Showing papers in "American Journal of Physiology-renal Physiology in 2009"
TL;DR: Data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.
Abstract: Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-...
370 citations
TL;DR: This review examines the understanding of uroepithelial regeneration and how specializations of the outermost umbrella cell layer contribute to barrier function and how they are co-opted by uropathogenic bacteria to infect the uroepsithelium.
Abstract: The uroepithelium sits at the interface between the urinary space and underlying tissues, where it forms a high-resistance barrier to ion, solute, and water flux, as well as pathogens. However, the uroepithelium is not simply a passive barrier; it can modulate the composition of the urine, and it functions as an integral part of a sensory web in which it receives, amplifies, and transmits information about its external milieu to the underlying nervous and muscular systems. This review examines our understanding of uroepithelial regeneration and how specializations of the outermost umbrella cell layer, including tight junctions, surface uroplakins, and dynamic apical membrane exocytosis/endocytosis, contribute to barrier function and how they are co-opted by uropathogenic bacteria to infect the uroepithelium. Furthermore, we discuss the presence and possible functions of aquaporins, urea transporters, and multiple ion channels in the uroepithelium. Finally, we describe potential mechanisms by which the uroepithelium can transmit information about the urinary space to the other tissues in the bladder proper.
332 citations
TL;DR: The structure-function relationships of GEnC fenestrations will be evaluated in depth, their role in health and disease explored, and the outlook for future study and therapeutic implications of these peculiar structures will be approached.
Abstract: Glomerular endothelial cell (GEnC) fenestrations are analogous to podocyte filtration slits, but their important contribution to the glomerular filtration barrier has not received corresponding attention. GEnC fenestrations are transcytoplasmic holes, specialized for their unique role as a prerequisite for filtration across the glomerular capillary wall. Glomerular filtration rate is dependent on the fractional area of the fenestrations and, through the glycocalyx they contain, GEnC fenestrations are important in restriction of protein passage. Hence, dysregulation of GEnC fenestrations may be associated with both renal failure and proteinuria, and the pathophysiological importance of GEnC fenestrations is well characterized in conditions such as preeclampsia. Recent evidence suggests a wider significance in repair of glomerular injury and in common, yet serious, conditions, including diabetic nephropathy. Study of endothelial cell fenestrations is challenging because of limited availability of suitable in vitro models and by the requirement for electron microscopy to image these sub-100-nm structures. However, extensive evidence, from glomerular development in rodents to in vitro studies in human GEnC, points to vascular endothelial growth factor (VEGF) as a key inducer of fenestrations. In systemic endothelial fenestrations, the intracellular pathways through which VEGF acts to induce fenestrations include a key role for the fenestral diaphragm protein plasmalemmal vesicle-associated protein-1 (PV-1). The role of PV-1 in GEnC is less clear, not least because of controversy over existence of GEnC fenestral diaphragms. In this article, the structure-function relationships of GEnC fenestrations will be evaluated in depth, their role in health and disease explored, and the outlook for future study and therapeutic implications of these peculiar structures will be approached.
295 citations
TL;DR: In this review, inducible experimental models of acquired nondiabetic podocyte diseases in rodents, namely, passive Heymann nephritis, puromycin aminonucleoside nephrosis, adriamycin nePHrosis, liopolysaccharide, crescentic glomerulonephritis and protein overload nephropathy models are discussed.
Abstract: Glomerular diseases remain the leading cause of chronic and end-stage kidney disease. Significant advances in our understanding of human glomerular diseases have been enabled by the development and better characterization of animal models. Diseases of the glomerular epithelial cells (podocytes) account for the majority of proteinuric diseases. Rodents have been extensively used experimentally to better define mechanisms of disease induction and progression, as well as to identify potential targets and therapies. The development of podocyte-specific genetically modified mice has energized the research field to better understand which animal models are appropriate to study acquired podocyte diseases. In this review we discuss inducible experimental models of acquired nondiabetic podocyte diseases in rodents, namely, passive Heymann nephritis, puromycin aminonucleoside nephrosis, adriamycin nephrosis, liopolysaccharide, crescentic glomerulonephritis, and protein overload nephropathy models. Details are given on the model backgrounds, how to induce each model, the interpretations of the data, and the benefits and shortcomings of each. Genetic rodent models of podocyte injury are excluded.
250 citations
TL;DR: Recent advances in understanding of the mechanisms of tubulointerstitial fibrosis are discussed, focusing on the regulation and role of the myofibroblast in this process, the role of recently recognized endogenous antifibrotic factors, controversy surrounding the effects of metalloproteinases, and the opportunities presented by new treatment strategies that abrogate and may even reverse fibrosis.
