Background:No reliable treatment exists for cancer-related muscle loss. Results: In muscles of mice with cancer, p-Stat3 stimulates proteolysis by activating caspase-3 and the ubiquitin-proteasome system through a C/EBP␦ and myostatin pathway. Conclusion: Inhibition of Stat3 suppresses cancer-induced muscle losses.Significance: A small-molecule Stat3 inhibitor could be integrated into therapeutic strategies for preventing cancer-induced muscle losses.

This study evaluated the effects of bone marrow-derived mesenchymal stem cells (BMSCs) or their conditioned medium (CM) on the repair and prevention of Acute Kidney Injury (AKI) induced by gentamicin (G). Animals received daily injections of G up to 20 days. On the 10th day, injections of BMSCs, CM, CM+trypsin, CM+RNase or exosome-like microvesicles extracted from the CM were administered. In the prevention groups, the animals received the BMSCs 24 h before or on the 5th day of G treatment. Creatinine (Cr), urea (U), FENa and cytokines were quantified. The kidneys were evaluated using hematoxylin/eosin staining and immunohystochemistry. The levels of Cr, U and FENa increased during all the periods of G treatment. The BMSC transplantation, its CM or exosome injections inhibited the increase in Cr, U, FENa, necrosis, apoptosis and also increased cell proliferation. The pro-inflammatory cytokines decreased while the anti-inflammatory cytokines increased compared to G. When the CM or its exosomes were incubated with RNase (but not trypsin), these effects were blunted. The Y chromosome was not observed in the 24-h prevention group, but it persisted in the kidney for all of the periods analyzed, suggesting that the injury is necessary for the docking and maintenance of BMSCs in the kidney. In conclusion, the BMSCs and CM minimized the G-induced renal damage through paracrine effects, most likely through the RNA carried by the exosome-like microvesicles. The use of the CM from BMSCs can be a potential therapeutic tool for this type of nephrotoxicity, allowing for the avoidance of cell transplantations.

Increased intrarenal renin-angiotensin system activity contributes to diabetic nephropathy. ANG II generation in mesangial cells (MC) is increased by high-glucose (HG) exposure. This study assessed the mechanisms involved in the glucose-induced ANG II generation in rat MC. Under basal conditions, MC mainly secreted prorenin. HG decreased prorenin secretion and induced a striking 30-fold increase in intracellular renin activity. After 72 h of HG exposure, only the mRNA levels for angiotensinogen and angiotensin-converting enzyme (ACE) were significantly elevated. However, after shorter periods of 24 h of HG stimulation the mRNA levels of the enzymes prorenin and cathepsin B, besides that for ACE, were significantly increased. The results suggest that the HG-induced increase in ANG II generation in MC results from an increase in intracellular renin activity mediated by at least three factors: a time-dependent stimulation of (pro)renin gene transcription, a reduction in prorenin enzyme secretion, and an increased rate of conversion of prorenin to active renin, probably mediated by cathepsin B. The increase in angiotensinogen mRNA in parallel to increased renin activity indicates that HG also increased the availability of the renin substrate. The consistent upregulation of ACE mRNA suggests that, besides renin, ACE is directly involved in the increased mesangial ANG II generation induced by HG.

Interest in the role of extracellular vesicles in various diseases including cancer has been increasing. Extracellular vesicles include microvesicles, exosomes, apoptotic bodies, and argosomes, and are classified by size, content, synthesis, and function. Currently, the best characterized are exosomes and microvesicles. Exosomes are small vesicles (40-100 nm) involved in intercellular communication regardless of the distance between them. They are found in various biological fluids such as plasma, serum, and breast milk, and are formed from multivesicular bodies through the inward budding of the endosome membrane. Microvesicles are 100-1000 nm vesicles released from the cell by the outward budding of the plasma membrane. The therapeutic potential of extracellular vesicles is very broad, with applications including a route of drug delivery and as biomarkers for diagnosis. Extracellular vesicles extracted from stem cells may be used for treatment of many diseases including kidney diseases. This review highlights mechanisms of synthesis and function, and the potential uses of well-characterized extracellular vesicles, mainly exosomes, with a special focus on renal functions and diseases.

