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 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.

Role of histamine H1 receptor in pain perception: a study of the receptor gene knockout mice

2000 ◽  
Vol 391 (1-2) ◽  
pp. 81-89 ◽  
Author(s):  
Jalal Izadi Mobarakeh ◽  
Shinobu Sakurada ◽  
Sou Katsuyama ◽  
Motoharu Kutsuwa ◽  
Atsuo Kuramasu ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Pain Perception ◽  
Gene Knockout ◽  
Receptor Gene ◽  
H1 Receptor ◽  
Histamine H1 Receptor ◽  
Gene Knockout Mice

High incidence of gallstone formation in CCK-A receptor gene knockout mice: Essential role of CCK-A receptor in gallstone formation

2001 ◽  
Vol 120 (5) ◽  
pp. A180
Author(s):  
Kyoko Miyasaka ◽  
Shinji Suzuki ◽  
Yuko Sato ◽  
Setsuko Kanai ◽  
Takako Kawanami ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Essential Role ◽  
Gene Knockout ◽  
Receptor Gene ◽  
Gallstone Formation ◽  
High Incidence ◽  
Gene Knockout Mice

Enhanced antinociceptive effects of morphine in histamine H2 receptor gene knockout mice

2006 ◽  
Vol 51 (3) ◽  
pp. 612-622 ◽  
Author(s):  
Jalal Izadi Mobarakeh ◽  
Kazuhiro Takahashi ◽  
Shinobu Sakurada ◽  
Atsuo Kuramasu ◽  
Kazuhiko Yanai
Keyword(s):  
Knockout Mice ◽  
Gene Knockout ◽  
Receptor Gene ◽  
Histamine H2 Receptor ◽  
H2 Receptor ◽  
Antinociceptive Effects ◽  
Gene Knockout Mice

scholarly journals Role of the medullary collecting duct in potassium excretion in potassium-adapted animals

1981 ◽  
Vol 20 (5) ◽  
pp. 655-662 ◽  
Author(s):  
Donald A. Schon ◽  
Karen A. Backman ◽  
John P. Hayslett
Keyword(s):  
Collecting Duct ◽  
Potassium Excretion ◽  
Medullary Collecting Duct

Effects of expression of p53 and Gadd45 on osmotic tolerance of renal inner medullary cells

2006 ◽  
Vol 291 (2) ◽  
pp. F341-F349 ◽  
Author(s):  
Qi Cai ◽  
Natalia I. Dmitrieva ◽  
Joan D. Ferraris ◽  
Luis F. Michea ◽  
Jesus M. Salvador ◽  
...  
Keyword(s):  
Gene Knockout ◽  
Collecting Duct ◽  
Wild Type ◽  
Growth And Survival ◽  
Osmotic Tolerance ◽  
Rate Of Increase ◽  
Gene Knockout Mice ◽  
Collecting Duct Cells ◽  
Urinary Concentrating Ability

The response of renal inner medullary (IM) collecting duct cells (mIMCD3) to high NaCl involves increased expression of Gadd45 and p53, both of which have important effects on growth and survival of the cells. However, mIMCD3 cells, being immortalized by SV40, proliferate rapidly, which is known to sensitize cells to high NaCl, whereas IM cells in situ proliferate very slowly and survive much higher levels of NaCl. In the present studies, we have examined the importance of Gadd45 and p53 for survival of normal IM cells in their usual high-NaCl environment by using more slowly proliferating second-passage mouse inner medullary epithelial (p2mIME) cells and comparing cells from wild-type and gene knockout mice. Acutely elevating NaCl (and/or urea) reduces Gadd45a, but increases Gadd45b and Gadd45g mRNA, depending on the mix of NaCl and urea and the rate of increase of osmolality. Nevertheless, p2mIME cells from Gadd45b−/−, Gadd45g−/−, and Gadd45bg−/− mice survive elevation of NaCl (or urea) essentially the same as do wild-type cells. p53−/− Cells do not tolerate as high a concentration of NaCl (or urea) as p53+/+ cells, but urinary concentrating ability of p53−/− mice is normal, as is the histology of inner medullas from p53−/− and Gadd45abg−/− mice. Thus although Gadd45 and p53 may play roles in osmotically stressed mIMCD3 cells, we do not find that their expression makes an important difference, either for Gadd45 in slower proliferating p2mIME cells or for Gadd45 or p53 in normal inner medullary epithelial cells in situ.

Role of SNAP-23 in trafficking of H+-ATPase in cultured inner medullary collecting duct cells

2001 ◽  
Vol 280 (4) ◽  
pp. C775-C781 ◽  
Author(s):  
Abhijit Banerjee ◽  
Guangmu Li ◽  
Edward A. Alexander ◽  
John H. Schwartz
Keyword(s):  
Botulinum Toxin ◽  
Apical Membrane ◽  
Collecting Duct ◽  
Snare Complex ◽  
Attachment Protein ◽  
Regulated Exocytosis ◽  
Inner Medullary Collecting Duct ◽  
Sensitive Factor ◽  
Medullary Collecting Duct

