scholarly journals Lithium: a versatile tool for understanding renal physiology

2013 ◽  
Vol 304 (9) ◽  
pp. F1139-F1149 ◽  
Author(s):  
Bellamkonda K. Kishore ◽  
Carolyn M. Ecelbarger
Keyword(s):  
Diabetes Insipidus ◽  
Glycogen Synthase ◽  
Purinergic Signaling ◽  
Collecting Duct ◽  
Renal Physiology ◽  
Urinary Concentration ◽  
Paradigm Shifts ◽  
Molecular Physiology ◽  
Versatile Tool

By virtue of its unique interactions with kidney cells, lithium became an important research tool in renal physiology and pathophysiology. Investigators have uncovered the intricate relationships of lithium with the vasopressin and aldosterone systems, and the membrane channels or transporters regulated by them. While doing so, their work has also led to 1) questioning the role of adenylyl cyclase activity and prostaglandins in lithium-induced suppression of aquaporin-2 gene transcription; 2) unraveling the role of purinergic signaling in lithium-induced polyuria; and 3) highlighting the importance of the epithelial sodium channel (ENaC) in lithium-induced nephrogenic diabetes insipidus (NDI). Lithium-induced remodeling of the collecting duct has the potential to shed new light on collecting duct remodeling in disease conditions, such as diabetes insipidus. The finding that lithium inhibits glycogen synthase kinase-3β (GSK3β) has opened an avenue for studies on the role of GSK3β in urinary concentration, and GSK isoforms in renal development. Finally, proteomic and metabolomic profiling of the kidney and urine in rats treated with lithium is providing insights into how the kidney adapts its metabolism in conditions such as acquired NDI and the multifactorial nature of lithium-induced NDI. This review provides state-of-the-art knowledge of lithium as a versatile tool for understanding the molecular physiology of the kidney, and a comprehensive view of how this tool is challenging some of our long-standing concepts in renal physiology, often with paradigm shifts, and presenting paradoxical situations in renal pathophysiology. In addition, this review points to future directions in research where lithium can lead the renal community.

scholarly journals Potential role of purinergic signaling in urinary concentration in inner medulla: insights from P2Y2 receptor gene knockout mice

2008 ◽  
Vol 295 (6) ◽  
pp. F1715-F1724 ◽  
Author(s):  
Yue Zhang ◽  
Jeff M. Sands ◽  
Donald E. Kohan ◽  
Raoul D. Nelson ◽  
Christopher F. Martin ◽  
...  
Keyword(s):  
Gene Knockout ◽  
Purinergic Signaling ◽  
Collecting Duct ◽  
Receptor Gene ◽  
Urinary Concentration ◽  
P2y2 Receptor ◽  
Concentration Gradients ◽  
Gene Knockout Mice ◽  
Medullary Collecting Duct

Osmotic reabsorption of water through aquaporin-2 (AQP2) in the inner medulla is largely dependent on the urea concentration gradients generated by urea transporter (UT) isoforms. Vasopressin (AVP) increases expression of both AQP2 and UT-A isoforms. Activation of the P2Y2 receptor (P2Y2-R) in the medullary collecting duct inhibits AVP-induced water flow. To gain further insights into the overarching effect of purinergic signaling on urinary concentration, we compared the protein abundances of AQP2 and UT-A isoforms between P2Y2-R knockout (KO) and wild-type (WT) mice under basal conditions and following AVP administration. Under basal conditions (a gel diet for 10 days), KO mice concentrated urine to a significantly higher degree, with 1.8-, 1.66-, and 1.29-fold higher protein abundances of AQP2, UT-A1, and UT-A2, respectively, compared with WT, despite comparable circulating AVP levels in both groups. Infusion of 1-desamino-8-d-arginine vasopressin (dDAVP; desmopressin; 1 ng/h sc) for 5 days resulted in 2.14-, 2.6-, and 2.22-fold higher protein abundances of AQP2, AQP3, and UT-A1, respectively, in the inner medullas of KO mice compared with WT mice. In response to acute (45 min) stimulation by AVP (0.2 unit/mouse sc), UT-A1 protein increased by 1.39- and 1.54-fold in WT and KO mice, respectively. These data suggest that genetic deletion of P2Y2-R results in increased abundances of key proteins involved in urinary concentration in the inner medulla, both under basal conditions and following AVP administration. Thus purinergic regulation may play a potential overarching role in balancing the effect of AVP on the urinary concentration mechanism.