A B S T R A C T A unilateral model of puromycin aminonucleoside (PAN)-induced albuminuria was produced in Munich-Wistar rats to examine the mechanisms responsible for renal salt retention. 2 wk after selective perfusion of left kidneys with PAN (n = 8 rats) or isotonic saline (control, n = 7 rats), increases in albumin excretion and decreases in sodium excretion were demonstrated in PAN-perfused but not in nonperfused kidneys of PAN-treated rats although systemic plasma protein concentration remained at control level. Total kidney glomerular filtration rate (GFR) and superficial single nephron (SN) GFR were also reduced selectively in PAN-perfused kidneys, on average by -30%, due primarily to a marked decline in the glomerular capillary ultrafiltration coefficient (Kf), which was also confined to PAN-perfused kidneys. Values for absolute proximal reabsorption (APR) were also selectively depressed in PAN-perfused kidneys, in keeping with a similarly selective decline in peritubular capillary oncotic pressure measured in these kidneys, the latter also a consequence of the fall in Kf. In a separate group of seven PAN-treated rats, however, no differences were detected between PANperfused and nonperfused kidneys in the absolute amount of sodium reaching the early (0. In two additional groups of PAN-treated rats, infusion of saralasin (0.3 mg/kg per h, iv.) led to substantial increases in total kidney GFR and SNGFR in PAN-perfused but not in nonperfused kidneys. Despite these increases in total and SNGFR, urinary sodium excretion by PAN-perfused kidneys remained at a level far below that for nonperfused kidneys, again indicating that the antinatriuresis characterizing the PAN-perfused kidney is due to alterations in sodium handling by the tubules rather than changes in GFR. These results therefore indicate (a) that reductions in Kf and depressed sodium reabsorption by proximal tubules and Henle's loop segments in this model are brought about by intrarenal rather than circulating or systemic factors, and (b) assuming that superficial nephrons are representative of the entire nephron population, renal salt retention in this model is due primarily to intrarenal factor(s) acting beyond the distal convolution.77±0

The activity of angiotensin I-converting enzyme (ACE) was determined in tubular fluid collected from several portions of the rat nephron and urine and in total and efferent arteriolar blood using hippuryl-L-His-Leu as substrate. ACE activity decreased 30% from the pre- to the postglomerular arterioles (P < 0.001), suggesting a role of the glomerulus in ACE clearance. The enzyme activity was found to be present throughout the rat nephron. However, the highest activities were found in the proximal tubule and urine (0.692 +/- 0.007 and 1.05 +/- 0.015 pmol x microl(-1) x min(-1), respectively). Compared with other segments, ACE activity decreased from the initial portion of the proximal tubule to the distal nephron and increased again in the urine. Along the proximal tubule, ACE was secreted and degraded and/or reabsorbed and then secreted again into the collecting duct; no ACE activity was found in the late distal tubule, but a high level was detected in the urine, indicating a potential physiological role in the inactivation of the kinins formed by kallikrein beyond the connecting tubules. Moreover, the possible role of mesangial cells (MC) in the decrease of intraglomerular ACE was also evaluated. The analysis of ACE gene showed that MC in culture are able to express ACE mRNA. Moreover, ACE is produced as an ectoenzyme and as a secreted form of the enzyme, indicating a potential effect of local angiotensin II production on MC function.

