American Journal of Physiology - Renal Physiology
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Effect of BNP on renal hemodynamics, tubular function and vasoactive hormones in humans The effect of a continuous infusion of human brain natriuretic peptide (BNP) was studied in 48 healthy men. The study was randomized, placebo controlled, and single blind. BNP was given in doses of 1, 2, or 4 pmol ⋅ kg−1 ⋅ min−1 for 60 min, and peak values of BNP in plasma were 38, 85, and 199 pmol/l, giving increments in plasma as seen in heart or renal failure. BNP infusion increased the urinary flow rate and the excretion of sodium in a dose-dependent way. The maximal effects were +65 and +156%, respectively. GFR increased and RPF decreased, the latter in a dose-dependent manner. Blood pressure, heart rate, angiotensin II, and aldosterone were all unaffected by infusion of BNP, whereas a direct inhibition of renin secretion was seen. With the use of the lithium clearance technique, we concluded that the tubular site of action is in both the proximal and distal segments, and the major effect on sodium handling is in the distal parts of the nephron.
American Journal of Physiology - Renal Physiology - Tập 274 Số 1 - Trang F63-F72 - 1998
Role of membrane proteins in permeability barrier function: uroplakin ablation elevates urothelial permeability Although water, small nonelectrolytes, and gases are freely permeable through most biological membranes, apical membranes of certain barrier epithelia exhibit extremely low permeabilities to these substances. The role of integral membrane proteins in this barrier function has been unclear. To study this problem, we have ablated the mouse gene encoding uroplakin III (UPIII), one of the major protein subunits in urothelial apical membranes, and measured the permeabilities of these membranes. Ablation of the UPIII gene greatly diminishes the amounts of uroplakins on the apical urothelial membrane (Hu P, Deng FM, Liang FX, Hu CM, Auerbach AB, Shapiro E, Wu XR, Kachar B, and Sun TT. J Cell Biol151: 961–972, 2000). Our results indicate that normal mouse urothelium exhibits high transepithelial resistance and low urea and water permeabilities. The UPIII-deficient urothelium exhibits a normal transepithelial resistance (normal 2,024 ± 122, knockout 2,322 ± 114 Ω · cm2 ; P > 0.5). However, the UPIII-deficient apical membrane has a significantly elevated water permeability (normal 0.91 ± 0.06, knockout 1.83 ± 0.14 cm/s × 10−5 ; P < 0.05). The urea permeability of the UPIII-deficient membrane also increased, although to a lesser extent (normal 2.22 ± 0.24, knockout 2.93 ± 0.31 cm/s × 10−6 ; P = 0.12). These results indicate that reduced targeting of uroplakins to the apical membrane does not significantly alter the tight junctional barrier but does double the water permeability. We provide the first demonstration that integral membrane proteins contribute to the apical membrane permeability barrier function of urothelium.
American Journal of Physiology - Renal Physiology - Tập 283 Số 6 - Trang F1200-F1207 - 2002
Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis In humans and experimental models of renal ischemia, tubular cells in various nephron segments undergo necrotic and/or apoptotic cell death. Various factors, including nucleotide depletion, electrolyte imbalance, reactive oxygen species, endonucleases, disruption of mitochondrial integrity, and activation of various components of the apoptotic machinery, have been implicated in renal cell vulnerability. Several approaches to limit the injury and augment the regeneration process, including nucleotide repletion, administration of growth factors, reactive oxygen species scavengers, and inhibition of inducers and executioners of cell death, proved to be effective in animal models. Nevertheless, an effective approach to limit or prevent ischemic renal injury in humans remains elusive, primarily because of an incomplete understanding of the mechanisms of cellular injury. Elucidation of cell death pathways in animal models in the setting of renal injury and extrapolation of the findings to humans will aid in the design of potential therapeutic strategies. This review evaluates our understanding of the molecular signaling events in apoptotic and necrotic cell death and the contribution of various molecular components of these pathways to renal injury.
American Journal of Physiology - Renal Physiology - Tập 284 Số 4 - Trang F608-F627 - 2003
Acute renal failure. I. Relative importance of proximal vs. distal tubular injury For more than 15 years, there has been an ongoing debate regarding the nephron segment(s) most severely injured in acute renal failure (ARF) induced by an ischemic or toxic insult. Although some investigators have argued that the proximal tubule (and particularly the S3 segment) is the major target of injury in ARF, others have held the view that damage to the distal nephron [particularly the medullary thick ascending limb (MTAL) segment] plays a more important role in this disease. In this discussion, the first of three on different aspects of ARF that have been hotly debated, we have invited several experts to discuss their opinions on this issue. The goals of this first discussion (and the subsequent two articles in this forum) are to establish areas of consensus in each area of controversy and also to identify unanswered questions that represent important areas for future research.