Abstract: Regardless of etiology, all patients with chronic renal disease show a progressive decline in renal function with time. Fibrosis, so-called scarring, is a key cause of this pathophysiology. Fibrosis involves an excess accumulation of extracellular matrix (primarily composed of collagen) and usually results in loss of function when normal tissue is replaced with scar tissue. While recent major advances have led to a much better understanding of this process, many problems remain. We for instance know little about why some wounds heal and others scar and little about how many putative antifibrotic agents work. This review discusses recent advances in our understanding of the mechanisms of tubulointerstitial fibrosis, focusing on the regulation and role of the myofibroblast in this process, the role of recently recognized endogenous antifibrotic factors, controversy surrounding the effects of metalloproteinases, and the opportunities presented by new treatment strategies that abrogate and may even reverse fibrosis.
242 citations
TL;DR: It is suggested that HDAC-2 plays an important role in the development of ECM accumulation and EMT in diabetic kidney and that ROS mediate TGF-beta1-induced activation of HDAC -2.
Abstract: Excessive accumulation of extracellular matrix (ECM) in the kidneys and epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells contributes to the renal fibrosis that is associ...
231 citations
TL;DR: First evidence for a role of Ctr1 in cisplatin uptake and nephrotoxicity is demonstrated, mainly expressed in both proximal and distal tubular cells in mouse kidneys.
Abstract: The usefulness and efficacy of cisplatin, a chemotherapeutic drug, are limited by its toxicity to normal tissues and organs, including the kidneys. The uptake of cisplatin in renal tubular cells is high, leading to cisplatin accumulation and tubular cell injury and death, culminating in acute renal failure. While extensive investigations have been focused on the signaling pathways of cisplatin nephrotoxicity, much less is known about the mechanism of cisplatin uptake by renal cells and tissues. In this regard, evidence has been shown for the involvement of organic cation transporters (OCT), specifically OCT2. The copper transporter Ctr1 is highly expressed in the renal tubular cells; however, its role in cisplatin nephrotoxicity is not known. In this study, we demonstrate that Ctr1 is mainly expressed in both proximal and distal tubular cells in mouse kidneys. We further show that Ctr1 is mainly localized on the basolateral side of these cells, a proposed site for cisplatin uptake. Importantly, downregulation of Ctr1 by small interfering RNA or copper pretreatment results in decreased cisplatin uptake. Consistently, downregulation of Ctr1 suppresses cisplatin toxicity, including cell death by both apoptosis and necrosis. Cimetidine, a pharmacological inhibitor of OCT2, can also partially attenuate cisplatin uptake. Notably, cimetidine can further reduce cisplatin uptake and cisplatin toxicity in Ctr1-downregulated cells. The results have demonstrated the first evidence for a role of Ctr1 in cisplatin uptake and nephrotoxicity.
229 citations
TL;DR: It is confirmed in wild-type mice (WT) that dietary NaCl restriction increases renal NCC expression and its phosphorylation, which is consistent with a regulation of NCC to modulate Na(+) delivery to downstream segments of Na(+)/K(+) exchange, thereby modulating K(+) excretion.
Abstract: The Na-Cl cotransporter NCC is expressed in the distal convoluted tubule, activated by phosphorylation, and has been implicated in renal NaCl and K+ homeostasis. The serum and glucocorticoid induci...
224 citations
TL;DR: It is suggested that local metabolic alterations in the kidney play important roles in the development of renal injury associated with metabolic syndrome in addition to systemic metabolic changes and an increase in body weight.
Abstract: Metabolic syndrome has been reported to be associated with chronic kidney disease, but the mechanisms remain unclear Although feeding of a high-fat diet (HFD) to C57BL/6 mice is reported to induce
220 citations
TL;DR: It is concluded that kidney fibrosis develops chronically following I/R injury, and this process is associated with the increase of ROS/oxidative stress.
Abstract: Recently, kidney fibrosis following transplantation has become recognized as a main contributor of chronic allograft nephropathy. In transplantation, transient ischemia is an inescapable event. Rea...
193 citations
TL;DR: It is suggested that pharmacological HDAC inhibition may induce antifibrotic activity by inactivation of renal interstitial fibroblasts and inhibition of renal tubular cell death and STAT3 may mediate those actions of HDACs.
