PPAR-γ agonist rosiglitazone ameliorates peritoneal deterioration in peritoneal dialysis rats with LPS-induced peritonitis through up-regulation of AQP-1 and ZO-1.

Peritonitis is still a major cause of the death in peritoneal dialysis (PD) patients despite the significant decline of the peritonitis rates in recent years. The present study is designed to evaluate the therapeutic potential of peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, on the structure and function of the peritoneum in a PD rat accompanied with peritonitis induced by lipopolysaccharide (LPS). Our data showed that the peritoneal membrane in the LPS-only group showed increased peritoneal thickness, vessel density, and hypercellularity compared with the PD-only group. Rosiglitazone administration significantly inhibited increase of the three indicators in PD rats with LPS treatment. In line with this, rosiglitazone improved function of the peritoneum in LPS-induced PD rats receiving rosiglitazone, which was reflected by decreased D/P urea and D/P albumin. Mechanistically, rosiglitazone-mediated improvements in the damaged structure and function of the peritoneum in PD rats with LPS treatment were associated with reduced inflammation and preserving mesothelial cell monolayer resulted from up-regulation of AQP-1 and ZO-1. Our findings thus suggest that peroxisome proliferator-activated receptor γ (PPAR-γ) activation might be a reasonable strategy to prevent and ameliorate peritoneal deterioration in PD patients, especially with peritonitis.

Pistacia integerrima ameliorates airway inflammation by attenuation of TNF-α, IL-4, and IL-5 expression levels, and pulmonary edema by elevation of AQP1 and AQP5 expression levels in mouse model of ovalbumin-induced allergic asthma.

BACKGROUND: Natural products are considered as an essential source for the search of new drugs. Pistacia integerrima galls (PI) have been used for the treatment of asthma and cough in traditional system of medicine. AIM/HYPOTHESIS: Current study investigates the immunomodulatory and anti-inflammatory activities of P. integerrima in mouse model of ovalbumin-induced allergic asthma. METHODS: Mice were intraperitoneally sensitized and subsequently challenged intranasally with ovalbumin to induce allergic asthma. Experimental group mice were treated with methanol extract of P. integerrima extract (200mg/kg b. w.) and Methylprednisolone (MP) (15mg/kg b. w.) for 07 consecutive days, alongside intranasal challenge. Lung tissues were stained with Hematoxyline and Eosin (H & E), and Periodic Acid-Schiff (PAS) stains for histopathological evaluation. Lung wet/dry weight ratio was measured as an index of lung tissue edema. Albumin was injected in the right ear 24h before sacrificing the mice and difference of weight was taken as a degree of delayed type hypersensitivity (DTH). mRNA expression levels of TNF-α, IL-4, IL-5, Aquaporin-1 (AQP1), and AQP5 were evaluated using reverse transcription polymerase chain reaction (RT-PCR) followed by gel electrophoresis. RESULTS: The data showed both PI extract and MP significantly alleviated DTH and nearly normalized total leukocyte count and differential leukocyte count in both blood and BALF. We found significantly suppressed goblet cell hyperplasia and inflammatory cell infiltration after treatment with both PI extract and MP. Expression levels of TNF-α, IL-4, and IL-5 were also found significantly reduced after treatment with both PI extract and MP, which might have resulted in the amelioration of airway inflammation. Current study displayed that both PI extract and MP significantly decreased lung wet/dry ratio, suggesting reduction in pulmonary edema. RT-PCR analysis showed significant increase in AQP1 and AQP5 expression levels after treatment with both PI extract and MP, which might have caused the alleviation of pulmonary edema. CONCLUSION: Our study displays that P. integerrima possesses significant anti-asthmatic activity which may be attributed to reduction in TNF-α, IL-4, and IL-5 expression levels, and increase in AQP1 and AQP5 expression levels.

Dexmedetomidine alleviates pulmonary edema by upregulating AQP1 and AQP5 expression in rats with acute lung injury induced by lipopolysaccharide.

This study aims to elucidate the mechanisms by which dexmedetomidine alleviates pulmonary edema in rats with acute lung injury induced by lipopolysaccharide (LPS). Male Wistar rats were randomly divided into five groups: normal saline control (NS) group, receiving intravenous 0.9% normal saline (5 mL/kg); LPS group, receiving intravenous LPS (10 mg/kg); small-dose dexmedetomidine (S) group, treated with a small dose of dexmedetomidine (0.5 µg · kg(-1) · h(-1)); medium-dose dexmedetomidine (M) group, treated with a medium dose of dexmedetomidine (2.5 µg · kg(-1) · h(-1)); high-dose dexmedetomidine (H) group, treated with a high dose of dexmedetomidine (5 µg · kg(-1) · h(-1)). The rats were sacrificed 6 h after intravenous injection of LPS or NS, and the lungs were removed for evaluating histological characteristics and determining the lung wet/dry weight ratio (W/D). The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß) in the lung tissues were assessed by enzyme- linked immunosorbent assay (ELISA). The mRNA and protein expression levels of aquaporin-1 (AQP1) and aquaporin-5 (AQP5) were detected by RT-PCR, immunohistochemistry, and Western blotting. The lung tissues from the LPS groups were significantly damaged, which were less pronounced in the H group but not in the small-dose dexmedetomidine group or medium-dose dexmedetomidine group. The W/D and the concentrations of TNF-α and IL-1ß in the pulmonary tissues were increased in the LPS group as compared with those in NS group, which were reduced in the H group but not in S group or M group (P<0.01). The expression of AQP1 and AQP5 was lower in the LPS group than in the NS group, and significantly increased in the H group but not in the S group or M group (P<0.01). Our findings suggest that dexmedetomidine may alleviate pulmonary edema by increasing the expression of AQP-1 and AQP-5.

