Air pollution aggravates renal ischaemia-reperfusion-induced acute kidney injury.

Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM2.5) and a decline in renal function. PM2.5 exerts harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischaemia-reperfusion injury (IRI) involves biological processes similar to those involved in PM2.5 toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM2.5 exposure on IRI-induced AKI. Through a unique environmentally controlled setup, mice were exposed to urban PM2.5 or filtered air for 12 weeks before IRI followed by euthanasia 48 h after surgery. Animals exposed to PM2.5 and IRI exhibited reduced glomerular filtration, impaired urine concentration ability, and significant tubular damage. Further, PM2.5 aggravated local innate immune responses and mitochondrial dysfunction, as well as enhancing cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation. This increased renal senescence and suppressed the anti-ageing protein klotho, leading to early fibrotic changes. In vitro studies using proximal tubular epithelial cells exposed to PM2.5 and hypoxia/reoxygenation revealed heightened activation of the STING pathway triggered by cytoplasmic mitochondrial DNA, resulting in increased tubular damage and a pro-inflammatory phenotype. In summary, our findings imply a role for PM2.5 in sensitising proximal tubular epithelial cells to IRI-induced damage, suggesting a plausible association between PM2.5 exposure and heightened susceptibility to CKD in individuals experiencing AKI. Strategies aimed at reducing PM2.5 concentrations and implementing preventive measures may improve outcomes for AKI patients and mitigate the progression from AKI to CKD. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Effects of terlipressin as early treatment for protection of brain in a model of haemorrhagic shock.

INTRODUCTION: We investigated whether treatment with terlipressin during recovery from hypotension due to haemorrhagic shock (HS) is effective in restoring cerebral perfusion pressure (CPP) and brain tissue markers of water balance, oxidative stress and apoptosis. METHODS: In this randomised controlled study, animals undergoing HS (target mean arterial pressure (MAP) 40 mmHg for 30 minutes) were randomised to receive lactated Ringer's solution (LR group; n =14; volume equal to three times the volume bled), terlipressin (TERLI group; n =14; 2-mg bolus), no treatment (HAEMO group; n =12) or sham (n =6). CPP, systemic haemodynamics (thermodilution technique) and blood gas analyses were registered at baseline, shock and 5, 30, 60 (T60), 90 and 120 minutes after treatment (T120). After the animals were killed, brain tissue samples were obtained to measure markers of water balance (aquaporin-4 (AQP4)), Na(+)-K(+)-2Cl(-) co-transporter (NKCC1)), oxidative stress (thiobarbituric acid reactive substances (TBARS) and manganese superoxide dismutase (MnSOD)) and apoptotic damage (Bcl-x and Bax). RESULTS: Despite the HS-induced decrease in cardiac output (CO) and hyperlactataemia, resuscitation with terlipressin recovered MAP and resulted in restoration of CPP and in cerebral protection expressed by normalisation of AQP4, NKCC1, TBARS and MnSOD expression and Bcl-x/Bax ratio at T60 and T120 compared with sham animals. In the LR group, CO and blood lactate levels were recovered, but the CPP and MAP were significantly decreased and TBARS levels and AQP4, NKCC1 and MnSOD expression and Bcl-x/Bax ratio were significantly increased at T60 and T120 compared with the sham group. CONCLUSIONS: During recovery from HS-induced hypotension, terlipressin was effective in normalising CPP and cerebral markers of water balance, oxidative damage and apoptosis. The role of this pressor agent on brain perfusion in HS requires further investigation.

N-acetyl-cysteine is associated to renal function improvement in patients with nephropathic cystinosis.

