scholarly journals Mouse Models and the Urinary Concentrating Mechanism in the New Millennium

2007 ◽  
Vol 87 (4) ◽  
pp. 1083-1112 ◽  
Author(s):  
Robert A. Fenton ◽  
Mark A. Knepper
Keyword(s):  
Water Conservation ◽  
Collecting Duct ◽  
Tubuloglomerular Feedback ◽  
Water Excretion ◽  
Renal Transporters ◽  
Concentrating Mechanism ◽  
New Information ◽  
Renal Micropuncture ◽  
Key Questions

Our understanding of urinary concentrating and diluting mechanisms at the end of the 20th century was based largely on data from renal micropuncture studies, isolated perfused tubule studies, tissue analysis studies and anatomical studies, combined with mathematical modeling. Despite extensive data, several key questions remained to be answered. With the advent of the 21st century, a new approach, transgenic and knockout mouse technology, is providing critical new information about urinary concentrating processes. The central goal of this review is to summarize findings in transgenic and knockout mice pertinent to our understanding of the urinary concentrating mechanism, focusing chiefly on mice in which expression of specific renal transporters or receptors has been deleted. These include the major renal water channels (aquaporins), urea transporters, ion transporters and channels (NHE3, NKCC2, NCC, ENaC, ROMK, ClC-K1), G protein-coupled receptors (type 2 vasopressin receptor, prostaglandin receptors, endothelin receptors, angiotensin II receptors), and signaling molecules. These studies shed new light on several key questions concerning the urinary concentrating mechanism including: 1) elucidation of the role of water absorption from the descending limb of Henle in countercurrent multiplication, 2) an evaluation of the feasibility of the passive model of Kokko-Rector and Stephenson, 3) explication of the role of inner medullary collecting duct urea transport in water conservation, 4) an evaluation of the role of tubuloglomerular feedback in maintenance of appropriate distal delivery rates for effective regulation of urinary water excretion, and 5) elucidation of the importance of water reabsorption in the connecting tubule versus the collecting duct for maintenance of water balance.

scholarly journals Gamble's “economy of water” revisited: studies in urea transporter knockout mice

2006 ◽  
Vol 291 (1) ◽  
pp. F148-F154 ◽  
Author(s):  
Robert A. Fenton ◽  
Chung-Lin Chou ◽  
Holly Sowersby ◽  
Craig P. Smith ◽  
Mark A. Knepper
Keyword(s):  
Collecting Duct ◽  
Specific Interaction ◽  
Special Role ◽  
Wild Type ◽  
Osmotic Diuresis ◽  
Nacl Transport ◽  
Water Excretion ◽  
Concentrating Mechanism ◽  
Excretion Rates

The Gamble phenomenon (initially described over 70 years ago as “an economy of water in renal function referable to urea”) suggested that urea plays a special role in the urinary concentrating mechanism and that the concentrating mechanism depends in some complex way on an interaction between NaCl and urea. In this study, the role of collecting duct urea transporters in the Gamble phenomenon was investigated in wild-type mice and mice in which the inner medulla collecting duct (IMCD) facilitative urea transporters, UT-A1 and UT-A3, had been deleted ( UT-A1/3−/− mice). The general features of the Gamble phenomenon were confirmed in wild-type mice, namely 1) the water requirement for the excretion of urea is less than for the excretion of an osmotically equivalent amount of NaCl; and 2) when fed various mixtures of urea and salt in the diet, less water is required for the excretion of the two substances together than the amount of water needed for the excretion of the two substances separately. In UT-A1/3−/− mice both of these elements of the phenomenon were absent, indicating that IMCD urea transporters play a central role in the Gamble phenomenon. A titration study in which wild-type mice were given progressively increasing amounts of urea showed that the ability of the kidney to reabsorb urea was saturable, resulting in osmotic diuresis above excretion rates of ∼6,000 μosmol/day. In the same titration experiments, when increasing amounts of NaCl were added to the diet, mice were unable to increase urinary NaCl concentrations to >420 mM, resulting in osmotic diuresis at NaCl excretion rates of ∼3,500 μosmol/day. Thus both urea and NaCl can induce osmotic diuresis when large amounts are given, supporting the conclusion that the decrease in water excretion with mixtures of urea and NaCl added to the diet (compared with pure NaCl or urea) is due to the separate abilities of urea and NaCl to induce osmotic diuresis, rather than to any specific interaction of urea transport and NaCl transport at an epithelial level.

