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Aim. To find out the links between the state of system and the risk and severity of impairment of renal function in patients after percutaneous coronary intervention (PCI). Material and methods. The free radical oxidation system’s response was assessed in patients with different degree of severity of the glomerular filtration impairment. The intensity of lipid peroxidation was evaluated by the concentration of malondialdehyde (MDA) in the red blood cells of patients. Results. Almost all 59 patients after PCI were observed with various degree of inhibition of renal filtration. The mean value of MDA significantly (p = 0,032) increased from 10,3 ± 1,7 mmol/g to 11,0 ± 1,8 mmol/g. The level of MDA was significantly higher (p

This study examined the prospective role of urinary sodium and potassium excretion in depressive symptoms among urban, low‐income adolescents, and whether these relationships vary by gender. A total of 84 urban adolescents (mean age 13.36 years; 50% male; 95% African American) self‐reported on their depressive symptoms at baseline and 1.5 years later. At baseline, the youth also completed a 12‐h (overnight) urine collection at home which was used to measure sodium and potassium excretion. After adjusting for baseline depressive symptoms, age, BMI percentile, and pubertal development, greater sodium excretion and lower potassium excretion predicted more severe depressive symptoms at follow‐up, with no significant gender differences. The results suggest that consumption of foods high in sodium and low in potassium contributes to the development of depressive symptoms in early adolescence, and that diet is a modifiable risk factor for adolescent depression. Interventions focusing on diet may improve mental health in urban adolescents.

We have previously demonstrated that dexamethasone administered to pregnant rats during specific times during gestation results in a reduction in glomerular number and hypertension in offspring at 2 and 6 months of age. In this study, we examined the effect of prenatal dexamethasone administered daily on days 15 and 16 of gestation in male and female offspring after 1 year of age on glomerular filtration rate. The prenatal dexamethasone male group had a higher systolic blood pressure than the vehicle male group. Females had lower systolic blood pressures than the males and prenatal dexamethasone did not affect blood pressure in female offspring. Prenatal dexamethasone resulted in a reduction in glomerular filtration rate in male but not in female rats. When corrected for body weight, the control male rats had a lower glomerular filtration rate than the control female rats. Males had greater protein excretion than females and prenatal dexamethasone increased the protein excretion only in male rats. Glomerulosclerosis was also greater in male rats than females but was not affected by prenatal dexamethasone. In summary, male rats appear to have evidence of a decline in glomerular filtration rate after 1 year of age and prenatal dexamethasone programs an accelerated decline in glomerular filtration rate in male but not in female offspring.

To provide insight into pharmacological treatment of hyperuricemia we developed a semi‐mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI. The model was qualified for prediction of the effect of patients' GFR and FE on concentration of UA in serum (sUA) and UA excretion in urine and their response to drug treatment, using data from 2 Phase I and 4 Phase III studies of lesinurad. Percent reduction in sUA from baseline by a XOI is predicted to be independent of GFR,FE or PUA. Uricosurics are more effective in underexcreters of UA or patients with normal GFR. Co‐administration of a XOI and an uricosuric agent should be considered for patients with high sUA first in the treatment algorithm of gout before uptitration of XOI. The XOI dose in combination with a uricosuric can be reduced compared to XOI alone for the same target sUA to the degree dependent on patient's GFR and FE. This exposure‐response model of UA can be used to rationally select the best drug treatment option to lower elevated sUA in gout patients under differing pathophysiological situations.

To test the hypothesis that use of oral contraceptives (OC) changes diurnal variation in fluid balance mechanisms including blood pressure, secretion of vasopressin and oxytocin, and renal water and electrolyte excretion. Fifteen naturally cycling (NC) women in mid-follicular phase and 11 long-term OC users were included in a 24-h standardized inpatient study for measurements of vasopressin, oxytocin, sodium, and osmolality in plasma as well as urinary excretion of electrolytes, aquaporin-2, and prostaglandin E2. Blood pressure and heart rate were monitored noninvasively. Plasma vasopressin showed circadian rhythm (P = 0.02) and were similar in both groups (P = 0.18) including nighttime increases (P < 0.001). There was no circadian rhythm in plasma oxytocin within (P = 0.84) or between groups (P = 0.22). OC users had significantly lower plasma osmolality (Δosm: 3.05 ± 0.29 mosm/kg, P = 0.04) and lower plasma sodium (ΔNa+: 0.91 ± 0.09 mmol/l, P = 0.05). The two groups showed similar nighttime decreases in diuresis (1.08 ± 0.04 mL/(kg·h), P < 0.001) and increases in urine osmolality (109 ± 9 mosm/kg, P = 0.02), but similar rates of excretion of Aquaporin-2, prostaglandin E2 and sodium. Nighttime decreases in mean arterial pressure of approximately 13% were significant in both groups (P < 0.001), but 24-h average mean arterial pressure was significantly higher in OC users than in controls (+4.7 ± 0.4 mmHg, P = 0.02). Packed cell volumes were similar between groups (P = 0.54). OC does not change the diurnal patterns of renal fluid excretion, but resets the osmoreceptors for vasopressin release and leads to a significant increase in arterial blood pressure.

