Activation of Thiazide-Sensitive Co-Transport by Angiotensin II in the cyp1a1-Ren2 Hypertensive Rat

Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage). Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP) rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ∼20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone

Microvascular Rarefaction and Hypertension in the Impaired Recovery and Progression of Kidney Disease Following AKI in Preexisting CKD States

Acute kidney injury (AKI) is a major complication in hospitalized patients and is associated with elevated mortality rates. Numerous recent studies indicate that AKI also significantly increases the risk of chronic kidney disease (CKD), end-stage renal disease (ESRD), hypertension, cardiovascular disease, and mortality in those patients who survive AKI. Moreover, the risk of ESRD and mortality after AKI is substantially higher in patients with preexisting CKD. However, the underlying mechanisms by which AKI and CKD interact to promote ESRD remain poorly understood. The recently developed models that superimpose AKI on rodents with preexisting CKD have provided new insights into the pathogenic mechanisms mediating the deleterious interactions between AKI and CKD. These studies show that preexisting CKD impairs recovery from AKI and promotes the development of mechanisms of CKD progression. Specifically, preexisting CKD exacerbates microvascular rarefaction, failed tubular redifferentiation, disruption of cell cycle regulation, hypertension, and proteinuria after AKI. The purpose of this review is to discuss the potential mechanisms by which microvascular rarefaction and hypertension contribute to impaired recovery from AKI and the subsequent progression of renal disease in preexisting CKD states

Modelling of the pollution emission from vehicles moving at the intersections

Ekologiczne właściwości silników pojazdów, np. natężenie emisji zanieczyszczeń, są zależne od warunków pracy silników, zdeterminowanych przebiegami prędkości jazdy pojazdu. Przebiegi prędkości pojazdów w centrach miejskich są zależne od parametrów charakteryzujących sterowanie ruchu na skrzyżowaniach. Istnieje zatem możliwość rozpatrywania zagadnienia optymalizacji sterowania ruchu pojazdów na skrzyżowaniach ze względu na minimalizację emisji zanieczyszczeń. W pracy przedstawiono ogólne zasady modelowania emisji zanieczyszczeń z pojazdów poruszających się na skrzyżowaniach, a teoretyczne rozważania zilustrowano wynikami badań symulacyjnych, wykonanych dla rzeczywistych warunków ruchu pojazdów w obszarze skrzyżowań.Ecological characteristics of vehicles engines, ex. the intensity of pollution emission, depends on the conditions of engine work determined by the course of vehicle speed. Courses of vehicles speed in the city centres depend on the parameters characterising traffic control at the intersections. Thus, there is a possibility of analysing the problem of traffic control at the intersections with respect to the minimisation of emission. In this paper general rules of emission modelling at the intersections are presented and the theoretical part are illustrated by the results of simulation researches out for the real traffic conditions in the area of intersections

EFFECTS OF PODODCYTE DYSFUNCTION ON THE SUSCEPTIBILITY TO HYPERTENSIVE GLOMERULOSCLEROSIS

Podocytes play an important role in maintaining the structural integrity of glomerular capillaries. There is a limited capacity of podocytes to reproduce; therefore, they are required to support a greater capillary surface area in states of glomerular hypertrophy (i.e., reduced podocyte density). Such reductions in podocyte density can lead to podocyte dysfunction and is thought to substantially increase the susceptibility to hypertension-induced renal injury and progression of chronic kidney disease. However, the extent to which reduced podocyte density increases the susceptibility to hypertension-induced renal injury remains unknown. The goal of this study was to determine the susceptibility to hypertension-induced renal injury in a rodent model of chronic kidney disease with podocyte dysfunction. Male Sprague-Dawley rats were subjected to normotensive renal mass reduction and instrumented with a radiotelemeter for the continuous measurement of blood pressure. After a two week recovery from surgery to allow for completion of renal compensatory increases in size and function, groups of rats were administered a single dose of puromycin aminonucleoside (PAN, 75 mg/kg i.p.), which acutely injures podocytes, or saline (sham). Rats were followed for 4 weeks following PAN or saline injection. At one week post PAN injection, some groups of rats were administered antihypertensive regimens consisting of hydralazine (50-300 mg/L) + hydrochlorothiazide (HCTZ, 25-75 mg/L) or enalapril (50-300 mg/L) + HCTZ (25-75 mg/L) via the drinking water for the remainder of the study. At the end of the study, glomerulosclerosis (GS) was assessed in a blinded fashion and podocyte density was determined using immunofluorescence detection of the podocyte marker Wilms Tumor 1 (WT1) on paraffin-embedded sections from perfused-fixed kidneys. No differences were observed between antihypertensive groups, thus these data are presented as a singled group. The average systolic BP (mmHg) was higher (P\u3c0.05) in rats administered PAN (144±3, n=12) vs. PAN + antihypertensives (127±2, n=20) and saline (130±4, n=17). The magnitude of glomerulosclerosis (GS, % glomeruli exhibiting GS in 100 evaluated) was greater (P\u3c0.05) in rats administered PAN (64±7%) vs. PAN + antihypertensives (30±6%) vs. saline (6±2%). The slope of the relationship between BP and GS (Δ%GS vs. ΔmmHg) was significantly greater (P\u3c0.05) in rats administered PAN (1.1) and PAN + antihypertensives (1.2) vs. saline (0.4). Podocyte density (podocytes/µm3x10-6) was assessed in non-injured glomeruli from a subset of rats from each group and was significantly greater (P\u3c0.05) in those administered PAN + antihypertensives (63±3, n=8) and tended to be greater (P=0.09) in those administered saline (56±4, n=7) as compared to those administered PAN (47±4, n=7). The number of podocytes per glomerular tuft tended to be lower and the average glomerular tuft area tended to be higher in rats administered PAN vs. the other groups; however, these differences were not statistically significant. These data demonstrate that acute podocyte dysfunction increases the susceptibility to BP-induced GS by ~ 3-fold and that lowering BP in such states mitigates further reductions in podocyte density and progression of kidney disease