Abstract 062: Regulation of Nephron Afferent Arteriole Resistance in Obesity: Role of Connecting Tubule Glomerular Feedback

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sumit R Monu ◽  
Mani Maheshwari ◽  
Hong Wang ◽  
Ed Peterson ◽  
Oscar Carretero
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
Connecting Tubule ◽  
Single Nephron ◽  
Renal Micropuncture ◽  
The Difference

In obesity, renal damage is caused by increase in renal blood flow (RBF), glomerular capillary pressure (P GC ), and single nephron glomerular filtration rate but the mechanism behind this alteration in renal hemodynamics is unclear. P GC is controlled mainly by the afferent arteriole (Af-Art) resistance. Af-Art resistance is regulated by mechanism similar to that in other arterioles and in addition, it is regulated by two intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to an increase in sodium chloride (NaCl) in the macula densa, via sodium–potassium-2-chloride cotransporter-2 (NKCC2) and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation and is mediated by connecting tubule via epithelial sodium channel (ENaC). CTGF is blocked by the ENaC inhibitor benzamil. Attenuation of TGF reduces Af-Art resistance and allows systemic pressure to get transmitted to the glomerulus that causes glomerular barotrauma/damage. In the current study, we tested the hypothesis that TGF is attenuated in obesity and that CTGF contributes to this effect. We used Zucker obese rats (ZOR) while Zucker lean rats (ZLR) served as controls. We performed in-vivo renal micropuncture of individual rat nephrons while measuring stop-flow pressure (P SF ), an index of P GC. TGF response was measured as a decrease in P SF induced by changing the rate of late proximal perfusion from 0 to 40nl/min in stepwise manner.CTGF was calculated as the difference of P SF value between vehicle and benzamil treatment, at each perfusion rate. Maximal TGF response was significantly less in ZOR (6.16 ± 0.52 mmHg) when compared to the ZLR (8.35 ± 1.00mmHg), p<0.05 , indicating TGF resetting in the ZOR. CTGF was significantly higher in ZOR (6.33±1.95 mmHg) when compared to ZLR (1.38±0.89 mmHg), p<0.05 . When CTGF was inhibited with the ENaC blocker Benzamil (1μM), maximum P SF decrease was 12.30±1.72 mmHg in ZOR and 10.60 ± 1.73 mmHg in ZLR, indicating that blockade of CTGF restored TGF response in ZOR. These observations led us to conclude that TGF is reset in ZOR and that enhanced CTGF contributes to this effect. Increase in CTGF may explain higher renal blood flow, increased P GC and higher glomerular damage in obesity.

scholarly journals Extracellular Nucleotides and P2 Receptors in Renal Function

2020 ◽  
Vol 100 (1) ◽  
pp. 211-269 ◽  
Author(s):  
Volker Vallon ◽  
Robert Unwin ◽  
Edward W. Inscho ◽  
Jens Leipziger ◽  
Bellamkonda K. Kishore
Keyword(s):  
Blood Flow ◽  
Fluid Transport ◽  
Collecting Duct ◽  
Extracellular Nucleotides ◽  
Tubuloglomerular Feedback ◽  
P2 Receptor ◽  
Extracellular Nucleotide ◽  
Membrane Expression ◽  
Receptor System