RESUMO -Os autores revisam aspectos recentes no diagnóstico INTRODUÇÃOA infecção do trato urinário (ITU) é uma patologia extremamente freqüente, que ocorre em todas as idades, do neonato ao idoso, mas durante o primeiro ano de vida, devido ao maior número de malformações congênitas, especialmente válvula de uretra posterior; acomete preferencialmente o sexo masculino. A partir deste período, durante toda a infância e principalmente na fase pré-escolar, as meninas são acometidas por ITU 10 a 20 vezes mais do que os meninos. Na vida adulta, a incidência de ITU se eleva e o predomínio no sexo feminino se mantém, com picos de maior acometimento no início ou relacionado à atividade sexual, durante a gestação ou na menopausa, de forma que 48% das mulheres apresentam pelo menos um episódio de ITU ao longo da vida 1 . Na mulher, a susceptibilidade à ITU se deve à uretra mais curta e a maior proximidade do ânus com o vestíbulo vaginal e uretra. No homem, o maior comprimento uretral, maior fluxo urinário e o fator antibacteriano prostático são protetores. O papel da circuncisão é controverso, mas a menor ligação de enterobactérias à mucosa do prepúcio pode exercer proteção contra ITU. A partir da 5ª a 6ª década, a presença do prostatismo torna o homem mais suscetível à ITU.A ITU é classificada como não complicada quando ocorre em paciente com estrutura e função do trato urinário normais e é adquirida fora de ambiente hospitalar. As condições que se associam à ITU complicada incluem as de causa obstrutiva (hipertrofia benigna de prós-tata, tumores, urolitíase, estenose de junção uretero-piélica, corpos estranhos, etc); anáto-mofuncionais (bexiga neurogênica, refluxo vesico-ureteral, rim-espongiomedular, nefrocalcinose, cistos renais, divertículos vesicais); metabólicas (insuficiência renal, diabetes mellitus, transplante renal); uso de catéter de demora ou qualquer tipo de instrumentação ; derivações ileais. A avaliação urológica em ITU deve ser indicada em neonatos e crianças, infecção persistente após 72 h de terapia, ITU recorrente em homens ou em transplantados renais e também em mulheres com reinfecções freqüentes.Existe consenso de que os microorganismos uropatogênicos como a Escherichia Coli colonizam o cólon, a região perianal, e nas mulheres, o intróito vaginal e a região perianal. Posteriormente, processa-se a ascenção facul- tativa para bexiga e/ou rins, pois em condições normais há competição entre estes microorganismos com a flora vaginal e perineal.O espectro clínico de ITU é muito amplo reunindo diferentes condições:Cistite: a aderência da bactéria à bexiga leva ao quadro de cistite bacteriana, ou infecção do trato urinário "baixo". A contagem de bactérias deveria permitir uma clara distinção entre contaminação e infecção. Entretanto, a utilidade e consistência do critério de Bacteriúria significante como³ 10 5 unidades formadoras de colônias por mililitro (UFC/mL) para o diagnóstico de ITU tem sido freqüentemente questionadas. A valorização dos sintomas de ITU, conforme descrição a seguir, deve prevalecer, ...

The aim of the present study was to examine the participation of the rostral ventrolateral medulla (RVLM) in the maintenance of hypertension in rats submitted to the renovascular Goldblatt (two-kidney, one clip) procedure. We inhibited or stimulated this area with the use of drugs such as glycine, L-glutamate, or kynurenic acid. (1) Bilateral microinjection of glycine (100 nmol, 200 nL, n = 13) into the RVLM of hypertensive rats produced a decrease in mean arterial blood pressure (MAP) from 177.2 +/- 29.3 to 102.3 +/- 20.9 mm Hg (P < .05), which was similar to the decrease produced by intravenous administration of hexamethonium. The inhibition of RVLM with glycine in normotensive rats produced a decrease in MAP from 106 +/- 17.1 to 59.7 +/- 7.3 mm Hg (P < .05, n = 9). (2) An impressive increase in MAP from 153.3 +/- 16.3 to 228 +/- 34.9 mm Hg (P < .05) occurred in hypertensive rats after microinjection of L-glutamate (50 nmol, 200 nL, n = 6) into the RVLM. The same procedure caused a significant but less intense increase in MAP from 105 +/- 13.8 to 148.3 +/- 24.9 mm Hg in normotensive rats (P < .05, n = 6). (3) A decrease in MAP from 151.6 +/- 25.3 to 96.8 +/- 22.5 mm Hg occurred in hypertensive rats after microinjection of the broad-spectrum glutamate antagonist kynurenic acid (4 nmol, 200 nL, n = 6) into the RVLM, whereas the same procedure did not change MAP in normotensive animals (n = 6). Heart rate was not significantly affected in any group.(ABSTRACT TRUNCATED AT 250 WORDS)