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone increasing postprandial insulin release. GLP‐1 also induces diuresis and natriuresis in humans and rodents. The GLP‐1 receptor is extensively expressed in the renal vascular tree in normotensive rats where acute GLP‐1 treatment leads to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP‐1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP‐1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect of acute intrarenal infusion of GLP‐1. We hypothesized that GLP‐1 would increase diuresis and natriuresis and reduce MAP in SHR. Immunohistochemical staining and in situ hybridization for the GLP‐1 receptor were used to localize GLP‐1 receptors in the kidney. Sevoflurane‐anesthetized normotensive Sprague–Dawley rats and SHR received a 20 min intrarenal infusion of GLP‐1 and changes in MAP, RBF, heart rate, dieresis, and natriuresis were measured. The vasodilatory effect of GLP‐1 was assessed in isolated interlobar arteries from normo‐ and hypertensive rats. We found no expression of GLP‐1 receptors in the kidney from SHR. However, acute intrarenal infusion of GLP‐1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP‐1 in SHR are caused either by extrarenal GLP‐1 receptors activating other mechanisms (e.g., insulin) to induce the renal changes observed or possibly by an alternative renal GLP‐1 receptor.

The diverse epithelial cell types of the kidneys are segregated into nephron segments and the collecting ducts in order to endow each tubular segment with unique functions. The rich diversity of the epithelial cell types is highlighted by the unique membrane channels and receptors expressed within each nephron segment. Our previous work identified a critical role for Myh9 and Myh10 in mammalian endocytosis. Here, we examined the expression patterns of Nonmuscle myosin 2 (NM2) heavy chains encoded by Myh9, Myh10, and Myh14 in mouse kidneys as these genes may confer unique nephron segment‐specific membrane transport properties. Interestingly, we found that each segment of the renal tubules predominately expressed only two of the three NM2 isoforms, with isoform‐specific subcellular localization, and different levels of expression within a nephron segment. Additionally, we identify Myh14 to be restricted to the intercalated cells and Myh10 to be restricted to the principal cells within the collecting ducts and connecting segments. We speculate that the distinct expression pattern of the NM2 proteins likely reflects the diversity of the intracellular trafficking machinery present within the different renal tubular epithelial segments.

In this study, we examined an ammonium conductance in the mouse thick ascending limb cell line ST‐1. Whole cell patch clamp was performed to measure currents evoked by NH 4Cl in the presence of BaCl2, tetraethylammonium, and BAPTA. Application of 20 mmol/L NH 4Cl induced an inward current (−272 ± 79 pA, n = 9). In current‐voltage (I–V) relationships, NH 4Cl application caused the I–V curve to shift down in an inward direction. The difference in current before and after NH 4Cl application, which corresponds to the current evoked by NH 4Cl, was progressively larger at more negative potentials. The reversal potential for NH4Cl was +15 mV, higher than the equilibrium potential for chloride, indicating that the current should be due to NH 4 +. We then injected ST‐1 poly(A) RNA into Xenopus oocytes and performed two‐electrode voltage clamp. NH 4Cl application in the presence of BaCl2 caused the I–V curve to be steeper. The NH 4 + current was retained at pH 6.4, where endogenous oocyte current was abolished. The NH 4 + current was unaffected by 10 μmol/L amiloride but abolished after incubation in Na+‐free media. These results demonstrate that the renal cell line ST‐1 produces an NH 4 + conductance.

Endogenous markers of kidney function are insensitive to early declines in glomerular filtration rate (GFR) and in rodent models, validated, practical alternatives are unavailable. In this study, we determined GFR by modeling the plasma clearance of two compounds, iohexol and inulin, and compared the findings to common endogenous markers. All plasma clearance methods of both iohexol and inulin detected a decline in renal function weeks prior to any increase in endogenous marker. Iohexol plasma clearance and inulin plasma clearance had a very high agreement and minimal bias when using 12‐sample models. However, only iohexol could be accurately simplified to a two‐sample, one‐compartment estimation strategy. Following an IV injection of low‐dose iohexol and two timed blood samples at 30 and 90 min, one can accurately approximate a complex 12‐sample strategy of plasma clearance. This method is simple enough to use in routine, longitudinal analysis of larger cohort animal studies.

Under high sodium intake renal dopamine (DA) increases while NOS I expression in macula densa cells (MD) decreases. To explore whether renal DA and NOS I, linked to natriuresis and to the stability of the tubuloglomerular feedback, respectively, act in concert to regulate renal plasma flow (RPF) and glomerular filtration rate (GFR). Male Wistar rats were studied under a normal sodium intake (NS, NaCl 0.24%) or a high sodium intake (HS, NaCl 1% in drinking water) during the 5 days of the study. For the last two days, the specific D1-like receptor antagonist SCH 23390 (1 mg kg bwt−1 day−1, sc) or a vehicle was administered. HS intake increased natriuresis, diuresis, and urinary DA while it decreased cortical NOS I expression (P

Transcutaneous assessment of fluorescein isothiocyanate (FITC)‐sinistrin clearance using a small animal imager has recently been validated as an accurate method for the measurement of glomerular filtration rate (GFR) in freely moving rats. This technique involves a brief, light period of anesthesia during which the imager is adhered to the rat and FITC‐sinistrin is administered. The rat is then moved to an experimental chamber where it is housed unrestrained for a 2‐h data collection period. This study assessed the impact of the experimental protocol on mean arterial pressure (MAP), heart rate, and locomotor activity in adult Sprague Dawley rats using radiotelemetry given that anesthesia and stress are known to affect arterial pressure and kidney function. These data were compared with time‐equivalent measurements made in the same rats at rest. MAP was low following anesthesia, but increased within 15 min and remained stable thereafter. Heart rate was not affected by the GFR protocol. Locomotor activity increased following anesthesia before decreasing to relatively low levels during the final 75‐min, the approximate period from which GFR is calculated. Moreover, MAP, heart rate, and locomotor activity during the final 75‐min of the data collection period were not different to that observed during an equivalent time period at baseline. Taken together, our findings suggest that this recently developed minimally invasive procedure for the measurement of GFR in unanesthetized rats does not negatively impact arterial pressure, heart rate, or locomotor activity. Thus, it is likely to be a valuable implement for acquiring serial measurements of GFR in unanesthetized rats.