BACKGROUND: Nephropathic cystinosis is an autosomal recessive systemic severe disease characterized by intralysosomal cystine storage. Cysteamine is an essential component of treatment. There is solid evidence that cystine accumulation itself is not responsible for all abnormalities in cystinosis; there is also a deficiency of glutathione in the cytosol. Patients with cystinosis can be more susceptible to oxidative stress. CASE-DIAGNOSIS/TREATMENT: The patient cohort comprised 23 cystinosis patients (16 males) aged <18 years (mean age 8.0 ± 3.6 years) with chronic kidney disease class I-IV with good adherence to treatment, including cysteamine. Oxidative stress was evaluated based on the levels of serum thiobarbituric acid-reactive substances (TBARS), and renal function was evaluated based on serum creatinine and cystatin C levels and creatinine clearance (Schwartz formula). N-Acetylcysteine (NAC), an antioxidant drug was given to all patients for 3 months (T1) at 25 mg/kg/day divided in three doses per day. The measured values at just before the initiation of NAC treatment (T0) served as the control for each patient. RESULTS: Median serum TBARS levels at T0 and T1 were 6.92 (range 3.3-29.0) and 1.7 (0.6-7.2)  nmol/mL, respectively (p < 0.0001). In terms of renal function at T0 and T1, serum creatinine levels (1.1 ± 0.5 vs. 0.9 ± 0.5 mg/dL, respectively; p < 0.0001), creatinine clearance (69.7 ± 32.2 vs. T1 = 78.5 ± 33.9 mL/min/1.73 m(2), respectively; p = 0.006), and cystatin c level (1.33 ± 0.53 vs. 1.15 ± 0.54 mg/l, respectively; p = 0.0057) were all significantly different at these two time points. Serum creatinine measurements at 6 (T -6) and 3 months (T -3) before NAC initiation and at 3 (T +3) and 6 months (T +6) after NAC had been withdrawn were also evaluated. CONCLUSION: During the 3-month period that our 23 cystinosis patients were treated with NAC, oxidative stress was reduced and renal function significantly improved. No side-effects were detected. Larger and controlled studies are needed to confirm these findings.

Catecholamine concentration as a predictor of mortality in emergency surgical patients.

BACKGROUND: Trauma and emergency surgery are major causes of morbidity and mortality. The objective of this study was to determine whether serum levels of epinephrine and norepinephrine are associated with aging and mortality. METHODS: This was a prospective observational cohort study conducted in a surgical critical care unit. We included 90 patients who were admitted for postoperative care, because of major trauma, or both. We collected demographic and clinical variables, as well as serum levels of epinephrine and norepinephrine. RESULTS: For patients in the > 60-year age group, the use of vasoactive drugs was found to be associated with an undetectable epinephrine level (OR [95% CI] = 6.36 [1.12, 36.08]), p = 0.05). For the patients with undetectable epinephrine levels, the in-hospital mortality was higher among those with a norepinephrine level ≥ 2006.5 pg/mL (OR [95% CI] = 4.00 [1.27, 12.58]), p = 0.03). CONCLUSIONS: There is an association between age and mortality. Undetectable serum epinephrine, which is more common in older patients, could contribute to poor outcomes. The use of epinephrine might improve the clinical prognosis in older surgical patients with shock.

Obesity aggravates acute kidney injury resulting from ischemia and reperfusion in mice.

In critically ill patients, overweight and obesity are associated with acute respiratory distress syndrome and acute kidney injury (AKI). However, the effect of obesity on ischemia-reperfusion injury (IRI)-induced AKI is unknown. We hypothesized that obesity would aggravate renal IRI in mice. We fed mice a standard or high-fat diet for eight weeks. The mice were divided into four groups and submitted to sham surgery or IRI: obese, normal, normal + IRI, obese, and obese + IRI. All studies were performed 48 h after the procedures. Serum glucose, cholesterol, and creatinine clearance did not differ among the groups. Survival and urinary osmolality were lower in the obese + IRI group than in the normal + IRI group, whereas urinary neutrophil gelatinase-associated lipocalin levels, tubular injury scores, and caspase 3 expression were higher. Proliferating cell nuclear antigen expression was highest in the obese + IRI group, as were the levels of oxidative stress (urinary levels of thiobarbituric acid-reactive substances and renal heme oxygenase-1 protein expression), whereas renal Klotho protein expression was lowest in that group. Expression of glutathione peroxidase 4 and peroxiredoxin 6, proteins that induce lipid peroxidation, a hallmark of ferroptosis, was lower in the obese + IRI group. Notably, among the mice not induced to AKI, macrophage infiltration was greater in the obese group. In conclusion, greater oxidative stress and ferroptosis might aggravate IRI in obese individuals, and Klotho could be a therapeutic target in those with AKI.