scholarly journals Differential expression and targeting of endogenous Arf1 and Arf6 small GTPases in kidney epithelial cells in situ

2004 ◽  
Vol 286 (4) ◽  
pp. C768-C778 ◽  
Author(s):  
Jaafar El Annan ◽  
Dennis Brown ◽  
Sylvie Breton ◽  
Sylvain Bourgoin ◽  
Dennis A. Ausiello ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Western Blotting ◽  
Collecting Duct ◽  
Small Gtpases ◽  
Renal Physiology ◽  
Principal Cells ◽  
Arf Gtpases ◽  
Kidney Epithelial Cells

ADP-ribosylation factors (Arfs) are small GTPases that regulate vesicular trafficking in exo- and endocytotic pathways. As a first step in understanding the role of Arfs in renal physiology, immunocytochemistry and Western blotting were performed to characterize the expression and targeting of Arf1 and Arf6 in epithelial cells in situ. Arf1 and Arf6 were associated with apical membranes and subapical vesicles in proximal tubules, where they colocalized with megalin. Arf1 was also apically expressed in the distal tubule, connecting segment, and collecting duct (CD). Arf1 was abundant in intercalated cells (IC) and colocalized with V-ATPase in A-IC (apical) and B-IC (apical and/or basolateral). In contrast, Arf6 was associated exclusively with basolateral membranes and vesicles in the CD. In the medulla, basolateral Arf6 was detectable mainly in A-IC. Expression in principal cells became weaker throughout the outer medulla, and Arf6 was not detectable in principal cells in the inner medulla. In some kidney epithelial cells Arf1 but not Arf6 was also targeted to a perinuclear patch, where it colocalized with TGN38, a marker of the trans-Golgi network. Quantitative Western blotting showed that expression of endogenous Arf1 was 26–180 times higher than Arf6. These data indicate that Arf GTPases are expressed and targeted in a cell- and membrane-specific pattern in kidney epithelial cells in situ. The results provide a framework on which to base and interpret future studies on the role of Arf GTPases in the multitude of cellular trafficking events that occur in renal tubular epithelial cells.

The Effect of Vasopressin on the Reabsorption of Sodium, Potassium and Urea by the Renal Tubules in Man

1970 ◽  
Vol 39 (4) ◽  
pp. 517-527 ◽  
Author(s):  
M. A. Barraclough ◽  
N. F. Jones
Keyword(s):  
Diabetes Insipidus ◽  
Collecting Duct ◽  
Normal Subjects ◽  
Solute Concentration ◽  
Tubular Reabsorption ◽  
Urinary Concentration ◽  
Renal Tubules ◽  
Confidence Limits ◽  
Patients With Diabetes ◽  
Sodium And Potassium

1. Changes in the urinary concentrations or urine/plasma (U/P) ratios of creatinine, urea, sodium and potassium were determined during the transition from water diuresis to antidiuresis when normal subjects and patients with diabetes insipidus were given injections of vasopressin. 2. In confirmation of previous work, it was found that after vasopressin administration the urinary concentration or U/P ratio of urea rose to a lesser degree than that of creatinine, indicating an increase in the tubular reabsorption of urea. 3. The urinary concentration, or U/P ratio, of sodium also rose to a lesser degree than that of creatinine. Thus vasopressin also increases the tubular reabsorption of sodium. 4. In contrast, the urinary concentration or U/P ratio of potassium tended to rise more than that of creatinine, indicating a decrease in the net tubular reabsorption of potassium. 5. Quantitative changes in the tubular handling of these urinary solutes were assessed by calculating the ratio—solute concentration during antidiuresis/solute concentration during diuresis—and then expressing this as a percentage of the corresponding ratio for creatinine. In subjects on a normal or high sodium intake the values thus obtained were: urea 72% (99% confidence limits 65–81%); sodium 79% (99% confidence limits 68–92%) and potassium 119% (99% confidence limits 102–139%). 6. In salt depleted subjects the values for these ratios were: urea 63% (99% confidence limits 60–65%) and sodium 36% (99% confidence limits 33–40%). Vasopressin had no consistent effect on potassium reabsorption in salt depleted subjects. 7. The effects of vasopressin on normal subjects and on patients with diabetes insipidus were similar. 8. It is suggested that these effects of vasopressin on sodium and potassium handling by the kidney occur in the collecting duct.

