Impaired urine concentration and absence of tissue ACE: involvement of medullary transport proteins

Klein, Janet D.; Quach, Du Le; Cole, Justin M.; Disher, Kevin M.; Mongiu, Anne K.; Wang, Xiaodan; Bernstein, Kenneth E.; Sands, Jeff M.

doi:10.1152/ajprenal.00326.2001

Cited by 36 publications

(24 citation statements)

References 33 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies by several groups demonstrate that administration of angiotensin II increases BSC-1 expression in rat kidneys (Kwon et al, 2003) and that expression of BSC-1 is reduced in mice lacking angiotensin-converting enzyme (Klein et al, 2002). Additionally, studies with angiotensin-converting enzyme inhibitors in rats with cardiac failure show that blockade of angiotensin II synthesis normalizes both BSC-1 expression and renal sodium excretion suggesting that angiotensin II influences renal sodium handling in cardiovascular disease via BSC-1 (Staahltoft et al, 2002).…”

Section: Increased Expression Of Bsc-1 In Shr 1057mentioning

confidence: 99%

Increased Expression of the Sodium Transporter BSC-1 in Spontaneously Hypertensive Rats

Sonalker

Tofovic²,

Jackson³

2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The purpose of this study was to compare the expression of BSC-1 (bumetanide-sensitive Na ϩ -K ϩ -2Cl Ϫ cotransporter) in kidneys of spontaneously hypertensive rats (SHR) versus Wistar-Kyoto (WKY) rats by immunoblotting and reverse transcription-polymerase chain reaction. To determine the specificity of any observed changes in BSC-1 expression, we also compared expression of the thiazide sensitive Na ϩ -Cl Ϫ cotransporter (TSC), the type-3 Na ϩ -H ϩ exchanger (NHE-3), Na ϩ -K ϩ -ATPase-␣ 1 , the inwardly rectifying K ϩ channel (ROMK-1), the type-1 Na ϩ -HCO 3 Ϫ cotransporter (NBC-1), aquaporin-1, and aquaporin-2. Analyses were performed on outer cortex, outer medulla, and inner medulla. BSC-1 protein was detected in outer medulla and was markedly (6-fold) higher in SHR. TSC protein was detected in the cortex and was not overexpressed in SHR. Aquaporin-1 protein was detected in all three regions and was not overexpressed in SHR. Aquaporin-2 and ROMK-1 proteins were detected in all three regions, but were moderately elevated (2-fold) only in the SHR inner medulla. Na ϩ -K ϩ -ATPase and NHE-3 proteins were detected in all three regions. Na ϩ -K ϩ -ATPase-␣ 1 was modestly (25%) increased in SHR outer and inner medulla, whereas NHE-3 was moderately (2-fold) increased in the SHR cortex and inner medulla. NBC-1 protein was detected only in the cortex and was higher (2-fold) in SHR. mRNA levels of BSC-1, aquaporin-2, and ROMK-1 were not elevated in SHR, indicating a post-translational mechanism of protein overexpression. High-dose furosemide increased fractional sodium excretion more in SHR than WKY (3-fold). We conclude that increased expression of BSC-1, and to a lesser extent, aquaporin-2, ROMK-1, NHE-3, and NBC-1 may contribute to the pathogenesis of hypertension in the SHR.

show abstract

Section: Increased Expression Of Bsc-1 In Shr 1057mentioning

confidence: 99%

Increased Expression of the Sodium Transporter BSC-1 in Spontaneously Hypertensive Rats

Sonalker

Tofovic²,

Jackson³

2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Thus in ACE.2 (tissue null) mice, the abnormal physiology must be the result of the lack of ACE and angiotensin II, as opposed to renal insufficiency. To understand the molecular basis for the inability to concentrate, we determined the abundance of several different transport proteins and ion channels typically associated with renal concentrating ability (26) (Fig. 2).…”

Section: Ace2: No Tissue Ace Expressionmentioning

confidence: 99%

New approaches to genetic manipulation of mice: tissue-specific expression of ACE