We read with great interest the recently published article in Physiological Reports on protein intake, renal acid load, and hemodynamic responses (Teunissen‐Beekman et al. 2016). In their study, Teunissen‐Beekman et al. examined effects of an increase in protein intake (60 g/day, given as a mix of protein isolates, 20% pea, 20% soy, 30% egg‐white, 30% milk) on glomerular filtration rate (GFR) and related renally relevant parameters in overweight individuals with untreated elevated blood pressure and normal kidney function. Contrary to the author's initial hypothesis, neither fasting nor postprandial GFR values (the latter adjusted for the fasting measurements) were higher in the protein‐supplemented group (PROT) compared with a second group (MALT) which instead received 60 g/day of maltodextrin on an isoenergetic basis. The authors reported overall remarkably high GFR values in their subjects along with a short temporary GFR decline within 30 min postprandially in the protein‐supplemented group that was not seen in MALT. As expected, the authors found a significantly higher renal acid load after 4 weeks on the protein supplement compared to 4 weeks on maltodextrin. 24‐h renal acid load was determined as urinary PRAL (uPRAL), a biomarker that characterizes the mineral component (including sulfate from sulfur‐containing amino acids) of total renal net acid excretion (NAE) without considering the organic acid component (Krupp et al. 2014). Unexpectedly, the observed uPRAL difference after 4 weeks on higher protein ingestion versus baseline was only about 15 mEq/day. This is half of what is known from the literature for protein increases of that magnitude (Remer and Manz 1994, 1995a). In accord herewith, in a separate article on the present diet experiment (Teunissen‐Beekman et al. 2012), the authors reported differences in urinary sulfate excretion after 4 weeks (for PROT vs. MALT, and for PROT vs. baseline) of 7–8 mmol/day corresponding to 15 mEq of renally excreted dietary acidity stemming from sulfur amino acid metabolism. However, 30 mEq/day of “sulfate acidity” would have been expected with an increase of 60 g/day of a protein mix of that composition (Remer and Manz 1995b). It appears worth considering, whether a lower compliance at the end of the 4 week observation period might have contributed to the too low acid excretion after protein supplementation of that magnitude. Interestingly, also the average renal acid load component (4) measured as uPRAL in 24‐h urine samples of both groups (PROT and MALT) has been found to be remarkably low, both at baseline and after 4 weeks of diet intervention. Mean uPRAL varied between ca. −5 mEq and ca. −20 mEq/day (Figure 4; Teunissen‐Beekman et al. 2016) confirming a largely alkalizing basic nutrition present already at run‐in. In contrast, healthy adults of the DONALD study with an average protein intake of 115 g/day – that is, almost comparable to PROT – show mean uPRAL values around +50 mEq/day corresponding to a NAE of ca. 90 mEq/day and reflecting a rather higher dietary acid load. The fact that the authors, notwithstanding, found a low uPRAL range throughout (

Renal ischemia/reperfusion (I/R) can lead to impaired urine concentration ability and increased fractional excretion of sodium (FeNa). Local ischemic pre conditioning improves renal water and sodium handling after I/R injury. Here, we investigate whether remote ischemic per conditioning (rIPeC) prevents dysregulation of renal water and salt handling in response to I/R injury and mechanisms that may be involved. Rats were subjected to right nephrectomy and randomized into a sham group or an I/R group. In the I/R group, rats were subjected to 37 min of renal ischemia and 3 days of reperfusion. rIPeC was applied to the abdominal aorta. Blood and urine were collected on day 3 postoperatively for clearance studies. The expression of aquaporins (AQPs) and the sodium transporter Na–K‐ATPase were analyzed using immunoblotting and immunohistochemistry. I/R injury resulted in polyuria, increased FeNa, and decreased urine osmolality compared to sham rats. rIPeC attenuated the increase in FeNa and the decrease in urine osmolality. Expression of AQP1, AQP2, phosphorylated AQP2 (pAQP2), and Na–K‐ATPase was downregulated in I/R rats. rIPeC attenuated the reductions in AQP2 and pAQP2 expression. Immunohistochemistry revealed decreased labeling of Na–K‐ATPase in the outer medulla in I/R kidneys compared to kidneys from sham and I/R + rIPeC rats. After renal ischemia, the expression of Na–K‐ATPase was substantially reduced in the outer medullary thick ascending limb. In conclusion, our data suggest that rIPeC might prevent dysregulation of renal water and salt handling via regulation of AQP2 expression and phosphorylation as well as via regulation of Na–K‐ATPase expression in I/R rat kidneys.

