific location, to a group of users who are either within the proximity currently or have just recently been there. The users are supposed to help each other; karma or some sort of point/score system can be added to distinguish the most helpful users in the community. A name is suggested for this system called “Lemmings” which stands for Location-based Mutual and Mobile Information Navigation System; it is based on a classical video game where a group of creatures have to work and win through the puzzle game together. The design presented is modular and it comprised of the logics, the data flows, and the database schema.