TREATMENT WITH HUMAN UMBILICAL CORD-DERIVED MESENCHYMAL STEM CELLS IN A PIG MODEL OF SEPSIS-INDUCED ACUTE KIDNEY INJURY: EFFECTS ON MICROVASCULAR ENDOTHELIAL CELLS AND TUBULAR CELLS IN THE KIDNEY.

ABSTRACT: Background: Approximately 50% of patients with sepsis develop acute kidney injury (AKI), which is predictive of poor outcomes, with mortality rates of up to 70%. The endothelium is a major target for treatments aimed at preventing the complications of sepsis. We hypothesized that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) could attenuate tubular and endothelial injury in a porcine model of sepsis-induced AKI. Methods: Anesthetized pigs were induced to fecal peritonitis, resulting in septic shock, and were randomized to treatment with fluids, vasopressors, and antibiotics (sepsis group; n = 11) or to that same treatment plus infusion of 1 × 10 6 cells/kg of hUC-MSCs (sepsis+MSC group; n = 11). Results: At 24 h after sepsis induction, changes in serum creatinine and mean arterial pressure were comparable between the two groups, as was mortality. However, the sepsis+MSC group showed some significant differences in comparison with the sepsis group: lower fractional excretions of sodium and potassium; greater epithelial sodium channel protein expression; and lower protein expression of the Na-K-2Cl cotransporter and aquaporin 2 in the renal medulla. Expression of P-selectin, thrombomodulin, and vascular endothelial growth factor was significantly lower in the sepsis+MSC group than in the sepsis group, whereas that of Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) was lower in the former. Conclusion: Treatment with hUC-MSCs seems to protect endothelial and tubular cells in sepsis-induced AKI, possibly via the TLR4/NF-κB signaling pathway. Therefore, it might be an effective treatment for sepsis-induced AKI.

Sildenafil reduces polyuria in rats with lithium-induced NDI.

Lithium (Li)-treated patients often develop urinary concentrating defect and polyuria, a condition known as nephrogenic diabetes insipidus (NDI). In a rat model of Li-induced NDI, we studied the effect that sildenafil (Sil), a phosphodiesterase 5 (PDE5) inhibitor, has on renal expression of aquaporin-2 (AQP2), urea transporter UT-A1, Na(+)/H(+) exchanger 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (NKCC2), epithelial Na channel (ENaC; α-, ß-, and γ-subunits), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase. We also evaluated cGMP levels in medullary collecting duct cells in suspension. For 4 wk, Wistar rats received Li (40 mmol/kg food) or no treatment (control), some receiving, in weeks 2-4, Sil (200 mg/kg food) or Li and Sil (Li+Sil). In Li+Sil rats, urine output and free water clearance were markedly lower, whereas urinary osmolality was higher, than in Li rats. The cGMP levels in the suspensions of medullary collecting duct cells were markedly higher in the Li+Sil and Sil groups than in the control and Li groups. Semiquantitative immunoblotting revealed the following: in Li+Sil rats, AQP2 expression was partially normalized, whereas that of UT-A1, γ-ENaC, and eNOS was completely normalized; and expression of NKCC2 and NHE3 was significantly higher in Li rats than in controls. Inulin clearance was normal in all groups. Mean arterial pressure and plasma arginine vasopressin did not differ among the groups. Sil completely reversed the Li-induced increase in renal vascular resistance. We conclude that, in experimental Li-induced NDI, Sil reduces polyuria, increases urinary osmolality, and decreases free water clearance via upregulation of renal AQP2 and UT-A1.

Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase.

The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-κB activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLP+EPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-l-arginine methyl ester (l-NAME) simultaneously with EPO administration (CLP+EPO+l-NAME). A fifth group (CLP+EPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLP+EPO rats presented significantly higher inulin clearance than did CLP and CLP+EPO+l-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLP+EPO rats; and inulin clearance was significantly higher in CLP+EPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLP+EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-α activation, NF-κB activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-κB downregulation.

Terlipressin combined with conservative fluid management attenuates hemorrhagic shock-induced acute kidney injury in rats.