scholarly journals A peek into Epac physiology in the kidney

2019 ◽  
Vol 317 (5) ◽  
pp. F1094-F1097 ◽  
Author(s):  
Viktor N. Tomilin ◽  
Oleh Pochynyuk
Keyword(s):  
Current Knowledge ◽  
Collecting Duct ◽  
Critical Role ◽  
Second Messenger ◽  
Electrolyte Transport ◽  
Urinary Concentration ◽  
Renal Epithelium ◽  
Downstream Effector

cAMP is a critical second messenger of numerous endocrine signals affecting water-electrolyte transport in the renal tubule. Exchange protein directly activated by cAMP (Epac) is a relatively recently discovered downstream effector of cAMP, having the same affinity to the second messenger as protein kinase A, the classical cAMP target. Two Epac isoforms, Epac1 and Epac2, are abundantly expressed in the renal epithelium, where they are thought to regulate water and electrolyte transport, particularly in the proximal tubule and collecting duct. Recent characterization of renal phenotype in mice lacking Epac1 and Epac2 revealed a critical role of the Epac signaling cascade in urinary concentration as well as in Na+ and urea excretion. In this review, we aim to critically summarize current knowledge of Epac relevance for renal function and to discuss the applicability of Epac-based strategies in the regulation of systemic water-electrolyte homeostasis.

scholarly journals The renal H+-K+-ATPases: physiology, regulation, and structure

2010 ◽  
Vol 298 (1) ◽  
pp. F12-F21 ◽  
Author(s):  
Michelle L. Gumz ◽  
I. Jeanette Lynch ◽  
Megan M. Greenlee ◽  
Brian D. Cain ◽  
Charles S. Wingo
Keyword(s):  
Atp Hydrolysis ◽  
Collecting Duct ◽  
Renal Physiology ◽  
Acid Base Balance ◽  
Α Subunit ◽  
New Information ◽  
Base Balance ◽  
Related Enzyme ◽  
Molecular Modeling Studies

The H+-K+-ATPases are ion pumps that use the energy of ATP hydrolysis to transport protons (H+) in exchange for potassium ions (K+). These enzymes consist of a catalytic α-subunit and a regulatory β-subunit. There are two catalytic subunits present in the kidney, the gastric or HKα1isoform and the colonic or HKα2isoform. In this review we discuss new information on the physiological function, regulation, and structure of the renal H+-K+-ATPases. Evaluation of enzymatic functions along the nephron and collecting duct and studies in HKα1and HKα2knockout mice suggest that the H+-K+-ATPases may function to transport ions other than protons and potassium. These reports and recent studies in mice lacking both HKα1and HKα2suggest important roles for the renal H+-K+-ATPases in acid/base balance as well as potassium and sodium homeostasis. Molecular modeling studies based on the crystal structure of a related enzyme have made it possible to evaluate the structures of HKα1and HKα2and provide a means to study the specific cation transport properties of H+-K+-ATPases. Studies to characterize the cation specificity of these enzymes under different physiological conditions are necessary to fully understand the role of the H+-K+ATPases in renal physiology.

Inherited secondary nephrogenic diabetes insipidus: concentrating on humans

2013 ◽  
Vol 304 (8) ◽  
pp. F1037-F1042 ◽  
Author(s):  
D. Bockenhauer ◽  
D. G. Bichet
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Collecting Duct ◽  
Lithium Treatment ◽  
Water Channel ◽  
Underlying Mechanism ◽  
Bartter Syndrome ◽  
Experimental Models ◽  
Urinary Concentration ◽  
Apparent Mineralocorticoid Excess

The study of human physiology is paramount to understanding disease and developing rational and targeted treatments. Conversely, the study of human disease can teach us a lot about physiology. Investigations into primary inherited nephrogenic diabetes insipidus (NDI) have contributed enormously to our understanding of the mechanisms of urinary concentration and identified the vasopressin receptor AVPR2, as well as the water channel aquaporin-2 (AQP2), as key players in water reabsorption in the collecting duct. Yet, there are also secondary forms of NDI, for instance as a complication of lithium treatment. The focus of this review is secondary NDI associated with inherited human diseases, such as Bartter syndrome or apparent mineralocorticoid excess. Currently, the underlying pathophysiology of this inherited secondary NDI is unclear, but there appears to be true AQP2 deficiency. To better understand the underlying mechanism(s), collaboration between clinical and experimental physiologists is essential to further investigate these observations in appropriate experimental models.