The conventional model on the distribution of electrolyte infusions states that water will distribute proportionally over both the intracellular (ICV) and extracellular (ECV) volumes, while potassium homes to the ICV and sodium to the ECV. Therefore, total body potassium is the most accurate measure of ICV and thus potassium balances can be used to quantify changes in ICV. In cardiothoracic patients admitted to the ICU we performed complementary balance studies to measure changes in ICV and ECV. In 39 patients, fluid, sodium, potassium, and electrolyte‐free water (EFW) balances were determined to detect changes in ICV and ECV. Cumulatively over 4 days, these patients received a mean ± SE infusion of 14.0 ± 0.6 L containing 1465 ± 79 mmol sodium, 196 ± 11 mmol potassium and 2.1 ± 0.1 L EFW. This resulted in strongly positive fluid (4.0 ± 0.6 L) and sodium (814 ± 75 mmol) balances but in negative potassium (−101 ± 14 mmol) and EFW (−1.1 ± 0.2 L) balances. We subsequently compared potassium balances (528 patients) and fluid balances (117 patients) between patients who were assigned to either a 4.0 or 4.5 mmol/L blood potassium target. Although fluid balances were similar in both groups, the additionally administered potassium (76 ± 23 mmol) in the higher target group was fully excreted by the kidneys (70 ± 23 mmol). These findings indicate that even in the context of rapid and profound volume expansion neither water nor potassium moves into the ICV.

The peptide uroguanylin (Ugn) is expressed at significant levels only in intestine and kidney, and is stored in both tissues primarily (perhaps exclusively) as intact prouroguanylin (proUgn). Intravascular infusion of either Ugn or proUgn evokes well‐characterized natriuretic responses in rodents. Furthermore, Ugn knockout mice display hypertension and salt handling deficits, indicating that the Na+ excretory mechanisms triggered when the peptides are infused into anesthetized animals are likely to operate under normal physiological conditions, and contribute to electrolyte homeostasis in conscious animals. Here, we provide strong corroborative evidence for this hypothesis, by demonstrating that UU gnV (the rate of urinary Ugn excretion) approximately doubled in conscious, unrestrained rats consuming a high‐salt diet, and decreased by ~15% after salt restriction. These changes in UU gnV were not associated with altered plasma proUgn levels (shown here to be an accurate index of intestinal proUgn secretion). Furthermore, enteric Ugn mRNA levels were unaffected by salt intake, whereas renal Ugn mRNA levels increased sharply during periods of increased dietary salt consumption. Together, these data suggest that diet‐evoked Ugn signals originate within the kidney, rather than the intestine, thus strengthening a growing body of evidence against a widely cited hypothesis that Ugn serves as the mediator of an entero‐renal natriuretic signaling axis, while underscoring a likely intrarenal natriuretic role for the peptide. The data further suggest that intrarenal Ugn signaling is preferentially engaged when salt intake is elevated, and plays only a minor role when salt intake is restricted.

Adequate water intake, supporting both cardiovascular function and evaporative cooling, is a critical factor in mitigating the effects of heat waves, which are expected to increase with global warming. However, the regulation of water intake during periods of intermittent heat exposure is not well understood. In this study, the effects of access to water or no access during intermittent heat exposure were assessed using male Sprague‐Dawley rats exposed to 37.5°C for 4 h/day. After 7 days of intermittent heat exposure, reductions in evaporative water loss were observed in all animals and reductions in water intake following heat exposure occurred as the days of heat exposure increased. Rats that were not allowed water during the 7 days of exposure had decreased rehydration levels, however, rats allowed access to water increased water intake during exposure and exhibited higher overall rehydration levels over the same time period. Peripheral administration of angiotensin II, mimicking activation of volemic thirst, or hypertonic saline solution, activating intracellular thirst, did not result in alteration of water intake in rats exposed to heat with access to water compared to control rats. In contrast, rats exposed to heat without access to water had reduced water intake after administration of hypertonic saline and increased water intake after administration of angiotensin II compared to control rats. These experiments demonstrate that thirst responses to intermittent heat exposure are altered by providing water during heat exposure and that intermittent heat exposure without access to water alters drinking responses to both intracellular and extracellular thirst challenges.

Early diabetic nephropathy is largely undetectable before substantial functional changes have occurred. In the present study, we investigated the distribution of electrolytes and urea in the early diabetic kidney in order to explore whether pathophysiological and metabolic changes appear concomitantly with a decreased sodium and urea gradient. By using hyperpolarized 13C urea it was possible to measure the essential intrarenal electrolyte gradients and the acute changes following furosemide treatment. No differences in either intrarenal urea or sodium gradients were observed in early diabetes compared to healthy controls. These results indicate that the early metabolic and hypertrophic changes occurring in the diabetic kidney prelude the later functional alterations in diabetic kidney function, thus driving the increased metabolic demand commonly occurring in the diabetic kidney.

An investigation of human biological variation in urinary organic acids, including pyroglutamic acid along with 39 other compounds, was previously reported in which levels were determined for 8 weeks in healthy adult subjects. Here, unique, 4‐week‐long physiological trends for one of those compounds, pyroglutamic acid (PGA), are reported. When PGA levels for an individual rose above 40 μg/mg creatinine, 4‐week downward progressions occurred until levels reached values near 15 μg/mg creatinine and the pattern was reversed when levels for an individual were below that level in the early weeks of the study. The pattern was especially prominent among 8 of the 13 menstruating female subjects suggesting a possible association with metabolic stress of the menstrual cycle. However, it also appeared in 3 of the 8 male subjects where other sources of metabolic stress may be present. The menstrual association is consistent with estrogen‐mediated increase in oxidative stress. Since PGA is linked to glutathione turnover, the consistency of extreme values across all individuals displaying the pattern indicates that 15 and 40 μg/mg creatinine may represent limits that trigger shifts in sulfur amino acid metabolism. This is the first observation of approximate month‐long cyclic responses in a glutathione‐related urinary marker in humans.