Abstract: Activation of renal interstitial fibroblasts is critically involved in the development of tubulointerstitial fibrosis in chronic kidney diseases. In this study, we investigated the effect of trichostatin A (TSA), a specific histone deacetylase (HDAC) inhibitor, on the activation of renal interstitial fibroblasts in a rat renal interstitial fibroblast line (NRK-49F) and the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO). α-Smooth muscle actin (α-SMA) and fibronectin, two hallmarks of fibroblast activation, were highly expressed in cultured NRK-49F cells, and their expression was inhibited in the presence of TSA. Similarly, administration of TSA suppressed the expression of α-SMA and fibronectin and attenuated the accumulation of renal interstitial fibroblasts in the kidney after the obstructive injury. Activation of renal interstitial fibroblasts was accompanied by phosphorylation of signal transducer and activator of transcription 3 (STAT3), and TSA treatment also abolished these responses. Furthermore, inhibition of the STAT3 pathway with AG490 inhibited expression of α-SMA and fibronectin in NRK-49F cells. Finally, TSA treatment inhibited tubular cell apoptosis and caspase-3 activation in the obstructive kidney. Collectively, we suggest that pharmacological HDAC inhibition may induce antifibrotic activity by inactivation of renal interstitial fibroblasts and inhibition of renal tubular cell death. STAT3 may mediate those actions of HDACs.
TL;DR: In kidney arterioles ACE2 is preferentially localized in the tunica media, and its expression is increased after administration of the angiotensin II type 1 receptor blocker, telmisartan.
Abstract: Angiotensin-converting enzyme (ACE)2 is a carboxypeptidase that degrades angiotensin II and other peptides. In the kidney, ACE2 localization within the glomerulus and tubules is cell specific. This...
TL;DR: Hyperuricemia has a pathogenic role in the mild tubulointerstitial injury associated with diabetic nephropathy but not glomerular damage in db/db mice.
Abstract: Hyperuricemia has recently been recognized to be a risk factor for nephropathy in the diabetic subject. We tested the hypothesis that lowering uric acid with a xanthine oxidase inhibitor might reduce renal injury in the diabetic mouse. Diabetic (db/db) mice were treated with allopurinol or no treatment for 8 wk. Serum uric acid, renal function, and histology were assessed at death. The direct effect of uric acid in human proximal tubular epithelial cells was also evaluated under normal or high glucose condition. We found that db/db mice developed hyperuricemia, albuminuria, mesangial matrix expansion, and mild tubulointerstitial disease. Allopurinol treatment significantly lowered uric acid levels, reduced albuminuria, and ameliorated tubulointerstitial injury, but it did not prevent mesangial expansion. The mechanism for protection was shown to be due to a reduction in inflammatory cells mediated by a reduction in ICAM-1 expression by tubular epithelial cells. Interestingly, allopurinol did not reduce oxidative stress in the kidney. An inflammatory role of uric acid on tubular cells was also confirmed by our in vitro evidence that uric acid directly induced ICAM-1 expression in the human proximal tubular cell. In conclusion, hyperuricemia has a pathogenic role in the mild tubulointerstitial injury associated with diabetic nephropathy but not glomerular damage in db/db mice. Lowering uric acid may reduce tubulointerstitial injury in diabetes.
TL;DR: Experimental evidence is summarized for and against the hypothesis that N-glycans attached to the membrane proteins can act as apical sorting signals, and the potential roles of the lectins, VIP36 and galectin-3, as putative apicals sorting receptors are discussed.
Abstract: Polarized distribution of plasma membrane transporters and receptors in epithelia is essential for vectorial functions of epithelia. This polarity is maintained by sorting of membrane proteins into...
TL;DR: It is shown that a member of the SLC20 gene family (PiT-2) is localized to the brush-border membrane (BBM) of the PT epithelia and that its abundance, confirmed by Western blot and immunohistochemistry of rat kidney slices, is regulated by dietary P(i).
Abstract: The principal mediators of renal phosphate (Pi) reabsorption are the SLC34 family proteins NaPi-IIa and NaPi-IIc, localized to the proximal tubule (PT) apical membrane. Their abundance is regulated...
TL;DR: The fundamental physiological limitations for aldosterone action in the brain are presented, including its limited blood-brain barrier penetration and its substantial competition from glucocorticoids.