Hemorrhagic shock (HS), a major cause of trauma-related mortality, is mainly treated by crystalloid fluid administration, typically with lactated Ringer's (LR). Despite beneficial hemodynamic effects, such as the restoration of mean arterial pressure (MAP), LR administration has major side effects, including organ damage due to edema. One strategy to avoid such effects is pre-hospitalization intravenous administration of the potent vasoconstrictor terlipressin, which can restore hemodynamic stability/homeostasis and has anti-inflammatory effects. Wistar rats were subjected to HS for 60 min, at a target MAP of 30-40 mmHg, thereafter being allocated to receive LR infusion at 3 times the volume of the blood withdrawn (liberal fluid management); at 2 times the volume (conservative fluid management), plus terlipressin (10 µg/100 g body weight); and at an equal volume (conservative fluid management), plus terlipressin (10 µg/100 g body weight). A control group comprised rats not subjected to HS and receiving no fluid resuscitation or treatment. At 15 min after fluid resuscitation/treatment, the blood previously withdrawn was reinfused. At 24 h after HS, MAP was higher among the terlipressin-treated animals. Terlipressin also improved post-HS survival and provided significant improvements in glomerular/tubular function (creatinine clearance), neutrophil gelatinase-associated lipocalin expression, fractional excretion of sodium, aquaporin 2 expression, tubular injury, macrophage infiltration, interleukin 6 levels, interleukin 18 levels, and nuclear factor kappa B expression. In terlipressin-treated animals, there was also significantly higher angiotensin II type 1 receptor expression and normalization of arginine vasopressin 1a receptor expression. Terlipressin associated with conservative fluid management could be a viable therapy for HS-induced acute kidney injury, likely attenuating such injury by modulating the inflammatory response via the arginine vasopressin 1a receptor.

Urinary sodium excretion is low prior to acute kidney injury in patients in the intensive care unit.

Background: The incidence of acute kidney injury (AKI) is high in intensive care units (ICUs), and a better understanding of AKI is needed. Early chronic kidney disease is associated with urinary concentration inability and AKI recovery with increased urinary solutes in humans. Whether the inability of the kidneys to concentrate urine and excrete solutes at appropriate levels could occur prior to the diagnosis of AKI is still uncertain, and the associated mechanisms have not been studied. Methods: In this single-center prospective observational study, high AKI risk in ICU patients was followed up for 7 days or until ICU discharge. They were grouped as "AKI" or "No AKI" according to their AKI status throughout admission. We collected daily urine samples to measure solute concentrations and osmolality. Data were analyzed 1 day before AKI, or from the first to the fifth day of admission in the "No AKI" group. We used logistic regression models to evaluate the influence of the variables on future AKI diagnosis. The expression of kidney transporters in urine was evaluated by Western blotting. Results: We identified 29 patients as "No AKI" and 23 patients as "AKI," the latter being mostly low severity AKI. Urinary sodium excretion was lower in "AKI" patients prior to AKI diagnosis, particularly in septic patients. The expression of Na+/H+ exchanger (NHE3), a urinary sodium transporter, was higher in "AKI" patients. Conclusions: Urinary sodium excretion is low before an AKI episode in ICU patients, and high expressions of proximal tubule sodium transporters might contribute to this.

Green propolis extract attenuates acute kidney injury and lung injury in a rat model of sepsis.

Sepsis is the leading cause of acute kidney injury (AKI) and lung injury worldwide. Despite therapeutic advances, sepsis continues to be associated with high mortality. Because Brazilian green propolis (GP) has promising anti-inflammatory, antioxidant, and immunomodulatory properties, we hypothesized that it would protect kidneys and lungs in rats induced to sepsis by cecal ligation and puncture (CLP). Male Wistar rats were divided into groups-control (sham-operated); CLP (CLP only); and CLP + GP (CLP and treatment with GP at 6 h thereafter)-all receiving volume expansion and antibiotic therapy at 6 h after the procedures. By 24 h after the procedures, treatment with GP improved survival, attenuated sepsis-induced AKI, and restored renal tubular function. Whole-blood levels of reduced glutathione were higher in the CLP + GP group. Sepsis upregulated the Toll-like receptor 4/nuclear factor-kappa B axis in lung and renal tissues, as well as increasing inflammatory cytokine levels and macrophage infiltration; all of those effects were attenuated by GP. Treatment with GP decreased the numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in renal and lung tissue, as well as protecting the morphology of the renal mitochondria. Our data open the prospect for clinical trials of the use of GP in sepsis.

