Urinary Monocyte Chemoattractant Protein-1 Levels and Interstitial Changes in the Renal Cortex and Their Relationship with Loss of Renal Function in Renal Transplant Patients with Delayed Graft Function

Background: Inflammatory cell infiltration and residual areas of fibrosis in kidneys after renal transplantation can lead to functional abnormalities with long-term implications. Objectives: The aim of this study was to determine urinary monocyte chemoattractant protein-1 (uMCP-1) levels, relative cortical interstitial area (RCIA), and cortical tubulointerstitial macrophage infiltration in renal transplant patients with delayed graft function (DGF) and their possible correlation with graft outcome. Design: Patients were followed after biopsies for one year, and their renal function and structure were evaluated, as well as parameters of inflammatory process. Setting: Clinical Hospital of the School of Medicine of Ribeirão Preto. Patients: Twenty-two cadaveric kidney transplant recipients with DGF were followed for one year. Measurements: Renal function, RCIA, macrophages infiltration and uMCP-1 levels were evaluated. Methods: Renal function was evaluated by plasma creatinine levels. RCIA was determined by morphometry. Immunohistochemical staining of macrophages was performed using an anti-CD68 monoclonal antibody. uMCP-1 levels were determined using a human MCP-1/CCL2 immunoassay kit. Results: There was a significant increase in uMCP-1 levels in transplant patients compared with controls ( p < 0.001). RCIA was 7.1% (6.4 to 9.2; median and 25th to 75th percentiles) in controls and 37.1% (28.1 to 43.7) in patients with kidney transplants ( p < 0.001). The patients who presented with a higher RCIA in the first biopsy showed higher levels of plasma creatinine one year after transplantation (r = 0.44; p < 0.05). The number of tubulointerstitial macrophages per 0.10 mm 2 grid field was higher in the renal cortex of transplant patients compared with the controls (19.4 (9.0 to 47.1) vs. 2.5 (1.8 to 3.4), p < 0.001). There was also a positive correlation between the RCIA and the number of tubulointerstitial macrophages in the renal cortex of these patients (r = 0.49; p < 0.001). Limitations: The number of patients studied was relatively small and may not be reflecting outcomes over a larger spectrum of kidney cadaveric transplants. Conclusions: Our results demonstrate increased levels of uMCP-1 in transplant patients with DGF, in addition to increased tubulointerstitial macrophage infiltration and RCIA, which could predict the outcome of renal function in these patients

Hydrogen sulfide inhibits preoptic prostaglandin E2 production during endotoxemia

AbstractHydrogen sulfide (H2S) is a gaseous neuromodulator endogenously produced in the brain by the enzyme cystathionine β-synthase (CBS). We tested the hypothesis that H2S acts within the anteroventral preoptic region of the hypothalamus (AVPO) modulating the production of prostaglandin (PG) E2 (the proximal mediator of fever) and cyclic AMP (cAMP). To this end, we recorded deep body temperature (Tb) of rats before and after pharmacological modulation of the CBS–H2S system combined or not with lipopolysaccharide (LPS) exposure, and measured the levels of H2S, cAMP, and PGE2 in the AVPO during systemic inflammation. Intracerebroventricular (icv) microinjection of aminooxyacetate (AOA, a CBS inhibitor; 100pmol) did not affect basal PGE2 production and Tb, but enhanced LPS-induced PGE2 production and fever, indicating that endogenous H2S plays an antipyretic role. In agreement, icv microinjection of a H2S donor (Na2S; 260nmol) reduced the LPS-induced PGE2 production and fever. Interestingly, we observed that the AVPO levels of H2S were decreased following the immunoinflammatory challenge. Furthermore, fever was associated with decreased levels of AVPO cAMP and increased levels of AVPO PGE2. The LPS-induced decreased levels of cAMP were reduced to a lesser extent by the H2S donor. The LPS-induced PGE2 production was potentiated by AOA (the CBS inhibitor) and inhibited by the H2S donor. Our data are consistent with the notion that the gaseous messenger H2S synthesis is downregulated during endotoxemia favoring PGE2 synthesis and lowering cAMP levels in the preoptic hypothalamus

Treatment with a p38 MAPK inhibitor attenuates cisplatin nephrotoxicity starting after the beginning of renal damage