Abstract: Pharmacological and physiological phenomena suggest that cells somewhere inside the central nervous system are responsive to aldosterone. Here, we present the fundamental physiological limitations for aldosterone action in the brain, including its limited blood-brain barrier penetration and its substantial competition from glucocorticoids. Recently, a small group of neurons with unusual sensitivity to circulating aldosterone were identified in the nucleus of the solitary tract. We review the discovery and characterization of these neurons, which express the enzyme 11β-hydroxysteroid dehydrogenase type 2, and consider alternative proposals regarding sites and mechanisms for mineralocorticoid action within the brain.
TL;DR: The molecular machinery, regulation, and function of autophagy, a cellular process of "self-eating" that can directly induce cell death or act as a mechanism of cell survival, is discussed.
Abstract: Autophagy is a cellular process of “self-eating.” During autophagy, a portion of cytoplasm is enveloped in double membrane-bound structures called autophagosomes, which undergo maturation and fusio...
TL;DR: This work provides a comprehensive guide to ROMK, spanning from the physiology in the kidney to the organization and regulation by intracellular factors to the structural basis of its function at the atomic level.
Abstract: The discovery of the renal outer medullary K+ channel (ROMK, Kir1.1), the founding member of the inward-rectifying K+ channel (Kir) family, by Ho and Hebert in 1993 revolutionized our understanding of potassium channel biology and renal potassium handling. Because of the central role that ROMK plays in the regulation of salt and potassium homeostasis, considerable efforts have been invested in understanding the underlying molecular mechanisms. Here we provide a comprehensive guide to ROMK, spanning from the physiology in the kidney to the organization and regulation by intracellular factors to the structural basis of its function at the atomic level.
TL;DR: It is demonstrated that HHcy-associated renal damage is related to decreased endogenous H(2)S generation in the body through its antioxidant properties, and supplemented with or without NaHS supplementation preventsHHcy- associated renal damage.
Abstract: Elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), is associated with end-stage renal diseases. Hcy metabolizes in the body to produce hydrogen sulfide (H2S), and studies h...
TL;DR: FGF23 can inhibit the activities of 1-alpha-hydroxylase and sodium-phosphate cotransporter in the kidney to influence the overall systemic phosphate balance and Klotho, a transmembrane protein, is involved in such regulation.
Abstract: Understanding the physiological regulation of mineral ion metabolism is essential for determining the pathomechanisms of skeletal, vascular, and renal diseases associated with an abnormal regulation of calcium and phosphate homeostasis. Normal calcium and phosphate balance is delicately maintained by endocrine factors that coordinate to influence the functions of the intestine, bone, parathyroid gland, and kidney. Under physiological conditions, the kidneys play an important role in maintaining normal mineral ion balance by fine-tuning the amount of urinary excretion of calcium and phosphate according to the body's needs. Fibroblast growth factor (FGF)23 regulates urinary phosphate excretion to maintain systemic phosphate homeostasis. The exact mode of action of the phosphaturic effects of FGF23 is not fully understood and is an intense area of research. Studies suggest, however, that FGF23, by interacting with FGF receptors, can initiate downstream signaling events and that Klotho, a transmembrane protein, facilitates the interaction of FGF23 with its receptor. FGF23 can inhibit the activities of 1-α-hydroxylase and sodium-phosphate cotransporter in the kidney to influence the overall systemic phosphate balance. This article briefly summarizes how FGF23 might coordinately regulate systemic phosphate homeostasis and how Klotho is involved in such regulation.
TL;DR: The results indicate that FXR activation could represent an effective therapy for treatment of abnormal renal lipid metabolism with associated inflammation, oxidative stress, and kidney pathology in patients affected by obesity.
Abstract: Diet-induced obesity is associated with proteinuria and glomerular disease in humans and rodents. We have shown that in mice fed a high-fat diet, increased renal expression of the transcriptional factor sterol-regulatory element binding protein-1 (SREBP-1) plays a critical role in renal lipid accumulation and increases the activity of proinflammatory cytokines and profibrotic growth factors. In the current study, we have determined a key role of the farnesoid X receptor (FXR) in modulating renal SREBP-1 activity, glomerular lesions, and proteinuria. We found that feeding a Western-style diet to DBA/2J mice results in proteinuria, podocyte loss, mesangial expansion, renal lipid accumulation, and increased expression of proinflammatory factors, oxidative stress, and profibrotic growth factors. Treatment of these mice with the highly selective and potent FXR-activating ligand 6-α-ethyl-chenodeoxycholic acid (INT-747) ameliorates triglyceride accumulation by modulating fatty acid synthesis and oxidation, improves proteinuria, prevents podocyte loss, mesangial expansion, accumulation of extracellular matrix proteins, and increased expression of profibrotic growth factors and fibrosis markers, and modulates inflammation and oxidative stress. Our results therefore indicate that FXR activation could represent an effective therapy for treatment of abnormal renal lipid metabolism with associated inflammation, oxidative stress, and kidney pathology in patients affected by obesity.