Water transport across the peritoneal membrane.

Peritoneal dialysis involves diffusive and convective transports and osmosis through the highly vascularized peritoneal membrane. The capillary endothelium offers the rate-limiting hindrance for solute and water transport. It can be functionally described in terms of a three-pore model including transcellular, ultrasmall pores responsible for free-water transport during crystalloid osmosis. Several lines of evidence have demonstrated that the water channel aquaporin-1 (AQP1) corresponds to the ultrasmall pore located in endothelial cells. Studies in Aqp1 mice have shown that deletion of AQP1 is reflected by a 50% decrease in ultrafiltration and a disappearance of the sodium sieving. Haploinsufficiency in AQP1 is also reflected by a significant attenuation of water transport. Conversely, studies in a rat model and in PD patients have shown that the induction of AQP1 in peritoneal capillaries by corticosteroids is reflected by increased water transport and ultrafiltration, without affecting the osmotic gradient and small-solute transport. Recent data have demonstrated that a novel agonist of AQP1, predicted to stabilize the open-state conformation of the channel, modulates water transport and improves ultrafiltration. Whether increasing the expression of AQP1 or gating the already existing channels would be clinically useful in PD patients remains to be investigated.

AqF026 is a pharmacologic agonist of the water channel aquaporin-1.

Aquaporin-1 (AQP1) facilitates the osmotic transport of water across the capillary endothelium, among other cell types, and thereby has a substantial role in ultrafiltration during peritoneal dialysis. At present, pharmacologic agents that enhance AQP1-mediated water transport, which would be expected to increase the efficiency of peritoneal dialysis, are not available. Here, we describe AqF026, an aquaporin agonist that is a chemical derivative of the arylsulfonamide compound furosemide. In the Xenopus laevis oocyte system, extracellular AqF026 potentiated the channel activity of human AQP1 by >20% but had no effect on channel activity of AQP4. We found that the intracellular binding site for AQP1 involves loop D, a region associated with channel gating. In a mouse model of peritoneal dialysis, AqF026 enhanced the osmotic transport of water across the peritoneal membrane but did not affect the osmotic gradient, the transport of small solutes, or the localization and expression of AQP1 on the plasma membrane. Furthermore, AqF026 did not potentiate water transport in Aqp1-null mice, suggesting that indirect mechanisms involving other channels or transporters were unlikely. Last, in a mouse gastric antrum preparation, AqF026 did not affect the Na-K-Cl cotransporter NKCC1. In summary, AqF026 directly and specifically potentiates AQP1-mediated water transport, suggesting that it deserves additional investigation for applications such as peritoneal dialysis or clinical situations associated with defective water handling.

Effects of different resuscitation fluids on pulmonary expression of aquaporin1 and aquaporin5 in a rat model of uncontrolled hemorrhagic shock and infection.

BACKGROUND: To investigate the effects of fluids resuscitation on pulmonary expression of aquaporin1 and aquaporin5 in a rat model of uncontrolled hemorrhagic shock and infection. METHODS: Sixty Sprague-Dawley rats were randomly assigned to five groups, sham operation group (Group C) and four treated groups: no fluid resuscitation group (Group NF), groups resuscitated with Lactated Ringer's (LR),7.5% NaCl (HTS) and Hydroxyl ethyl starch (HES) respectively. Three-phased uncontrolled hemorrhagic shock and infection model was used. Phase I: Massive hemorrhage with a mean arterial pressure of 35-40 mmHg for 60 min, and followed by infection of lipopolysaccharide. Then some animals were resuscitated with solutions mentioned above, until 90 min. Phase II: At hemorrhagic shock 90 minutes, phase II of 60 minutes began with hemostasis and returning of all the initial shed blood. Phase III: Observation phase for 3.5 hours. After phase III, arterial blood gas analysis and the survival rates of the rats were recorded, Wet-to-dry lung weight ratio, BALF protein, pulmonary permeability index, and expressions of aquaporin1 and aquaporin5 were tested. RESULTS: The expressions of aquaporin1 and aquaporin5 were decreased in treatment groups comparing with sham operation group. Group HES and Group HTS decreased pulmonary vascular permeability and Wet-to-dry lung weight ratio, improved arterial blood gas analysis and survival rates, and attenuated the decreased pulmonary expression of aquaporin1 and aquaporin5 after the "two-hit", comparing with groups NF and LR,but these beneficial effects were blunted in group HTS. CONCLUSION: The expression of aquaporin1 and aquaporin5 may play important roles in formation of pulmonary edema. Resuscitation with HTS and HES, especially HES can reduce lung injury after hemorrhagic shock, partly by up-regulating the expressions of aquaporin1 and aquaporin5.

Aquaporin-1: new developments and perspectives for peritoneal dialysis.

Peritoneal dialysis involves diffusive and convective transport and osmosis through the highly vascularized peritoneal membrane. Several lines of evidence have demonstrated that the water channel aquaporin-1 (AQP1) corresponds to the ultrasmall pore predicted by the model of peritoneal transport. Proof-of-principle studies have shown that upregulation of the expression of AQP1 in peritoneal capillaries results in increased water permeability and ultrafiltration, without affecting the osmotic gradient or small solute permeability. Conversely, studies in Aqp1 mice have shown that haplo-insufficiency for AQP1 results in significant attenuation of water transport. Recent studies have demonstrated that AQP1 is involved in the migration of different cell types, including endothelial cells. In parallel, chemical screening has identified lead compounds that could act as antagonists or agonists of AQPs, with description of putative binding sites and potential mechanisms of gating the water channel. By modulating water transport, these pharmacological agents could have clinically relevant effects in targeting specific tissues or disease states.