Aims: Cisplatin (CP) promotes increased production of reactive oxygen species, which can activate p38 mitogen activated protein kinases (p38 MAPKs) leading to apoptosis and increased expression of proinflammatory mediators that intensify the cytotoxic effects of CP. We investigated the effect of the treatment with S13203580, a p38 MAPKs inhibitor, on oxidative stress, on the oxidation-associated signal, p38 MAPK and on apoptosis in U-injected rats, starting after the beginning of the renal damage. Main methods: Rats (n = 21) were injected with CP (5 mg/kg, i.p.) and 3 and 4 days after some of them (n = 8) were treated with SB203580 (0.5 mg/kg, i.p.). Controls (n = 6) received saline (i.p.). Two or five days after saline or CP injections, plasma creatinine, urinary volume, sodium and potassium fractional excretions, blood urea nitrogen and urinary lipid peroxidation were measured. The kidneys were removed for histological, apoptosis, immunohistochemical and Western blot studies. Key findings: CP caused abnormalities in kidney functions and structure associated with raised urinary peroxidation levels and higher number of apoptotic cells in the outer medulla. The immunostaining studies showed increased numbers of macrophages/monocytes and p-p38 MAPKs positive cells in the renal outer medulla. The increase of p-p38 MAPKs expression was confirmed by Western blot analysis. All of these alterations were attenuated by treatment with S13203580. Significance: These data suggest that the beneficial effect of SB203580 on CP-induced renal damage might be related, in part, to the blockade of p38 MAPK activation with reduction of the inflammatory process, oxidative stress and apoptotic cell death. (C) 2009 Elsevier Inc. All rights reserved

Chronic renal failure in male and female rats

Gender influences the progression of chronic renal failure (CRF). We studied male (M) and female (F) Wistar rats for 90 days: castrated (CMc, n=7; CFc, n=6) and non castrated controls (CM, n=9; CF, n=6); castrated (CRFMc, n=8; CRFFc, n=6) and non castrated animals submitted to 5/6 nephrectomy (CRFM, n=13; CRFF, n=6). Data are expressed as mean ± SEM. Proteinuria (PTN) was higher in CRFM (554 ± 69mg/24h) compared to CRFMc (277 ± 85 mg/24h), but not in females (CRFF=193 ± 20mg/24h, CRFFc=164 ± 71mg/24h). Mesangial fractional volume increased in all CRF animals. CRF animals showed an increase of glomerular sclerosis index (GSI) and tubulointerstitial damage (TID) but in a smaller proportion in male castrated animals; the opposite occurred with females: castration induced an increase of these parameters. CRF animals showed increased cortical and glomerular fibronectin (FN) rates. Castration decreased glomerular and cortical FN rates in CRFM but not in females. In conclusion, proteinuria was higher in CRFM and probably led to glomerular and interstitial damage, as well as to FN accumulation, castration seems to protect against development of PTN, TID and FN accumulation in males. Castrated female rats presented mesangial expansion, with no changes in PTN, TID and FN rates. It seems that female sex hormones do not protect against renal disease progression, instead, we suggest that male sex hormones lead to acceleration of CRF

Renal Development and Blood Pressure in Offspring from Dams Submitted to High-Sodium Intake during Pregnancy and Lactation

Exposure to an adverse environment in utero appears to programme physiology and metabolism permanently, with long-term consequences for health of the fetus or offspring. It was observed that the offspring from dams submitted to high-sodium intake during pregnancy present disturbances in renal development and in blood pressure. These alterations were associated with lower plasma levels of angiotensin II (AII) and changes in renal AII receptor I (AT1) and mitogen-activated protein kinase (MAPK) expressions during post natal kidney development. Clinical and experimental evidence show that the renin-angiotensin system (RAS) participates in renal development. Many effects of AII are mediated through MAPK pathways. Extracellular signal-regulated protein kinases (ERKs) play a pivotal role in cellular proliferation and differentiation. In conclusion, high-sodium intake during pregnancy and lactation can provoke disturbances in renal development in offspring leading to functional and structural alterations that persist in adult life. These changes can be related at least in part with the decrease in RAS activity considering that this system has an important role in renal development

Ontogenetic role of angiontensin-converting enzyme in rats: Thirst and sodium appetite evaluation