Abnormal vascular permeability is a hallmark of sepsis‐mediated injury to various organs. An intact endothelial barrier is critical to homeostasis and prevents leakage of abnormal quantities of fluid and protein, including proinflammatory cytokines and chemokines, into the extravascular space. Barrier disruption leads to distributive shock as well as organ dysfunction and edema (Lee and Slutsky 2010). Extensive research implicates tumor necrosis factor‐ α (TNF) in this process. TNF binds receptors on the endothelial cell surface and activates intracellular Rho GTPases. This increases Rho‐associated kinase (ROCK) activity which inactivates myosin light chain (MLC) phosphatase and, in the presence of myosin light chain kinase (MLCK), leads to MLC phosphorylation. As a result, actin filaments reorganize into stress fibers, and cells exhibit increased actomyosin contractility, leading to endothelial barrier disruption (Marcos‐Ramiro et al. 2014). Endothelial permeability in the kidney has unique manifestations. Similar to other organs, dysfunction of endothelia in the peritubular capillaries leads to reduced blood flow and inflammation that contribute to AKI pathogenesis (Molitoris 2014). In addition, the specialized glomerular endothelium, together with the glomerular epithelium (i.e., podocytes) and associated basement membrane, forms the kidney's filtration barrier. Disruption of the filtration barrier leads to proteinuria, or the abnormal accumulation of protein in the …

International audience; Low-energy extracorporeal shock wave therapy (SWT) has been shown to improve myocardial dysfunction, hind limb ischemia, erectile function, and to facilitate cell therapy and healing process. These therapeutic effects were mainly due to promoting angiogenesis. Since chronic kidney diseases are characterized by renal fibrosis and capillaries rarefaction, they may benefit from a proangiogenic treatment. The objective of our study was to determine whether SWT could ameliorate renal repair and favor angiogenesis in L-NAME-induced hypertensive nephropathy in rats. SWT was started when proteinuria exceeded 1 g/mmol of creatinine and 1 week after L-NAME removal. SWT consisted of implying 0.09 mJ/mm 2 (400 shots), 3 times per week. After 4 weeks of SWT, blood pressure, renal function and urinary protein excretion did not differ between treated (LN + SWT) and untreated rats (LN). Histo-logical lesions including glomerulosclerosis and arteriolosclerosis scores, tubular dilatation and interstitial fibrosis were similar in both groups. In addition, peritubular capillaries and eNOS, VEGF, VEGF-R, SDF-1 gene expressions did not increase in SWT-treated compared to untreated animals. No procedural complications or adverse effects were observed in control (C + SWT) and hypertensive rats (LN + SWT). These results suggest that extracorporeal kidney shock wave therapy does not induce angiogenesis and does not improve renal function and structure, at least in the model of hypertensive nephropa-thy although the treatment is well tolerated.

Mice are used extensively in physiological research. Automated home‐cage systems have been developed to study single‐housed animals. Increased stress by different housing conditions might affect greatly the results when investigating metabolic responses. Urinary corticosteroid concentration is considered as a stress marker. The aim of the study was to compare the effects of different housing conditions and an automated home‐cage system with indirect calorimetry located in an environmental chamber on corticosterone levels in mice. Male mice were housed in different conditions and in automated home‐cage system to evaluate the effects of housing and measuring conditions on urine corticosterone levels. Corticosterone levels in single‐housed mice in the laboratory animal center were consistently lower compared with the group‐housed mice. Single‐housed mice in a separate, small animal unit showed a rise in their corticosterone levels a day after they were separated to their individual cages, which decreased during the following 2 days. The corticosterone levels of group‐housed mice in the same unit were increased during the first 7 days and then decreased. On day 7, the corticosterone concentrations of group‐housed mice were significantly higher compared with that of single‐housed mice, including the metabolic measurement protocol. In conclusion, single housing caused less stress when compared with group‐housed mice. In addition, the urine corticosterone levels were decreased in single‐housed mice before the metabolic measurement started. Thus, stress does not affect the results when utilizing the automated system for measuring metabolic parameters like food and water intake and calorimetry.

The effects of heat acclimation on water intake and urine output responses to thermal dehydration and other thirst stimuli were studied in male Sprague–Dawley rats. Rats were heat acclimated by continuous exposure to a 34°C environment for at least 6 weeks. Thermal dehydration‐induced thirst was brought about by exposing the heat‐acclimated rats and control rats housed at 24°C to a 37.5°C environment for 4 h without access to food or water. Heat acclimation reduced evaporative and urinary water losses and the increases in plasma sodium and osmolality during thermal dehydration, which led to a reduction in thermal dehydration‐induced thirst. Heat acclimation reduced the rate of rehydration following thermal dehydration but did not alter the final rehydration level, indicating that heat acclimation does not alter the primary control of thermal dehydration‐induced thirst. Heat acclimation did not alter water intake or urine output following administration of hypertonic saline, which selectively stimulates intracellular thirst, but led to greater water intake following administration of angiotensin II, which plays an important role in extracellular/volemic thirst, and following water deprivation, which activates both thirst pathways. Cardiovascular responses to angiotensin II were not altered by heat acclimation. Heat acclimation thus reduces water loss during heat exposure in rats, but does not have major effects on thermal dehydration‐induced or extracellular thirst but does appear to alter volemic thirst.

