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RGS2 Proteins Regulate Blood Pressure

William J. Welch
JASN November 2010, 21 (11) 1809-1810; DOI: https://doi.org/10.1681/ASN.2010090977
William J. Welch
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The kidney is capable of regulating systemic BP primarily because of its role in hormone release and fluid balance. Although it is clear that the kidney participates in the development of many forms of hypertension, direct evidence is often lacking. Studies that correlate renal function and BP offer only secondary evidence but have provided reproducible models. In a few models and in some patient populations, the kidney is more clearly identified as the source of hypertension. For example, increased release of renin from an obstructed renal artery disease leads to hypertension. Experimentally, this disease has been successfully modeled to study the effects of endogenous high levels of renin and angiotensin II that follows. However, other kidney-linked models of hypertension are not identified so easily.

Previous studies using kidney transplantation in rats began to identify the role but often not the mechanism of renal-dependent hypertension. Studies that transplanted kidneys from spontaneously hypertensive rats (SHR) to normotensive rats and conversely normotensive kidneys into SHR consistently revealed that the ambient BP follows the transplanted kidney.1–3 Subsequent studies also showed that the kidney determines the BP response to high salt intake in Dahl salt-sensitive rats4 and in renovascular hypertensive kidneys.5

Renal cross-transplantation studies of mice have now started to appear and add to our understanding of the role of the kidney in regulating BP. This technique in mice has the potential to identify the kidney source of various hypertensive genes. The challenge lies with the more complex surgery required in mice. However, Coffman and colleagues6 previously explored the role of the renin-angiotensin system on the regulation of BP in gene-deleted mice and in transplantation studies to separate the effects of the kidney versus nonrenal tissue. In a previous study, they transplanted kidneys from the hypotensive angiotensin II type 1a receptor–deficient mice into wild-type mice to show that BP again follows the transplanted kidney.

In this issue of JASN, Gurley et al.7 use the cross-transplantation method to study the role of the regulator of G protein signaling type 2 (RGS2) that is implicated in hypertension. There is growing evidence that G protein–coupled receptor (GPCR)-mediated control of vascular tone and BP is an important regulatory step in the development of hypertension. GPCRs are activated by several ligands, including angiotensin II. GTPase proteins (GAPs) modulate signaling by GPCRs and evidence now suggests the GAP RGS2 may be a key regulator of this process. Mice lacking RGS2 develop hypertension for unknown reasons.8 Gurley et al.7 now show that transplanting kidneys from hypertensive RGS2−/− mice increases BP in wild-type mice, demonstrating the dominant effect of the kidneys for this gene.

The clear results from this study are due to the elegant surgical skills of this group, who have perfected the ability to transplant kidneys in mice. This sets the stage for even more studies that should be able to associate the role of the kidney in the regulation of BP in several single gene-deleted models. This study does not define the mechanism by which RGS2 regulates BP or how its inhibition or absence causes hypertension. The specific ligands that interact with RGS2 are not explored either. The study does demonstrate that the effects of RGS2 in the kidney have more profound effects on BP than systemic effects of RGS2.

Of course, there remain difficulties with the interpretation of these and future studies. First, as the authors discuss, it is not clear how the kidney mediates hypertension and that both epithelial and vascular targets could be involved. Second, the absence of data on GFR makes this evaluation more difficult. However, the effects of GFR per se may have been factored out by the transplant controls. Regardless of these concerns with this method in mice, the BP results are compelling.

DISCLOSURES

None.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • See related article, “Renal Actions of RGS2 Control Blood Pressure,” on pages 1847–1851.

  • Copyright © 2010 by the American Society of Nephrology

REFERENCES

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    1. Rettig R,
    2. Folberth C,
    3. Stauss H,
    4. Kopf D,
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    6. Unger T
    : Role of the kidney in primary hypertension: a renal transplantation study in rats. Am J Physiol Renal Electrolyte Physiol 27: F606–F611, 1990
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    1. Rettig R,
    2. Stauss H,
    3. Folberth C,
    4. Ganten R,
    5. Waldherr R,
    6. Unger T
    : Hypertension transmitted by kidneys from stroke-prone spontaneously hypertensive rats. Am J Physiol Renal Fluid Electrolyte Physiol 26: F197–F203, 1989
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    1. Kopf D,
    2. Waldherr R,
    3. Rettig R
    : Source of kidney determines blood pressure in young renal transplanted rats. Am J Physiol Renal Fluid Electrolyte Physiol 34: F104–F111, 1993
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    1. Morgan DA,
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    3. Mark AL
    : Effects of interstrain renal transplantation on NaCl-induced hypertension in Dahl rats. Hypertension 15: 436–442, 1990
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    1. Rettig R,
    2. Folberth CG,
    3. Stauss H,
    4. Kopf D,
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    : Hypertension in rats induced by renal grafts from renovascular donors. Hypertension 15: 429–435, 1990
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Crowley SD,
    2. Gurley SB,
    3. Oliverio MI,
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    5. Griffiths R,
    6. Flannery PJ,
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    8. Kim HS,
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    11. Coffman TM
    : Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J Clin Invest 115: 1092–1099, 2005
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    : Renal actions of RGS2 control blood pressure. J Am Soc Nephrol 21: 1847–1851, 2010
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  8. 8.↵
    1. Tang KM,
    2. Wang GR,
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    10. Zhu Y,
    11. Mendelsohn ME
    : Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med 9: 1506–1512, 2003
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Journal of the American Society of Nephrology: 21 (11)
Journal of the American Society of Nephrology
Vol. 21, Issue 11
1 Nov 2010
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RGS2 Proteins Regulate Blood Pressure
William J. Welch
JASN Nov 2010, 21 (11) 1809-1810; DOI: 10.1681/ASN.2010090977

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RGS2 Proteins Regulate Blood Pressure
William J. Welch
JASN Nov 2010, 21 (11) 1809-1810; DOI: 10.1681/ASN.2010090977
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