Lineage-negative bone marrow cells protect against chronic renal failure.

Progressive renal failure continues to be a challenge. The use of bone marrow cells represents a means of meeting that challenge. We used lineage-negative (Lin(-)) cells to test the hypothesis that Lin(-) cell treatment decreases renal injury. Syngeneic Fischer 344 rats were divided into four groups: sham (laparotomy only, untreated); Nx (five-sixth nephrectomy and untreated); NxLC1 (five-sixth nephrectomy and receiving 2 x 10(6) Lin(-) cells on postnephrectomy day 15); and NxLC3 (five-sixth nephrectomy and receiving 2 x 10(6) Lin(-) cells on postnephrectomy days 15, 30, and 45). On postoperative day 16, renal mRNA expression of interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-6 was lower in NxLC rats than in Nx rats. On postnephrectomy day 60, NxLC rats presented less proteinuria, glomerulosclerosis, anemia, renal infiltration of immune cells, and protein expression of monocyte chemoattractant protein-1, as well as decreased interstitial area. Immunostaining for proliferating cell nuclear antigen showed that, in comparison with sham rats, Nx rats presented greater cell proliferation, whereas NxLC1 rats and NxLC3 rats presented less cell proliferation than did Nx rats. Protein expression of the cyclin-dependent kinase inhibitor p21 and of vascular endothelial growth factor increased after nephrectomy and decreased after Lin(-) cell treatment. On postnephrectomy day 120, renal function (inulin clearance) was significantly better in Lin(-) cell-treated rats than in untreated rats. Lin(-) cell treatment significantly improved survival. These data suggest that Lin(-) cell treatment protects against chronic renal failure.

Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression.

Sirolimus, an antiproliferative immunosuppressant, induces hypomagnesemia and hypokalemia. Rosiglitazone activates renal sodium- and water-reabsorptive pathways. We evaluated whether sirolimus induces renal wasting of magnesium and potassium, attempting to identify the tubule segments in which this occurs. We tested the hypothesis that reduced expression of the cotransporter NKCC2 forms the molecular basis of this effect and evaluated the possible association between increased urinary excretion of magnesium and renal expression of the epithelial Mg2+ channel TRPM6. We then analyzed whether rosiglitazone attenuates these sirolimus-induced tubular effects. Wistar rats were treated for 14 days with sirolimus (3 mg/kg body wt in drinking water), with or without rosiglitazone (92 mg/kg body wt in food). Protein abundance of NKCC2, aquaporin-2 (AQP2), and TRPM6 was assessed using immunoblotting. Sirolimus-treated animals presented no change in glomerular filtration rate, although there were marked decreases in plasma potassium and magnesium. Sirolimus treatment reduced expression of NKCC2, and this was accompanied by greater urinary excretion of sodium, potassium, and magnesium. In sirolimus-treated animals, AQP2 expression was reduced. Expression of TRPM6 was increased, which might represent a direct stimulatory effect of sirolimus or a compensatory response. The finding that rosiglitazone prevented or attenuated all sirolimus-induced renal tubular defects has potential clinical implications.

Human umbilical cord-derived mesenchymal stromal cells protect against premature renal senescence resulting from oxidative stress in rats with acute kidney injury.