We investigated the influence of captopril (an angiotensin converting enzyme inhibitor) treatment during pregnancy and lactation period on hydromineral balance of the male adult offspring, particularly, concerning thirst and sodium appetite. We did not observe significant alterations in basal hydromineral (water intake, 0.3 M NaCl intake, volume and sodium urinary concentration) or cardiovascular parameters in adult male rats perinatally treated with captopril compared to controls. However, male offspring rats that perinatally exposed to captopril showed a significant attenuation in water intake induced by osmotic stimulation, extracellular dehydration and beta-adrenergic stimulation. Moreover, captopril treatment during perinatal period decreased the salt appetite induced by sodium depletion. This treatment also attenuated thirst and sodium appetite aroused during inhibition of peripheral angiotensin 11 generation raised by low concentration of captopril in the adult offspring. Interestingly. perinatal exposure to captopril did not alter water or salt intake induced by i.c.v. administration of angiotensin I or angiotensin II. These results showed that chronic inhibition of angiotensin converting enzyme during pregnancy and lactation modifies the regulation of induced thirst and sodium appetite in adulthood. (C) 2009 Elsevier Inc. All rights reserved.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq

Previous Exercise Effects in Cisplatin-Induced Renal Lesions in Rats

Background/Aims: Physical training has beneficial effects on endothelial function and can influence the regeneration of the endothelial cell. We investigated the effect of physical training on cisplatin (CP)-induced acute kidney injury and assessed the impact of training on endothelial structure and function, and on the inflammatory processes in rats. Methods: We injected male Wistar rats subjected to previous physical training in treadmill running (trained, TR) or not (sedentary, SED) with CP (5 mg/kg) (TR+CP and SED+CP groups, respectively). Five days after the injections, blood and urine samples were collected to evaluate renal function and kidneys were harvested for morphological, immunohistochemical, enzyme-linked immunosorbent assay, and analysis of nitric oxide (NO) levels. Results: Rats treated with CP showed increased levels of plasma creatinine and sodium and potassium fractional excretion. These alterations were associated with increase in tubulointerstitial lesions and macrophage number, reduction of endothelial cells, and increased VEGF, vimentin, and α-smooth muscle actin expression in the outer renal medulla in the SED+CP group. We also found increased levels of renal IL-1β and increased excretion of monocyte chemoattractant protein-1 and transforming growth factor-β compared with controls. These changes were milder in trained rats, associated with increased levels of renal tissue NO, and increased expression of p-eNOS and stromal cell-derived factor-1α (a chemokine involved in kidney repair) in the kidneys of CP-injected trained rats. Conclusions: The protective effect of previous training in CP-treated rats was associated with reduced endothelial cell lesions and increased renal production of NO in trained rats

Alpha-tocopherol prevents intrauterine undernutrition-induced oligonephronia in rats

The role of alpha-tocopherol during nephrogenesis was investigated in rats subjected to maternal undernutrition, which reduces the number of nephrons. alpha-tocopherol (350 mg/kg, p.o.) was administered daily to well-nourished or malnourished Wistar dams during pregnancy, or to prenatal undernourished rats during lactation. The kidneys of 1- and 25-day-old offspring were removed to evaluate expression of angiotensin II (Ang II) and to correlate this with expression of proliferating cell nuclear antigen, alpha-smooth muscle actin, fibronectin and vimentin in the glomeruli and tubulointerstitial space. One-day-old prenatally undernourished rats had reduced expression of Ang II and of kidney development markers, and presented with an enlarged nephrogenic zone. Maternal administration of alpha-tocopherol restored the features of normal kidney development in undernourished rats. Twenty-five-day-old prenatally undernourished progeny had fewer glomeruli than the control group. Conversely, animals from mothers that received alpha-tocopherol during lactation presented with the same number of glomeruli and the same glomerular morphometrical profile as the control group. Analyzing the levels of thiobarbituric acid reactive substances in the liver in conjunction with kidney development markers, it is plausible that alpha-tocopherol had antioxidant and non-antioxidant actions. This study provides evidence that alpha-tocopherol treatment restored Ang II expression, and subsequently restored renal structural development.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior[CAPES/PROCAD-NF 519/2010]Fundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco (FACEPE)[IBPG-1228-2.07/08]Fundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco (FACEPE)[BIC-0408-2.07/09]Fundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco (FACEPE)[AMD-0017-2.00/10]CNPq Conselho Nacional de Desenvolvimento Cientifico e Tecnologic