TL;DR: Urinary FABP1 can detect human AKI earlier than serum creatinine and can distinguish the risk population for AKI, and is developed as a new renal biomarker.
Abstract: In the development of novel therapeutic strategies for kidney disease, new renal biomarkers for early detection and accurate evaluation of renal injury are urgently required for both acute kidney injury (AKI) and chronic kidney disease (CKD). Fatty acid-binding protein 1 (FABP1) is expressed in renal proximal tubule cells and shed into urine in response to hypoxia caused by decreased peritubular capillary blood flow. To clarify the role of urinary FABP1 in kidney disease, we established human FABP1 transgenic mice and evaluated the responses of FABP1 to several AKI and CKD models. Moreover, there are accumulating clinical data that urinary FABP1 can detect human AKI earlier than serum creatinine and can distinguish the risk population for AKI. Investigation with “humanized” FABP1 transgenic mice and measurement of clinical samples allowed us to develop urinary FABP1 as a new renal biomarker. Further clinical studies are necessary to confirm the potential of urinary FABP1 for clinical application.
TL;DR: Injection of antisense oligonucleotide morpholinos to elicit selective gene knockdown of ammonia (Rhag, Rhbg, and Rhcg1) or urea transporters (UT) was used as a tool to assess the relative importance of each transporter to nitrogen excretion in developing zebrafish (Danio rerio).
Abstract: Injection of antisense oligonucleotide morpholinos to elicit selective gene knockdown of ammonia (Rhag, Rhbg, and Rhcg1) or urea transporters (UT) was used as a tool to assess the relative importan...
TL;DR: It is shown in mice that Npt2a and NPT2c have independent roles in the regulation of plasma P(i) and bone mineralization.
Abstract: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessively inherited disorder, characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and...
TL;DR: This study indicates that Na-P(i) transport activity and NaPi-2b protein expression are differentially regulated in the duodenum vs. the jejunum and that postprandial upregulation of NaPi -2b could be a potential target for treatment of hyperphosphatemia.
Abstract: Hyperphosphatemia associated with chronic kidney disease is one of the factors that can promote vascular calcification, and intestinal Pi absorption is one of the pharmacological targets that prevents it. The type II Na-Pi cotransporter NaPi-2b is the major transporter that mediates Pi reabsorption in the intestine. The potential role and regulation of other Na-Pi transporters remain unknown. We have identified expression of the type III Na-Pi cotransporter PiT-1 in the apical membrane of enterocytes. Na-Pi transport activity and NaPi-2b and PiT-1 proteins are mostly expressed in the duodenum and jejunum of rat small intestine; their expression is negligible in the ileum. In response to a chronic low-Pi diet, there is an adaptive response restricted to the jejunum, with increased brush border membrane (BBM) Na-Pi transport activity and NaPi-2b, but not PiT-1, protein and mRNA abundance. However, in rats acutely switched from a low- to a high-Pi diet, there is an increase in BBM Na-Pi transport activity in the duodenum that is associated with an increase in BBM NaPi-2b protein abundance. Acute adaptive upregulation is restricted to the duodenum and induces an increase in serum Pi that produces a transient postprandial hyperphosphatemia. Our study, therefore, indicates that Na-Pi transport activity and NaPi-2b protein expression are differentially regulated in the duodenum vs. the jejunum and that postprandial upregulation of NaPi-2b could be a potential target for treatment of hyperphosphatemia.
TL;DR: It is demonstrated that Ephx2 gene deletion decreases blood pressure, attenuates renal inflammation, and ameliorates glomerular injury in DOCA-salt hypertension.
Abstract: Inhibition of soluble epoxide hydrolase (sEH) has been shown to be renal protective in rat models of salt-sensitive hypertension. Here, we hypothesize that targeted disruption of the sEH gene (Ephx...
TL;DR: It is demonstrated that pulmonary endothelial apoptosis is a direct mediator of the distant organ dysfunction during experimental AKI.
Abstract: Distant organ effects of acute kidney injury (AKI) are a leading cause of morbidity and mortality. While little is known about the underlying mechanisms, limited data suggest a role for inflammatio...
TL;DR: Long-term O-3FA supplementation can reduce or reverse upregulation of prooxidant, proinflammatory, and profibrotic pathways and attenuate tubulointerstitial fibrosis in the remnant kidney.