BACKGROUND: Mesenchymal stromal cells (MSCs) represent an option for the treatment of acute kidney injury (AKI). It is known that young stem cells are better than are aged stem cells at reducing the incidence of the senescent phenotype in the kidneys. The objective of this study was to determine whether AKI leads to premature, stress-induced senescence, as well as whether human umbilical cord-derived MSCs (huMSCs) can prevent ischaemia/reperfusion injury (IRI)-induced renal senescence in rats. METHODS: By clamping both renal arteries for 45 min, we induced IRI in male rats. Six hours later, some rats received 1 × 106 huMSCs or human adipose-derived MSCs (aMSCs) intraperitoneally. Rats were euthanised and studied on post-IRI days 2, 7 and 49. RESULTS: On post-IRI day 2, the kidneys of huMSC-treated rats showed improved glomerular filtration, better tubular function and higher expression of aquaporin 2, as well as less macrophage infiltration. Senescence-related proteins (ß-galactosidase, p21Waf1/Cip1, p16INK4a and transforming growth factor beta 1) and microRNAs (miR-29a and miR-34a) were overexpressed after IRI and subsequently downregulated by the treatment. The IRI-induced pro-oxidative state and reduction in Klotho expression were both reversed by the treatment. In comparison with huMSC treatment, the treatment with aMSCs improved renal function to a lesser degree, as well as resulting in a less pronounced increase in the renal expression of Klotho and manganese superoxide dismutase. Treatment with huMSCs ameliorated long-term kidney function after IRI, minimised renal fibrosis, decreased ß-galactosidase expression and increased the expression of Klotho. CONCLUSIONS: Our data demonstrate that huMSCs attenuate the inflammatory and oxidative stress responses occurring in AKI, as well as reducing the expression of senescence-related proteins and microRNAs. Our findings broaden perspectives for the treatment of AKI.

Vasopressin analog terlipressin attenuates kidney injury in hemorrhagic shock.

BACKGROUND: In hemorrhagic shock (HS), volume replacement with crystalloid solution can restore the hemodynamic status and decrease mortality. However, it can also lead to tissue edema and pulmonary congestion, as well as increasing vascular permeability. Here, we analyzed the effects that resuscitation with lactated Ringer's solution (LRS) or administration of the vasopressin analog terlipressin has on renal function in a porcine model of HS. METHODS: Using pressure-controlled bleeding, we induced pigs to HS, maintaining mean arterial pressure (MAP) at 40 mm Hg for 30 min. Animals were divided into 4 groups: sham (anesthesia only); shock-only (HS induction); shock+LRS (HS induction and subsequent resuscitation with LRS at 3 times the volume of blood removed); and shock+Terli (HS induction and subsequent bolus administration of 2 mg of terlipressin). Parameters were evaluated at baseline, then at 30, 60, and 120 min after treatment (T30, T60, and T120, respectively). Animals were euthanized at T60 or T120. RESULTS: Both treatments restored MAP to baseline values. At T30 and T60, creatinine clearance was highest in shock+LRS pigs, whereas it was highest in shock+Terli pigs at T120. Both treatments initially induced hyponatremia, although urinary excretion of all ions was higher in shock+LRS pigs at T30. Both treatments restored Na-K-2Cl cotransporter expression, whereas only terlipressin restored aquaporin 2 expression. Both treatments also prevented HS-induced acute tubular necrosis. Expression of the vasopressin receptors V1a and V2 was highest in shock-only pigs. At T120, V1a expression was lowest in shock+LRS pigs. DISCUSSION: Terlipressin might be useful for preventing HS-induced acute kidney injury.

Serum and Urinary Values of CA 19-9 and TGFß1 in a Rat Model of Partial or Complete Ureteral Obstruction.

INTRODUCTION: Abnormal levels of serum and urinary markers occur in the presence of renal damage associated to obstructive uropathy. Urinary and serum transforming growth factor beta 1 (TGFß1) and carbohydrate antigen (CA 19-9) have not yet been evaluated in an experimental model of obstructive uropathy. MATERIAL AND METHODS: Rats were divided into seven groups: reference, sham operation, unilateral nephrectomy, complete unilateral ureteral obstruction, partial unilateral ureteral obstruction, partial bilateral ureteral obstruction, and unilateral nephrectomy with contralateral partial ureteral obstruction. Kidney and ureter morphometry, TGFß1 and CA 19-9 serum and urinary concentrations and CA 19-9 renal tissue expression were analyzed. Correlation of these markers to complete, partial obstruction, or unobstructed groups was performed. RESULTS: Pathological findings correlated positively with the degree of ureteral obstruction, but negatively with urinary CA 19-9 levels. Marked underexpression of CA 19-9 was observed in kidneys with complete ureteral obstruction. No statistically significant differences were found for urinary and serum TGFß1 and also for serum CA 19-9. CONCLUSION: Urinary CA 19-9 correlated negatively with ureteral obstruction grade. Immunohistochemistry depicted CA 19-9 expression on epithelial tubular cells cytoplasm, suggesting renal origin. Serum and urinary TGFß1 did not show alterations in response to severity and length of urinary obstruction, which might be associated with less intense renal remodeling.