The trafficking of H+-ATPase vesicles to the apical membrane of inner medullary collecting duct (IMCD) cells utilizes a mechanism similar to that described in neurosecretory cells involving soluble N-ethylmaleimide-sensitive factor attachment protein target receptor (SNARE) proteins. Regulated exocytosis of these vesicles is associated with the formation of SNARE complexes. Clostridial neurotoxins that specifically cleave the target (t-) SNARE, syntaxin-1, or the vesicle SNARE, vesicle-associated membrane protein-2, reduce SNARE complex formation, H+-ATPase translocation to the apical membrane, and inhibit H+ secretion. The purpose of these experiments was to characterize the physiological role of a second t-SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)-23, a homologue of the neuronal SNAP-25, in regulated exocytosis of H+-ATPase vesicles. Our experiments document that 25–50 nM botulinum toxin (Bot) A or E cleaves rat SNAP-23 and thereby reduces immunodetectable and35S-labeled SNAP-23 by >60% within 60 min. Addition of 25 nM BotE to IMCD homogenates reduces the amount of the 20 S-like SNARE complex that can be immunoprecipitated from the homogenate. Treatment of intact IMCD monolayers with BotE reduces the amount of H+-ATPase translocated to the apical membrane by 52 ± 2% of control and reduces the rate of H+ secretion by 77 ± 3% after acute cell acidification. We conclude that SNAP-23 is a substrate for botulinum toxin proteolysis and has a critical role in the regulation of H+-ATPase exocytosis and H+ secretion in these renal epithelial cells.

Response of rat inner medullary collecting duct to epidermal growth factor

1989 ◽  
Vol 256 (6) ◽  
pp. F1117-F1124 ◽  
Author(s):  
R. C. Harris
Keyword(s):  
Growth Factor ◽  
Binding Sites ◽  
Collecting Duct ◽  
Affinity Binding ◽  
Inner Medullary Collecting Duct ◽  
Duct Cells ◽  
Epidermal Growth ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct

Urine is an abundant source of epidermal growth factor (EGF) and prepro-EGF has been localized to the thick ascending limb and distal convoluted tubule of the kidney. However, the functional role of EGF in the kidney is poorly understood. Determination of EGF receptors and functional responses to EGF in intrarenal structures distal to the site of renal EGF production may prove critical to our understanding of the role of this peptide. These studies were designed to investigate the response to EGF of rat inner medullary collecting duct cells in culture and in freshly isolated suspensions. Primary cultures of inner medullary collecting duct cells demonstrated equilibrium binding of 125I-labeled EGF at 4 and 23 degrees C. At 23 degrees C, there was 89 +/- 1% specific binding (n = 30). Scatchard analysis of 125I-EGF binding suggested the presence of both high-affinity binding with a dissociation constant (Kd) of 5 X 10(-10) M and maximal binding sites (Ro) of 2.7 X 10(3) binding sites/cell and low-affinity binding, with Kd of 8.3 X 10(-9) M and Ro of 1.8 X 10(4) binding sites/cell. Bound EGF, 68 +/- 3%, was internalized by 45 min. EGF binding was not inhibited by antidiuretic hormone, atrial natriuretic peptide or bradykinin at 23 degrees C, but there was concentration-dependent inhibition of binding by transforming growth factor-alpha. Incubation with phorbol myristate acetate decreased 125I-EGF binding in a concentration-dependent manner. 125I-EGF binding was also demonstrated in freshly isolated suspensions of rat inner medullary collecting duct cells.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Role of PKC and AMPK in hypertonicity-stimulated water reabsorption in rat inner medullary collecting ducts

2019 ◽  
Vol 316 (2) ◽  
pp. F253-F262 ◽  
Author(s):  
Josephine K. Liwang ◽  
Joseph A. Ruiz ◽  
Lauren M. LaRocque ◽  
Fitra Rianto ◽  
Fuying Ma ◽  
...  
Keyword(s):  
Water Permeability ◽  
Collecting Duct ◽  
Adenosine Monophosphate ◽  
Osmotic Water Permeability ◽  
Water Reabsorption ◽  
Compound C ◽  
Ampk Phosphorylation ◽  
Osmotic Water ◽  
Medullary Collecting Duct

Hypertonicity increases water permeability, independently of vasopressin, in the inner medullary collecting duct (IMCD) by increasing aquaporin-2 (AQP2) membrane accumulation. We investigated whether protein kinase C (PKC) and adenosine monophosphate kinase (AMPK) are involved in hypertonicity-regulated water permeability. Increasing perfusate osmolality from 150 to 290 mosmol/kgH2O and bath osmolality from 290 to 430 mosmol/kgH2O significantly stimulated osmotic water permeability. The PKC inhibitors chelerythrine (10 µM) and rottlerin (50 µM) significantly reversed the increase in osmotic water permeability stimulated by hypertonicity in perfused rat terminal IMCDs. Chelerythrine significantly increased phosphorylation of AQP2 at S261 but not at S256. Previous studies show that AMPK is stimulated by osmotic stress. We tested AMPK phosphorylation under hypertonic conditions. Hypertonicity significantly increased AMPK phosphorylation in inner medullary tissues. Blockade of AMPK with Compound C decreased hypertonicity-stimulated water permeability but did not alter phosphorylation of AQP2 at S256 and S261. AICAR, an AMPK stimulator, caused a transient increase in osmotic water permeability and increased phosphorylation of AQP2 at S256. When inner medullary tissue was treated with the PKC activator phorbol dibutyrate (PDBu), the AMPK activator metformin, or both, AQP2 phosphorylation at S261 was decreased with PDBu or metformin alone, but there was no additive effect on phosphorylation with PDBu and metformin together. In conclusion, hypertonicity regulates water reabsorption by activating PKC. Hypertonicity-stimulated water reabsorption by PKC may be related to the decrease in endocytosis of AQP2. AMPK activation promotes water reabsorption, but the mechanism remains to be determined. PKC and AMPK do not appear to act synergistically to regulate water reabsorption.

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