Sodium and fluid retention is a hallmark and a therapeutic challenge of the nephrotic syndrome (NS). Studies support the “overfill” theory of NS with pathophysiological proteolytic activation of the epithelial sodium channel (ENaC) which explains the common observation of suppressed renin –angiotensin system and poor therapeutic response to ACE inhibitors. Blockade of ENaC by the diuretic amiloride would be a rational intervention compared to the traditionally used loop diuretics. We describe a 38‐year‐old male patient with type1 diabetes who developed severe hypertension (200/140 mmHg), progressive edema (of at least 10 L), and overt proteinuria (18.5 g/24 h), despite combined administration of five antihypertensive drugs. Addition of amiloride (5 mg/day) to treatment resulted in resolution of edema, weight loss of 7 kg, reduction in blood pressure (150/100–125/81 mmHg), increased 24 h urinary sodium excretion (127–165 mmol/day), decreased eGFR (41–29 mL/min), and increased plasma potassium concentration (4.6–7.8 mmol/L). Blocking of ENaC mobilizes nephrotic edema and lowers blood pressure in NS. However, acute kidney injury and dangerous hyperkalemia is a potential risk if amiloride is added to multiple other antihypertensive medications as ACEi and spironolactone. The findings support that ENaC is active in NS and is a relevant target in adult NS patients.

Topiroxostat is a novel inhibitor of xanthine oxidase, and is postulated to exert a renoprotective effect. Puromycin aminonucleoside nephrosis (PAN) is a rat model of minimal change nephrotic syndrome. In this study, we examined whether topiroxostat ameliorates the kidney injury in PAN rats that was induced by a single intraperitoneal injection of PA (100 mg/kg body weight). Rats were divided into four groups: control rats, PAN rats, control rats treated with topiroxostat (1.0 mg/kg/day), and PAN rats treated with topiroxostat. Topiroxostat significantly reduced the amount of uric acid in the kidney cortex, while serum UA concentration remained unaffected by this treatment. Urinary protein excretion decreased significantly on day 10 in PAN rats upon topiroxostat treatment. Podocyte injury in PAN rats, as indicated by the reduction in WT‐1‐positive cell numbers and podocin immunoreactivity and foot process effacement, was partially yet significantly alleviated with topiroxostat treatment. In the kidney cortex, the increase in oxidative stress markers such as nitrotyrosine and 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG) and the enhanced expressions of xanthine oxidase and NADPH oxidase 4 (NOX4) in PAN rats were significantly ameliorated by topiroxostat. Using cultured podocytes NOX4 expression was upregulated by adding 12 mg/dL UA into the culture medium. These results suggest that topiroxostat ameliorates proteinuria and kidney injury in PAN rats by lowering oxidative stress and tissue UA concentration. The renoprotective effects of topiroxostat could be attributed to its potential to inhibit xanthine oxidase and NOX4 in concert with suppression of intracellular UA production.

Previously, we reported that 20% fructose diet causes salt‐sensitive hypertension. In this study, we hypothesized that a high salt diet supplemented with 20% fructose (in drinking water) stimulates salt‐sensitive hypertension by increasing salt retention through decreasing renal nitric oxide. Rats in metabolic cages consumed normal rat chow for 5 days (baseline), then either: (1) normal salt for 2 weeks, (2) 20% fructose in drinking water for 2 weeks, (3) 20% fructose for 1 week, then fructose + high salt (4% NaCl) for 1 week, (4) normal chow for 1 week, then high salt for 1 week, (5) 20% glucose for 1 week, then glucose + high salt for 1 week. Blood pressure, sodium excretion, and cumulative sodium balance were measured. Systolic blood pressure was unchanged by 20% fructose or high salt diet. 20% fructose + high salt increased systolic blood pressure from 125 ± 1 to 140 ± 2 mmHg (P

A maternal low‐protein diet has been shown to program hypertension and a reduction in glomerular filtration rate in adult offspring. This study examined the effect of continuous administration of enalapril in the drinking water and transient administration of enalapril administered from 21 to 42 days of age on blood pressure and glomerular filtration rate (GFR) in male rats whose mothers were fed a 20% protein diet (control) or a 6% protein diet (programmed) during the last half of pregnancy. After birth all rats were fed a 20% protein diet. Programmed rats (maternal 6% protein diet) were hypertensive at 15 months of age compared to control rats and both continuous and transient administration of enalapril had no effect on blood pressure on control offspring, but normalized the blood pressure of programmed offspring. GFR was 3.2 ± 0.1 mL/min in the control group and 1.7 ± 0.1 mL/min in the programmed rats at 17 months of age (P

Milan normotensive (MNS) rats are more susceptible to the development of renal disease than Milan hypertensive (MHS) rats, but the genes and pathways involved are unknown. This study compared the myogenic response of isolated perfused afferent arterioles (Af‐Art) and autoregulation of renal blood flow (RBF) and glomerular capillary pressure (Pgc) in 6–9‐week‐old MNS and MHS rats. The diameter of the Af‐Art of MHS rats decreased significantly from 14.3 ± 0.5 to 11.5 ± 0.6 μ m when perfusion pressure was elevated from 60 to 120 mmHg. In contrast, the diameter of Af‐Art of MNS rats did not decrease. RBF was well autoregulated in MHS rats, but it increased by 26% in MNS rats. Pgc rose by 11 mmHg when renal perfusion pressure (RPP) was increased from 100 to 140 mmHg in MNS but not in MHS rats. Protein excretion increased from 10 ± 1 to 245 ± 36 mg/day in MNS rats as they aged from 3 to 11 months but it did not increase in MHS rats. We also compared the development of proteinuria in MNS and MHS rats following the induction of diabetes with streptozotocin. Protein excretion rose from 16 ± 3 to 234 ± 43 mg/day in MNS rats, but it remained unaltered in MHS rats. These data indicate that the myogenic response of the Af‐art is impaired in MNS rats and increased transmission of pressure to the glomerulus may contribute to renal injury in MNS rats similar to what is seen in fawn‐hooded hypertensive and Dahl salt‐sensitive rats.