The role of dexamethasone in scorpion venom-induced deregulation of sodium and water transport in rat lungs.

BACKGROUND: Severe scorpion envenomation can evolve to lung injury and, in some cases, death. The lung injury could be attributed to acute left ventricular failure and increased pulmonary vascular permeability secondary to the release of inflammatory mediators. In clinical practice, corticosteroids have been administered to reduce the early side effects of the anti-venom. We propose to study the effects of Tityus serrulatus venom and dexamethasone on pulmonary expression of sodium and water transporters, as well as on the inflammatory response. METHODS: Wistar rats were injected intraperitoneally with saline (control group), dexamethasone, and saline (2.0 mg/kg body weight-60 min before saline injection; dexamethasone + saline group), venom (T. serrulatus venom-3.8 mg/kg body weight), or dexamethasone and venom (2.0 mg/kg body weight-60 min before venom injection; dexamethasone + venom group). At 60 min after venom/saline injection, experiments were performed in ventilated and non-ventilated animals. We analyzed sodium transporters, water transporters, and Toll-like receptor 4 (TLR4) by Western blotting, macrophage infiltration by immunohistochemistry, and serum interleukin (IL) by cytokine assay. RESULTS: In the lung tissue of non-ventilated envenomed animals, protein expression of the epithelial sodium channel alpha subunit (α-ENaC) and aquaporin 5 (AQP5) were markedly downregulated whereas that of the Na-K-2Cl cotransporter (NKCC1) and TLR4 was elevated although expression of the Na,K-ATPase alpha 1 subunit was unaffected. Dexamethasone protected protein expression of α-ENaC, NKCC1, and TLR4 but not that of AQP5. We found that IL-6, IL-10, and tumor necrosis factor alpha were elevated in the venom and dexamethasone + venom groups although CD68 expression in lung tissue was elevated only in the venom group. Among the ventilated animals, both envenomed groups presented hypotension at 50 min after injection, and the arterial oxygen tension/fraction of inspired oxygen ratio was lower at 60 min than at baseline. CONCLUSIONS: Our results suggest that T. serrulatus venom and dexamethasone both regulate sodium transport in the lung and that T serrulatus venom regulates sodium transport via the TLR4 pathway.

Vitamin D deficiency aggravates nephrotoxicity, hypertension and dyslipidemia caused by tenofovir: role of oxidative stress and renin-angiotensin system.

Vitamin D deficiency (VDD) is prevalent among HIV-infected individuals. Vitamin D has been associated with renal and cardiovascular diseases because of its effects on oxidative stress, lipid metabolism and renin-angiotensin-aldosterone system (RAAS). Tenofovir disoproxil fumarate (TDF), a widely used component of antiretroviral regimens for HIV treatment, can induce renal injury. The aim of this study was to investigate the effects of VDD on TDF-induced nephrotoxicity. Wistar rats were divided into four groups: control, receiving a standard diet for 60 days; VDD, receiving a vitamin D-free diet for 60 days; TDF, receiving a standard diet for 60 days with the addition of TDF (50 mg/kg food) for the last 30 days; and VDD+TDF receiving a vitamin D-free diet for 60 days with the addition of TDF for the last 30 days. TDF led to impaired renal function, hyperphosphaturia, hypophosphatemia, hypertension and increased renal vascular resistance due to downregulation of the sodium-phosphorus cotransporter and upregulation of angiotensin II and AT1 receptor. TDF also increased oxidative stress, as evidenced by higher TBARS and lower GSH levels, and induced dyslipidemia. Association of TDF and VDD aggravated renovascular effects and TDF-induced nephrotoxicity due to changes in the redox state and involvement of RAAS.