The understanding of the nucleotide/P2 receptor system in the regulation of renal hemodynamics and transport function has grown exponentially over the last 20 yr. This review attempts to integrate the available data while also identifying areas of missing information. First, the determinants of nucleotide concentrations in the interstitial and tubular fluids of the kidney are described, including mechanisms of cellular release of nucleotides and their extracellular breakdown. Then the renal cell membrane expression of P2X and P2Y receptors is discussed in the context of their effects on renal vascular and tubular functions. Attention is paid to effects on the cortical vasculature and intraglomerular structures, autoregulation of renal blood flow, tubuloglomerular feedback, and the control of medullary blood flow. The role of the nucleotide/P2 receptor system in the autocrine/paracrine regulation of sodium and fluid transport in the tubular and collecting duct system is outlined together with its role in integrative sodium and fluid homeostasis and blood pressure control. The final section summarizes the rapidly growing evidence indicating a prominent role of the extracellular nucleotide/P2 receptor system in the pathophysiology of the kidney and aims to identify potential therapeutic opportunities, including hypertension, lithium-induced nephropathy, polycystic kidney disease, and kidney inflammation. We are only beginning to unravel the distinct physiological and pathophysiological influences of the extracellular nucleotide/P2 receptor system and the associated therapeutic perspectives.

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.

Role of the renin–angiotensin–aldosterone system in collecting duct-derived endothelin-1 regulation of blood pressureThis article is one of a selection of papers published in the special issue (part 1 of 2) on Forefronts in Endothelin.

2008 ◽  
Vol 86 (6) ◽  
pp. 329-336 ◽  
Author(s):  
Yuqiang Ge ◽  
Yufeng Huang ◽  
Donald E. Kohan
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
Plasma Renin ◽  
Similar Degree ◽  
Water Excretion ◽  
Renin Angiotensin ◽  
Endothelin 1 ◽  
And Control ◽  
Renin Content

Renal collecting duct (CD)-specific knockout of endothelin-1 (ET-1) causes hypertension and impaired Na excretion. A previous study noted failure to suppress the renin–angiotensin–aldosterone axis in these knockout (KO) mice, hence the current investigation was undertaken to examine the role of this system in CD ET-1 KO. Renal renin content was similar in kidneys from CD ET-1 KO and control mice during normal Na intake; high-Na intake suppressed renal renin content to a similar degree in KO and control. Plasma renin concentrations paralleled changes in renal renin content. Valsartan, an angiotensin receptor blocker (ARB), abolished the hypertension in CD ET-1 KO mice during normal Na intake. High-Na intake + ARB treatment increased blood pressure in CD ET-1 KO, but not in controls. High-Na intake was associated with reduced Na excretion in CD ET-1 KO animals, but no changes in water excretion or creatinine clearance were noted. Spironolactone, an aldosterone antagonist, also normalized blood pressure in CD ET-1 KO mice during normal Na intake, whereas high-Na intake + spironolactone raised blood pressure only in CD ET-1 KO animals. In summary, hypertension in CD ET-1 KO is partly due to angiotensin II and aldosterone. We speculate that CD-derived ET-1 may regulate, via a novel pathway, renal renin production.

The effect of water deprivation on signalling molecules that utilise cGMP in the spinifex hopping mouse Notomys alexis.

2004 ◽  
Vol 26 (2) ◽  
pp. 191 ◽  
Author(s):  
RA Heimeier ◽  
RC Bartolo ◽  
JA Donald
Keyword(s):  
Water Conservation ◽  
Water Deprivation ◽  
Free Water ◽  
Distal Colon ◽  
Proximal Colon ◽  
Mrna Levels ◽  
Physiological Mechanisms ◽  
Water Excretion ◽  
Signalling Molecules

In mammals the natriuretic and guanylin peptides influence renal and intestinal fluid content and electrolyte transport by binding to and activating guanylyl cyclase (GC) receptors that in turn stimulate production of the intracellular second messenger guanosine 3?:5?-cyclic monophospate (cGMP). However, the role of natriuretic and guanylin peptides in desert mammals is not understood. The spinifex hopping-mouse (Notomys alexis), has a suite of behavioural and physiological mechanisms that permits survival for extended periods without access to free water. Because signalling molecules that generate cGMP are known to promote water excretion, it was predicted that natriuretic and guanylin peptide synthesis would be down regulated in water-deprived N. alexis, and thus reduce the amount of water lost in the urine and faeces. However, in the kidney ANP and GC-A mRNA levels were increased in water-deprived mice, but CNP and GC-B mRNA levels were decreased. Water deprivation increased guanylin and uroguanylin mRNA expression in the distal colon, but it remained unchanged in the kidney and proximal colon. The expression of GC-C mRNA increased in the proximal colon but not in the distal colon. This study shows that water deprivation differentially affects the expression of regulatory molecules that stimulate cGMP production, and that a down-regulation associated with water conservation does not uniformly occur.