American Journal of Physiology - Renal Physiology - Tập 275 Số 5 - Trang F623-F632 - 1998
The betaine-GABA transporter (BGT1, slc6a12) is predominantly expressed in the liver and at lower levels in the kidneys and at the brain surface The Na+ - and Cl− -dependent GABA-betaine transporter (BGT1) has received attention mostly as a protector against osmolarity changes in the kidney and as a potential controller of the neurotransmitter GABA in the brain. Nevertheless, the cellular distribution of BGT1, and its physiological importance, is not fully understood. Here we have quantified mRNA levels using TaqMan real-time PCR, produced a number of BGT1 antibodies, and used these to study BGT1 distribution in mice. BGT1 (protein and mRNA) is predominantly expressed in the liver (sinusoidal hepatocyte plasma membranes) and not in the endothelium. BGT1 is also present in the renal medulla, where it localizes to the basolateral membranes of collecting ducts (particularly at the papilla tip) and the thick ascending limbs of Henle. There is some BGT1 in the leptomeninges, but brain parenchyma, brain blood vessels, ependymal cells, the renal cortex, and the intestine are virtually BGT1 deficient in 1- to 3-mo-old mice. Labeling specificity was assured by processing tissue from BGT1-deficient littermates in parallel as negative controls. Addition of 2.5% sodium chloride to the drinking water for 48 h induced a two- to threefold upregulation of BGT1, tonicity-responsive enhancer binding protein, and sodium- myo-inositol cotransporter 1 (slc5a3) in the renal medulla, but not in the brain and barely in the liver. BGT1-deficient and wild-type mice appeared to tolerate the salt treatment equally well, possibly because betaine is one of several osmolytes. In conclusion, this study suggests that BGT1 plays its main role in the liver, thereby complementing other betaine-transporting carrier proteins (e.g., slc6a20) that are predominantly expressed in the small intestine or kidney rather than the liver.
American Journal of Physiology - Renal Physiology - Tập 302 Số 3 - Trang F316-F328 - 2012
Roles of the podocyte in glomerular function The podocyte is the most differentiated cell type in the glomerulum, which forms a crucial component of the glomerular filtration barrier. It has been assumed that podocyte foot processes counteract the elastic force of the glomerular basement membrane and that vasoactive hormones may regulate the contractile state of their foot processes and thereby modulate the ultrafiltration coefficient Kf . Podocyte damage leads to proteinuria, and podocyte injury occurs in many glomerular diseases, which may progress to chronic renal failure. The understanding of the regulation of physiological properties of the podocyte and the mechanisms of its cellular response to injury may thus provide a clue to the understanding of the pathogenesis of proteinuria and glomerular diseases. In the past it was difficult to study cellular functions in this cell type, because of its unique anatomic location and the difficulty in characterizing podocytes in cell culture. However, recent advances in physiological, molecular biological, and cell culture techniques have increased the knowledge of the role of the podocyte in glomerular function. The present review attempts to outline new aspects of podocyte function in the glomerulum.
American Journal of Physiology - Renal Physiology - Tập 278 Số 2 - Trang F173-F179 - 2000
Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function The Na-K-ATPase is characterized by a complex molecular heterogeneity that results from the expression and differential association of multiple isoforms of both its α- and β-subunits. At present, as many as four different α-polypeptides (α1, α2, α3, and α4) and three distinct β-isoforms (β1, β2, and β3) have been identified in mammalian cells. The stringent constraints on the structure of the Na pump isozymes during evolution and their tissue-specific and developmental pattern of expression suggests that the different Na-K-ATPases have evolved distinct properties to respond to cellular requirements. This review focuses on the functional properties, regulation, and possible physiological relevance of the Na pump isozymes. The coexistence of multiple α- and β-isoforms in most cells has hindered the understanding of the roles of the individual polypeptides. The use of heterologous expression systems has helped circumvent this problem. The kinetic characteristics of different Na-K-ATPase isozymes to the activating cations (Na+ and K+ ), the substrate ATP, and the inhibitors Ca2+ and ouabain demonstrate that each isoform has distinct properties. In addition, intracellular messengers differentially regulate the activity of the individual Na-K-ATPase isozymes. Thus the regulation of specific Na pump isozymes gives cells the ability to precisely coordinate Na-K-ATPase activity to their physiological requirements.