Sex differences in podocyte density are largely due to sex differences in kidney size

Chronic kidney disease (CKD) affects over 15% of the adult population and is a leading cause of morbidity and mortality. Clinical studies have demonstrated that the rate of CKD progression is accelerated in males; however, the underlying mechanisms are poorly understood. Sex differences in podocyte density may contribute to the sex disparity in CKD progression. Podocytes are terminally differentiated visceral epithelial cells whose major role is to support the glomerular capillaries against relatively high filtration pressures. While kidney size is, on average, greater in males, which could impact the susceptibility to CKD progression by decreasing podocyte density, there is limited data regarding sex differences in podocyte density. Therefore, we tested the hypothesis that male rats would exhibit reduced podocyte density as compared to female rats. Sprague-Dawley rats (8-10-weeks-old, n=16 female; n=16 male) were subjected to either right uninephrectomy (UNX, n=8/sex) or sham UNX (i.e., intact kidneys, n=8/sex). Six weeks later, kidneys were perfusion-fixed, harvested, and paraffin-embedded. To assess podocyte density, kidney sections (5 um) were stained with a podocyte-specific primary antibody (Wilms Tumor 1 (WT-1), 1:60), a fluorescent secondary antibody (1:200), and DAPI (300nM) to identify nuclei. Merged WT-1/DAPI images of 20 randomly selected glomeruli per section were analyzed (CellSens) to determine glomerular tuft area, podocyte number, and podocyte diameter. Podocyte density was calculated as the number of podocytes/glomerular tuft volume. A 2-way-ANOVA with Holm-Sidak post hoc analysis was used to assess differences among groups. Linear regression analysis was used to assess the relationship between glomerular tuft volume and podocyte density and diameter. All data are reported as mean ± standard error and P\u3c0.05 was considered statistically significant. Body weight was 59% greater (P\u3c0.05) in male vs. female rats within both intact and UNX groups, but there were no significant differences between intact and UNX groups within each sex. Absolute kidney weight was 57% greater (P\u3c0.05) in male vs. female rats and 59% greater (P\u3c0.05) in UNX vs. intact groups within sexes. Glomerular tuft volume was 25% greater (P\u3c0.05) in male vs. female rats and 22% greater (P\u3c0.05) in UNX vs. intact groups within sexes. Podocyte number per glomerular tuft was not significantly different between male vs. female rats or between intact vs. UNX groups within each sex. Podocyte density was 12% less (P\u3c0.05) in male vs. female rats and 20% less (P\u3c0.05) in UNX vs. intact groups within each sex. Linear regression analysis revealed that 56% of the variability in podocyte density as well as podocyte diameter was explained by variability in glomerular tuft volume (P\u3c0.0001). In conclusion, sex differences in podocyte density are largely dependent on sex differences in kidney weight and glomerular tuft volume. The well-known sex differences in kidney weight in clinical populations may therefore contribute to the sex disparity in susceptibility to hypertensive renal injury and rate of CKD progression. Future studies are planned to examine the effects of manipulating kidney weight and podocyte density within sexes on the susceptibility to hypertensive renal injury