scholarly journals Role of connecting tubule glomerular feedback in obesity related renal damage

2018 ◽  
Vol 315 (6) ◽  
pp. F1708-F1713 ◽  
Author(s):  
Sumit R. Monu ◽  
Mani Maheshwari ◽  
Edward L. Peterson ◽  
Oscar A. Carretero
Keyword(s):  
Sodium Channel ◽  
Renal Damage ◽  
Epithelial Sodium Channel ◽  
Indirect Measurement ◽  
Tubuloglomerular Feedback ◽  
Nacl Transport ◽  
Connecting Tubule ◽  
Renal Micropuncture ◽  
Flow Pressure

Zucker obese rats (ZOR) have higher glomerular capillary pressure (PGC) that can cause renal damage. PGC is controlled by afferent (Af-Art) and efferent arteriole (Ef-Art) resistance. Af-Art resistance is regulated by factors that regulate other arterioles, such as myogenic response. In addition, it is also regulated by 2 intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to increased NaCl in the macula densa and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in NaCl transport in the connecting tubule via the epithelial sodium channel. Since CTGF is an Af-Art dilatory mechanism, we hypothesized that increased CTGF contributes to TGF attenuation, which in turn increases PGC in ZOR. We performed a renal micropuncture experiment and measured stop-flow pressure (PSF), which is an indirect measurement of PGC in ZOR. Maximal TGF response at 40 nl/min was attenuated in ZOR (4.47 ± 0.60 mmHg) in comparison to the Zucker lean rats (ZLR; 8.54 ± 0.73 mmHg, P < 0.05), and CTGF was elevated in ZOR (5.34 ± 0.87 mmHg) compared with ZLR (1.12 ± 1.28 mmHg, P < 0.05). CTGF inhibition with epithelial sodium channel blocker normalized the maximum PSF change in ZOR indicating that CTGF plays a significant role in TGF attenuation (ZOR, 10.67 ± 1.07 mmHg vs. ZLR, 9.5 ± 1.53 mmHg). We conclude that enhanced CTGF contributes to TGF attenuation in ZOR and potentially contribute to progressive renal damage.

Renal tubular actions of ANF

1991 ◽  
Vol 69 (10) ◽  
pp. 1537-1545 ◽  
Author(s):  
Mark A. Knepper ◽  
Scott P. Lankford ◽  
Yoshio Terada
Keyword(s):  
Proximal Tubule ◽  
Collecting Duct ◽  
Volume Overload ◽  
Tubuloglomerular Feedback ◽  
Thick Ascending Limb ◽  
Short Term ◽  
Nacl Transport ◽  
Water Excretion ◽  
Collecting Ducts ◽  
Renal Tubular

Many of the earliest investigations of the renal effects of atrial natriuretic factor (ANF) pointed to the glomerulus as a major site of the peptide's action. More recently, there have been many reports showing various effects of ANF on renal tubular epithelia, including collecting ducts, thick ascending limbs of Henle's loop, thin limbs of Henle's loops, and proximal tubules. The purpose of this review is to summarize the evidence for renal tubular actions of ANF and analyze it from the perspective of the specialized functions of the individual nephron segments, addressing the question: can renal tubule effects of ANF play a significant role in the precise day-to-day regulation of renal NaCl and water excretion? Based on these considerations, we propose that long-term renal tubular action of ANF may be distinct from its short-term natriuretic effect. The short-term action of ANF to accelerate salt and water excretion may play a role in the overall response to acute volume overload. This action of ANF appears to be largely due to an ANF-mediated increase in glomerular filtration rate accompanied by a blunting of the tubuloglomerular feedback mechanism, perhaps with some contribution from ANF-mediated inhibition of fluid absorption in the proximal tubule. In contrast, contributions of ANF to the precise day-to-day regulation of salt and water excretion are likely to be chiefly due to ANF-mediated inhibition of NaCl and water absorption in collecting ducts, but may also involve actions of ANF on the loop of Henle.Key words: collecting duct, thick ascending limb, proximal tubule, NaCl transport, water transport.