Abstract: Significant reduction of renal mass initiates a series of hemodynamic and nonhemodynamic events which lead to proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal failure. Lipid mediators derived from fatty acids participate in regulation of renal hemodynamic and nonhemodynamic processes that influence progression of renal disease. Composition of cellular fatty acids and hence related signaling responses are influenced by their dietary contents. Consumption of omega-3 fatty acids (O-3FA) has proven effective in mitigating atherosclerosis. We tested the hypothesis that O-3FA supplementation may retard progression and attenuate upregulation of pathways involved in oxidative stress, inflammation, and fibrosis in rats with renal mass reduction. Sprague-Dawley rats were subjected to 5/6 nephrectomy [chronic renal failure (CRF)] and randomly assigned to the untreated and O-3FA-treated (0.3 g.kg(-1).day(-1) by gastric gavage for 12 wk) groups. Sham-operated rats served as controls. The untreated CRF rats exhibited proteinuria, hypertension, azotemia, upregulations of renal tissue NAD(P)H oxidase, MCP-1, COX-2, PAI-1, TGF-beta, Smad2, alpha-smooth muscle actin, fibronectin, and hepatocyte growth factor, activation of ERK1/2 and NF-kappaB, downregulation of Smad7, intense mononuclear leukocyte infiltration, tubulointerstitial fibrosis, and glomerulosclerosis. O-3FA supplementation significantly lowered COX-2, NAD(P)H oxidase (NOX-4, gp91(phox), p47(phox), p22(phox)), PAI-1, TGF-beta, connective tissue growth factor, alpha-smooth muscle actin, fibronectin, Smad2, and MCP-1, raised Smad7, and attenuated ERK1/2 and NF-kappaB activation, tubulointerstitial fibrosis, and inflammation. Thus, long-term O-3FA supplementation can reduce or reverse upregulation of prooxidant, proinflammatory, and profibrotic pathways and attenuate tubulointerstitial fibrosis in the remnant kidney.
TL;DR: Current understanding of apical membrane delivery, cell surface stability, endocytosis, retrieval, and recycling of ENaC and the molecular partners that have so far been shown to participate in these processes are discussed.
Abstract: The epithelial Na+ channel (ENaC) is a major regulator of salt and water reabsorption in a number of epithelial tissues. Abnormalities in ENaC function have been directly linked to several human disease states including Liddle's syndrome, psuedohypoaldosteronism, and cystic fibrosis and may be implicated in states as diverse as salt-sensitive hypertension, nephrosis, and pulmonary edema. ENaC activity in epithelial cells is highly regulated both by open probability and number of channels. Open probability is regulated by a number of factors, including proteolytic processing, while ENaC number is regulated by cellular trafficking. This review discusses current understanding of apical membrane delivery, cell surface stability, endocytosis, retrieval, and recycling of ENaC and the molecular partners that have so far been shown to participate in these processes. We review known sites and mechanisms of hormonal regulation of trafficking by aldosterone, vasopressin, and insulin. While many details of the regulation of ENaC trafficking remain to be elucidated, knowledge of these mechanisms may provide further insights into ENaC activity in normal and disease states.
TL;DR: The studies suggest that the renal AQP1 expression level is possibly controlled by its urinary exosomal excretion and indicate that urinary exo-AQP1 is a novel urinary biomarker for renal I/R injury.
Abstract: Urinary exosomes, secreted into urine from renal epithelial cells, are known to contain many types of renal functional membrane proteins. Here, we studied whether renal ischemia-reperfusion (I/R) affects urinary exosomal aquaporin-1 (AQP1) excretion in rats subjected to renal I/R and patients who underwent renal transplantation. Immunoblotting studies demonstrated reduction of the urinary exosomal AQP1 level even at 6 h after renal I/R, and the level continued to be low over 96 h after I/R. Renal AQP1 mRNA and protein analyses revealed that the decreased excretion of urinary exosomal AQP1 is associated with renal AQP1 protein retention in the early phase and with a decreased expression level of renal AQP1 in the later phase of renal I/R injury. Decreased abundance of urinary exosomal AQP1 in a recipient patient was also observed at 48 h after renal allograft transplantation. No significant decrease in urinary exosomal AQP1 was observed in a rat model of nephropathy or in patients with proteinuria. Our studies suggest that the renal AQP1 expression level is possibly controlled by its urinary exosomal excretion and indicate that urinary exosomal AQP1 is a novel urinary biomarker for renal I/R injury.