Cole

Xiao

Adams

et al. 2003

American Journal of Physiology-Renal Physiology

Self Cite

View full text Add to dashboard Cite

. New approaches to genetic manipulation of mice: tissue-specific expression of ACE. Am J Physiol Renal Physiol 284: F599-F607, 2003; 10.1152/ajprenal.00308. 2002The renin-angiotensin system (RAS) plays a central role in body physiology, controlling blood pressure and blood electrolyte composition. ACE.1 (null) mice are null for all expression of angiotensin-converting enzyme (ACE). These mice have low blood pressure, the inability to concentrate urine, and a maldevelopment of the kidney. In contrast, ACE.2 (tissue null) mice produce one-third normal plasma ACE but no tissue ACE. They also have low blood pressure and cannot concentrate urine, but they have normal indices of renal function. These mice, while very informative, show that the null approach to creating knockout mice has intrinsic limitations given the many different physiological systems that no longer operate in an animal without a functioning RAS. To investigate the fine control of body physiology by the RAS, we developed a novel promoter swapping approach to generate a more selective tissue knockout of ACE expression. We used this to create ACE.3 (liver ACE) mice that selectively express ACE in the liver but lack all ACE within the vasculature. Evaluation of these mice shows that endothelial expression of ACE is not required for blood pressure control or normal renal function. Targeted homologous recombination has the power to create new strains of mice expressing the RAS in selected subsets of tissues. Not only will these new genetic models be useful for studying blood pressure regulation but also they show great promise for the investigation of the function of the RAS in complicated disease models.angiotensin-converting enzyme; blood pressure; angiotensin II; liver; renin-angiotensin system ROUGHLY ONE-HALF OF ALL AMERICANS die from cardiovascular disease. Put differently, more Americans die of cardiovascular disease than the next seven leading causes of death combined (1). To understand cardiovascular disease, one must understand how the body regulates blood pressure, a complex process governed by many different components, including multiple vasoconstrictors and vasodilators. Among these is the renin-angiotensin system (RAS), which produces the vasoconstrictor angiotensin II. The basic physiology by which angiotensinogen is degraded to angiotensin II has been known for many years, with the importance of this system underscored by the enormous clinical utility of pharmaceuticals that interrupt angiotensin II formation or action. So with all that is known about the RAS, what could conceivably be new? In fact, the use of targeted homologous recombination in mouse embryonic stem (ES) cells has produced a startling series of insights into the operation and functional importance of the RAS. This progress has been so rapid and dramatic as to implicate the RAS as easily the most important regulator of cardiovascular function as measured through blood pressure control.The use of homologous recombination to modify genes relies on the properties of cul...

show abstract

“…We have also recently reported that ACE 2/2 mice have reductions in several medullary transporters, including UT-A1, ClC-K1, NKCC2/ BSC1, and AQP1. 21 However, the precise role of renal ACE and angiotensin II in the urine concentrating mechanism is not well understood. In the ACE 1/3 mouse, the kidney contains roughly 5.3% to 7.8% the ACE level present in the kidney of a wild-type mouse.…”

Section: Characteristics Of Ace Micementioning

confidence: 99%

Mice Lacking Endothelial ACE

et al. 2003

Self Cite

View full text Add to dashboard Cite

Abstract-Recently, the concept of local renin-angiotensin systems (RAS) capable of generating angiotensin II apart from the circulation has received considerable attention. To investigate this, we generated ACE 1/3 mice in which one allele of ACE is null and the second allele was engineered to express ACE on the surface of hepatocytes. ACE 1/3 mice express no endothelial ACE and lack ACE within the lungs. Their kidneys contain Ͻ7.8% the enzyme levels present in control mice. Plasma conversion of angiotensin I to angiotensin II was 43.3% normal. The baseline blood pressure and renal function of the ACE 1/3 mice were normal, probably as a function of a marked increase of both plasma angiotensin I and angiotensin II. When exposed to 2 weeks of a salt-free diet (a stress diet stimulating the RAS), blood pressure in ACE 1/3 mice decreased to 92.3Ϯ2.0 mm Hg, a level significantly lower than that of wild-type control mice. The ACE 1/3 mice demonstrate the plasticity of the RAS and show that significant compensation is required to maintain normal, basal blood pressure in a mouse with an impaired local vascular and renal RAS. Key Words: mice, knockout Ⅲ angiotensin-converting enzyme Ⅲ angiotensin II Ⅲ endothelium Ⅲ blood pressure T he renin-angiotensin system (RAS) is a principle regulator of blood pressure and electrolyte homeostasis within the body. Inhibitors of this system have found broad use in the modern treatment of hypertension, congestive heart failure, and diabetic nephropathy. The RAS was originally characterized as a circulating, endocrine network, but in recent years the concept of a local RAS has gained considerable attention. In part, this is due to the finding that multiple organs express all of the components necessary to recapitulate a functional, local RAS in situ. [1][2][3][4][5] Although in theory, multiple tissues may regulate the production of angiotensin II independent from the circulation, the physiological and pathophysiological role of tissue RAS in organs such as the kidney and the vasculature is not known.Recently, we engineered a mouse with an altered profile in its expression of ACE. 6 This animal, termed ACE.3, does not produce vascular ACE but instead expresses the enzyme on the cell membrane of hepatocytes. This was accomplished by using targeted homologous recombination to substitute the control of ACE expression from its endogenous promoter to an albumin promoter. 7 As such, the liver of the homologous recombinant mouse (termed ACE 3/3 to indicate two targeted alleles) produces 87-fold more ACE than that of a wild-type animal. The only extrahepatic source of tissue ACE in the ACE 3/3 mouse is in the kidney, which has roughly 14% of wild-type levels. This expression is limited to the proximal tubule and is not observed within renal vascular endothelium or adventitia. This residual ACE expression is probably due to the specificity of the albumin promoter, since the original characterization of albumin promoter cassettes similar to that used in the ACE 3/3 mice showed low levels of repor...

show abstract

Impaired urine concentration and absence of tissue ACE: involvement of medullary transport proteins

Cited by 36 publications

References 33 publications

Increased Expression of the Sodium Transporter BSC-1 in Spontaneously Hypertensive Rats

Increased Expression of the Sodium Transporter BSC-1 in Spontaneously Hypertensive Rats

New approaches to genetic manipulation of mice: tissue-specific expression of ACE

Mice Lacking Endothelial ACE

Contact Info

Product

Resources

About