Increased renal endothelin‐1 (ET‐1) production and an ETA receptor‐dependent increase in glomerular albumin permeability (Palb) accompany type 1 diabetes mellitus (T1D). We hypothesized that T1D‐induced oxidative stress contributes to renal ET‐1 production and glomerular Palb. Male rats with streptozotocin‐induced T1D were provided free access to drinking water without additives (T1D rats) or containing the free radical scavenger tempol (1 mmol/L; T1D+Tempol). After 3 weeks, T1D+Tempol rats displayed lower urinary excretion of thiobarbituric acid reactive substances and glomerular superoxide production (dihydroethidium staining) compared to T1D rats. Urinary ET‐1 excretion and inner medullary (but not cortical or outer medullary) prepro‐ET‐1 mRNA expression were lower in the T1D+Tempol group than in the T1D group. Palb, measured as the change in volume of isolated glomeruli upon exposure to oncotic gradients of albumin, was significantly lower in the T1D+Tempol group than in the T1D group. Tempol treatment did not alter protein excretion or creatinine clearance. These data support the postulate that oxidative stress contributes to glomerular Palb and renal ET‐1 production during the early phase of type 1 diabetes.

Podocytes play a central role in the formation of the glomerular filtration barrier in the kidney, and their dysfunction has been shown to result in multiple proteinuric kidney diseases. In this study, we sought to determine whether NF‐κB, a proinflammatory signaling, within podocytes was involved in renal ischemia‐reperfusion (I/R) injury. Podocyte‐specific IκBΔN transgenic (Pod‐IκBΔN) mice, in which NF‐κB was inhibited specifically in podocytes, were generated by the Cre‐loxP technology, and their phenotype was compared with control mice after bilateral renal ischemia. The effect of systemic administration of a NF‐κB inhibitor, pyrrolidinedithiocarbamate (PDTC), on renal I/R injury was also examined. Pod‐IκBΔN mice were phenotypically normal before surgery. Following renal I/R injury, serum concentrations of urea nitrogen and creatinine were elevated in both Pod‐IκBΔN and control mice to a similar extent, whereas PDTC treatment attenuated the elevation of these parameters. Renal histological damage in I/R‐injured Pod‐IκBΔN mice was also similar to I/R‐injured control mice, although it was improved by PDTC treatment. Moreover, I/R induced accumulation of inflammatory cells, such as neutrophils and macrophages, was reduced by PDTC treatment, but not by podocyte‐specific NF‐κB inhibition. These results provide evidence that the NF‐κB activity in podocytes does not contribute to the pathogenesis of renal I/R injury.

Magnesium is one of the most abundant cations in the human body and plays a key role as a metabolic enzyme cofactor and regulatory ion for neurons and cardiomyocytes. Hypomagnesemia due to isolated primary renal magnesium wasting is a rare clinical condition typically associated with neurological hyperexcitability. Exercise‐related gastrointestinal symptoms are caused by ischemic, mechanical, or neurohormonal changes. The role of hypomagnesemia in gastrointestinal symptoms is not well understood. We present a case of a 15‐year‐old male who presented with exercise‐induced abdominal pain, nausea, and vomiting, who was found to have profound hypomagnesemia and inappropriately elevated fractional excretion of magnesium (FEMg). Testing for multiple intrinsic and extrinsic etiologies of renal magnesium wasting was inconclusive. He was diagnosed with primary renal magnesium wasting and his symptoms resolved acutely with intravenous magnesium sulfate and with long‐term oral magnesium chloride. Primary renal magnesium wasting is a rare clinical entity that can cause extreme hypomagnesemia. It has not been associated previously with exercise‐induced gastrointestinal symptoms. The effects of hypomagnesemia on the human gastrointestinal tract are not well established. This case offers unique insights into the importance of magnesium homeostasis in the gastrointestinal tract. Exercise‐induced splanchnic hypoperfusion may contribute to gastrointestinal symptoms observed in this chronically hypomagnesemic patient.

Measuring glomerular filtration rate (GFR) by dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) as part of standard of care clinical MRI exams (e.g., in pediatric solid tumor patients) has the potential to reduce diagnostic burden. However, enthusiasm for this relatively new GFR test may be curbed by the limited amount of cross‐calibration studies with reference GFR techniques and the vast variety of MR tracer model algorithms causing confusion on the choice of model. To advance MRI‐based GFR quantification via improved GFR modeling and comparison with associated 99mTc‐DTPA‐GFR, 29 long‐term Wilms' tumor survivors (19.0–43.3 years, [median 32.0 ± 6.0 years]) treated with nephrectomy, nonnephrotoxic chemotherapy ± radiotherapy underwent MRI with Gd‐DTPA administration and a 99mTc‐DTPA GFR test. For DCE‐MRI‐based GFR estimation, a subject‐specific two‐compartment (SS‐2C) model was developed that uses individual hematocrit values, automatically defines subject‐specific uptake intervals, and fits tracer‐uptake curves by incorporating these measures. The association between reference 99mTc‐DTPA GFR and MR‐GFRs obtained by SS‐2C, three published 2C uptake, and inflow–outflow models was investigated via linear regression analysis. Uptake intervals varied from 64 sec to 141 sec [96 sec ± 21 sec] and hematocrit values ranged from 30% to 49% [41% ± 4%]; these parameters can therefore not be assumed as constants in 2C modeling. Our MR‐GFR estimates using the SS‐2C model showed accordingly the highest correlation with 99mTc‐DTPA‐GFRs (R 2 = 0.76, P