Bradykinin B2 receptor antagonist increases chloride and water absorption in rat medullary collecting duct

1996 ◽  
Vol 271 (2) ◽  
pp. R352-R360 ◽  
Author(s):  
H. Mukai ◽  
W. R. Fitzgibbon ◽  
G. Bozeman ◽  
H. S. Margolius ◽  
D. W. Ploth
Keyword(s):  
Water Absorption ◽  
Receptor Antagonist ◽  
Collecting Duct ◽  
Left Kidney ◽  
Water Excretion ◽  
Excretory Function ◽  
Before And After ◽  
Medullary Collecting Duct ◽  
Hoe 140

This study tested the hypothesis that intrarenal kinins play a regulatory role in electrolyte excretion by altering Cl- absorption in the collecting duct. We measured Cl- and insulin concentrations in tubular fluid samples obtained from medullary collecting ducts (MCD) of Dahl/Rapp salt-resistant (SR/ Jr) rats by microcatheterization of ducts of Bellini before and after treatment with the bradykinin receptor antagonist HOE-140. Tubular fluid was obtained from paired terminal inner medullary (t-IMCD) and outer medullary (OMCD) collecting duct sites of the left kidney. HOE-140 (n = 7) or vehicle (n = 5) was infused intravenously, and the collections were repeated. HOE-140 did not alter glomerular filtration rate but decreased urine flow rate (P < 0.05) and absolute and fractional Cl- excretion (P < 0.01). HOE-140 did not alter the fraction of filtered Cl- delivered (FDCl) to the OMCD but decreased FDCl to the t-IMCD from 2.3 +/- 0.3 to 1.3 +/- 0.3% (P < 0.05). The fraction of filtered Cl- absorbed per millimeter between the collection sites was increased from 0.2 +/- 0.1 to 0.6 +/- 0.1% (P < 0.05). Fractional absorption of water along the MCD was also increased (P < 0.05). No changes in excretory function or tubular Cl- or water absorption were observed in vehicle-treated rats. These studies show that kinin B2 receptor blockade enhances Cl- and water absorption in the MCD, a finding that supports a role of renal kinins in the regulation of NaCl and water excretion.

scholarly journals Canadian Society of Thoracic Radiology/Canadian Association of Radiologists Consensus Statement Regarding Chest Imaging in Suspected and Confirmed COVID-19

2020 ◽  
Vol 71 (4) ◽  
pp. 470-481 ◽  
Author(s):  
Carole Dennie ◽  
Cameron Hague ◽  
Robert S. Lim ◽  
Daria Manos ◽  
Brett F. Memauri ◽  
...  
Keyword(s):  
Consensus Statement ◽  
World Health ◽  
Canadian Society ◽  
Canadian Association ◽  
New Information ◽  
Reporting Structure ◽  
Novel Coronavirus ◽  
Health Organization ◽  
Key Questions

On March 11, 2020, the World Health Organization declared infection related to a novel coronavirus (SARS-CoV-2) a pandemic. The role and impact of imaging predates this declaration and continues to change rapidly. This article is a consensus statement provided by the Canadian Society of Thoracic Radiology and the Canadian Association of Radiologists outlining the role of imaging in COVID-19 patients. The objectives are to answer key questions related to COVID-19 imaging of the chest and provide guidance for radiologists who are interpreting such studies during this pandemic. The role of chest radiography (CXR), computed tomography (CT), and lung ultrasound is discussed. This document attempts to answer key questions for the imager when dealing with this crisis, such as “When is CXR appropriate in patients with suspected or confirmed COVID-19 infection?” or “How should a radiologist deal with incidental findings of COVID-19 on CT of the chest done for other indications?” This article also provides recommended reporting structure for CXR and CT, breaking diagnostic possibilities for both CXR and CT into 3 categories: typical, nonspecific, and negative based on imaging findings with representative images provided. Proposed reporting language is also outlined based on this structure. As our understanding of this pandemic evolves, our appreciation for how imaging fits into the workup of patients during this unprecedented time evolves as well. Although this consensus statement was written using the most recent literature, it is important to maintain an open mind as new information continues to surface.

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