scholarly journals Physiology and Pathophysiology of Renal Aquaporins

1999 ◽  
Vol 10 (3) ◽  
pp. 647-663
Author(s):  
SØREN NIELSEN ◽  
TAE-HWAN KWON ◽  
BIRGITTE MØNSTER CHRISTENSEN ◽  
DOMINIQUE PROMENEUR ◽  
JØRGEN FRØKIÆR ◽  
...  
Keyword(s):  
Water Balance ◽  
Diabetes Insipidus ◽  
Proximal Tubule ◽  
Nephrogenic Diabetes Insipidus ◽  
Collecting Duct ◽  
Water Channels ◽  
Apical Plasma Membrane ◽  
Water Reabsorption ◽  
Balance Disorders

Abstract. The discovery of aquaporin membrane water channels by Agre and coworkers answered a long-standing biophysical question of how water specifically crosses biologic membranes, and provided insight, at the molecular level, into the fundamental physiology of water balance and the pathophysiology of water balance disorders. Of nine aquaporin isoforms, at least six are known to be present in the kidney at distinct sites along the nephron and collecting duct. Aquaporin-1 (AQP1) is extremely abundant in the proximal tubule and descending thin limb, where it appears to provide the chief route for proximal nephron water reabsorption. AQP2 is abundant in the collecting duct principal cells and is the chief target for vasopressin to regulate collecting duct water reabsorption. Acute regulation involves vasopressin-regulated trafficking of AQP2 between an intracellular reservoir and the apical plasma membrane. In addition, AQP2 is involved in chronic/adaptational regulation of body water balance achieved through regulation of AQP2 expression. Importantly, multiple studies have now identified a critical role of AQP2 in several inherited and acquired water balance disorders. This concerns inherited forms of nephrogenic diabetes insipidus and several, much more common acquired types of nephrogenic diabetes insipidus where AQP2 expression and/or targeting are affected. Conversely, AQP2 expression and targeting appear to be increased in some conditions with water retention such as pregnancy and congestive heart failure. AQP3 and AQP4 are basolateral water channels located in the kidney collecting duct, and AQP6 and AQP7 appear to be expressed at lower abundance at several sites including the proximal tubule. This review focuses mainly on the role of AQP2 in water balance regulation and in the pathophysiology of water balance disorders.

scholarly journals Purinergic signaling is enhanced in the absence of UT-A1 and UT-A3

2019 ◽  
Author(s):  
Nathaniel J. Himmel ◽  
Richard T. Rogers ◽  
Sara K. Redd ◽  
Yirong Wang ◽  
Mitsi A. Blount
Keyword(s):  
Purinergic Signaling ◽  
Collecting Duct ◽  
Elevated Serum ◽  
Urinary Concentration ◽  
Mrna Levels ◽  
Urea Transport ◽  
Tissue Samples ◽  
Protein Levels ◽  
Summary Statement ◽  
Renal Tubular

AbstractATP is an important paracrine regulator of renal tubular water and urea transport. The activity of P2Y2, the predominant P2Y receptor of the medullary collecting duct, is mediated by ATP, and modulates urinary concentration. To investigate the role of purinergic signaling in the absence of urea transport in the collecting duct, we housed wild-type (WT) and UT-A1/A3 null (UT-A1/A3 KO) mice in metabolic cages to monitor urine output, and collected tissue samples for analysis. We confirmed that UT-A1/A3 KO mice are polyuric, and concurrently observed lower levels of urinary cAMP as compared to WT, despite elevated serum vasopressin (AVP) levels. Because P2Y2 inhibits AVP-stimulated transport by dampening cAMP synthesis, we suspected that, similar to other models of AVP-resistant polyuria, purinergic signaling is increased in UT-A1/A3 KO mice. In fact, we observed that both urinary ATP and purinergic-mediated prostanoid (PGE2) levels were elevated. Tissue analysis shows that P2Y2 mRNA levels remain unchanged, while P2Y2 protein levels are elevated in KO mice. Collectively, our data suggest that the reduction of medullary osmolality due to the lack of UT-A1 and UT-A3 induces an AVP-resistant polyuria that is possibly exacerbated by, or at least correlated with, enhanced purinergic signaling.Summary statementPhysiological analyses suggest that mice lacking urea transporters have increased renal purinergic signaling, perhaps contributing to previously observed vasopressin-resistant polyurias.

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