American Journal of Physiology - Renal Physiology - Tập 275 Số 5 - Trang F633-F650 - 1998
Increase of core temperature affected the progression of kidney injury by repeated heat stress exposure An epidemic of chronic kidney disease of unknown etiology (Mesoamerican nephropathy) has emerged in hot regions of Central America. We have demonstrated that dehydration associated with recurrent heat exposure causes chronic kidney disease in animal models. However, the independent influence of core body temperature on kidney injury has not been explored. In the present study, we tested the hypothesis that kidney injury could be accelerated by increasing body temperature independent of external temperature. Wild-type mice were exposed to heat (39.5°C, 30 min, 2 times daily) with or without the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) for 10 days. Core temperature, renal function, proteinuria, and renal histological and biochemical analyses were performed. Isolated mitochondria markers of oxidative stress were evaluated from kidney tissue. DNP increased body core temperature in response to heat by 1°C (42 vs. 41°C), which was transient. The mild increase in temperature correlated with worsening albuminuria ( R = 0.715, P < 001), renal tubular injury, and interstitial infiltration of monocytes/macrophages. Tubular injury was marked in the outer medulla. This was associated with a reduction in kidney tissue ATP levels (nonheated control: 16.71 ± 1.33 nmol/mg and DNP + heat: 13.08 ± 1.12 nmol/mg, P < 0.01), reduced mitochondria, and evidence for mitochondrial oxidative stress. The results of the present study suggest that kidney injury in heat stress is markedly worsened by increasing core temperature. This is consistent with the hypothesis that clinical and subclinical heat stroke may play a role in Mesoamerican nephropathy.
American Journal of Physiology - Renal Physiology - Tập 317 Số 5 - Trang F1111-F1121 - 2019
BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) uses deoxyhemoglobin as an endogenous contrast agent for the noninvasive assessment of tissue oxygen bioavailability. We hypothesized that intrarenal oxygenation was impaired in patients with chronic allograft nephropathy (CAN). Ten kidney-transplant recipients with CAN and nine healthy volunteers underwent BOLD-MRI. Medullary R2* (MR2*) and cortical R2* (CR2*) levels (measures directly proportional to tissue deoxyhemoglobin levels) were determined alongside urine and serum markers of oxidative stress (OS): hydrogen peroxide (H2 O2 ), F2 -isoprostanes, total nitric oxide (NO), heat shock protein 27 (HSP27), and total antioxidant property (TAOP). Mean MR2* and CR2* levels were significantly decreased in CAN (increased local oxyhemoglobin concentration) compared with healthy volunteers (20.7 ± 1.6 vs. 23.1 ± 1.8/s, P = 0.03 and 15.9 ± 1.9 vs. 13.6 ± 2.3/s, P = 0.05, respectively). There was a significant increase in serum and urine levels of H2 O2 and serum HSP27 levels in patients with CAN. Conversely, urine NO levels and TAOP were significantly increased in healthy volunteers. Multiple linear regression analyses showed a significant association between MR2* and CR2* levels and serum/urine biomarkers of OS. BOLD-MRI demonstrated significant changes in medullary and cortical oxygen bioavailability in allografts with CAN. These correlated with serum/urine biomarkers of OS, suggesting an association between intrarenal oxygenation and OS.
American Journal of Physiology - Renal Physiology - Tập 292 Số 2 - Trang F513-F522 - 2007
Visfatin: a new player in mesangial cell physiology and diabetic nephropathy Visfatin is an adipocytokine that improves insulin resistance and has an antidiabetic effect. However, the role of visfatin in the kidney has not yet been reported. In this experiment, the synthesis and physiological action of visfatin in cultured mesangial cells (MCs) were studied to investigate the role of visfatin in diabetic nephropathy. Visfatin was found synthesized in MCs as well as adipocytes. Visfatin synthesis was markedly increased, not by angiotensin II, but by high glucose stimuli. In addition, visfatin treatment induced a rapid uptake of glucose, peaking at 20 min after visfatin treatment in a dose-dependent manner. A small inhibiting RNA against insulin receptor significantly blocked visfatin-mediated glucose uptake. Visfatin stimuli also enhanced intracellular NAD levels, and treatment with FK866, which is a specific inhibitor of nicotinamide phosphoribosyltransferase (Nampt), significantly inhibited visfatin-induced NAD synthesis and glucose uptake. Visfatin treatment increased glucose transporter-1 (GLUT-1) protein expression in isolated cellular membranes, and pretreatment with cytochalasin B completely inhibited visfatin-induced glucose uptake. Moreover, immunofluorescent microscopy showed the migration of cytosolic GLUT-1 into cellular membranes after visfatin treatment. In accordance with these results, the activation of protein kinase B was detected after visfatin treatment. Furthermore, visfatin treatment dramatically increased the synthesis of profibrotic molecules including transforming growth factor-β1, plasminogen activator inhibitor-1, and type I collagen, and pretreatment with cytochalasin B completely inhibited visfatin-induced upregulation of profibrotic molecules. These results suggest that visfatin is produced in MCs, which are a novel target for visfatin, and play an important role in the pathogenesis of diabetic nephropathy.
American Journal of Physiology - Renal Physiology - Tập 295 Số 5 - Trang F1485-F1494 - 2008
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