The increased deposition of iron in the kidneys that occurs with glomerulopathy hinders the functional and structural recovery of the tubules and promotes progression of chronic kidney disease (CKD). Here, we evaluated whether epoetin beta pegol (continuous erythropoietin receptor activator: CERA), which has a long half‐life in blood and strongly suppresses hepcidin‐25, exerts renoprotection in a rat model of chronic progressive glomerulonephritis (cGN). cGN rats showed elevated urinary total protein excretion (uTP) and plasma urea nitrogen (UN) from day 14 after the induction of kidney disease (day 0) and finally declined into end‐stage kidney disease (ESKD), showing reduced creatinine clearance with glomerulosclerosis, tubular dilation, and tubulointerstitial fibrosis. A single dose of CERA given on day 1, but not on day 16, alleviated increasing uTP and UN, thereby delaying ESKD. In the initial disease phase, CERA significantly suppressed urinary 8‐OHdG and liver‐type fatty acid–binding protein (L‐FABP), a tubular damage marker. CERA also inhibited elevated plasma hepcidin‐25 levels and alleviated subsequent iron accumulation in kidneys in association with elevated urinary iron excretion and resulted in alleviation of growth of Ki67‐positive tubular and glomerular cells. In addition, at day 28 when the exacerbation of uTP occurs, a significant correlation was observed between iron deposition in the kidney and urinary L‐FABP. In our study, CERA mitigated increasing kidney damage, thereby delaying CKD progression in this glomerulonephritis rat model. Alleviation by CERA of the exacerbation of kidney damage could be attributable to mitigation of tubular damage that might occur with lowered iron deposition in tubules.

The aim of the present study was to further understand the changes in renal filtration that occur in the early stages of diabetes mellitus. Diabetes was induced in male Wistar rats by a single injection of streptozotocin. Glycemia, body weight, 24-h urine volume and urinary excretion of creatinine, protein and glycosaminoglycans were measured 10 and 30 days after diabetes induction. All the diabetic animals used in the present study were hyperglycemic, did not gain weight, and presented proteinuria and creatinine hyperfiltration. In contrast, the glycosaminoglycan excretion decreased. Dextran sulfates of different molecular weights (6.0 to 11.5 kDa) were administered to the diabetic rats, and to age-matched, sham-treated controls. Most of the dextran sulfate was excreted during the first 24 h, and the amounts excreted in the urine were inversely proportional to the dextran sulfate molecular weight for all groups. Nevertheless, diabetic rats excreted less and accumulated more dextran sulfate in kidney and liver, as compared to controls. These differences, which were observed only for the dextran sulfates of higher molecular weights (>7 kDa), increased with the duration of diabetes. Our findings suggest differential renal processing mechanisms for proteins and sulfated polysaccharides, with the possible involvement of kidney cells.

Bu çalışma, Bursa Uludağ ÜniversitesiVeteriner Fakültesinde S. D. Yaman 'in danışmanlığında Deniz Mısırlıoğlu tarafından yazılan "Böbreklerdeki filtrasyon değişikliklerine bağlı olarak böbrek üstü bezlerinde meydana gelen değişmeler" adlı doktora tezine dayanılarak hazırlanmıştır. Bu çalışmada, böbrek bozukluklannın böbrek üstü bezlerinde değişikliğe yol açıp, açmadığı araştırılmıştır. Sonuçta adrenal bezlerde renal lezyonlarla paralel seyreden ve istatistik önemi büyük olan bazı değişiklikler saptanmıştır. Bu değişiklikler; a) Stromal bağ dokunun genel artışı ve burada oluşalt metaplazik değişmeler, b) Korteks'te yığınlar halinde degra­nüle hücrelerin bulunuşu, c) Z. glomernlosa katında vasküler genişlemeler ve hücrelerinde atrofi, d) Adrenal korteks'te hiperplazi, e) Medülla ve korteks'te adenoid yapılar halinde korteks adacıklan oluşumu şeklinde ta­nımlanmıştır. The aim of this study was to examine the possible effects of renal disorders on the adrenal glands. The adrenal glands demonstrated statisticaly very important changes and these lesions were in a strict collelation with the severity of renal damage. Findings were summarized as follows: a) General increase of stroma, b) Clumps of degranulated cells in cortex, c) Atrophia and sinusoidol enlargemellls in Z. glomenılo­ sa, d) Hyperplasia of cortical layers, e) Adenoid stnıctures of cortical origin in cortex and medulla.

The last 5 years have witnessed tremendous advances in both light- and electron-microscopic techniques in the biomedical sciences. Application of these new cutting-edge methods to glomerular biology has advanced considerably and, in part, completed our endeavor to draw a detailed map of the glomerular tuft. The scope of this review is to illustrate these new insights within both the morphometry of podocyte cells and the architecture of the glomerular filtration barrier and to assess whether these findings have indeed had an impact on our biological understanding of glomerular function.