Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor–dependent pathway
Shigeru Shibata, … , Miki Nagase, Toshiro Fujita
Shigeru Shibata, … , Miki Nagase, Toshiro Fujita
Published July 18, 2011
Citation Information: J Clin Invest. 2011;121(8):3233-3243. https://doi.org/10.1172/JCI43124.
View: Text | PDF
Research Article Nephrology

Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor–dependent pathway

Abstract

Hypertension is a leading contributor to cardiovascular mortality worldwide. Despite this, its underlying mechanism(s) and the role of excess salt in cardiorenal dysfunction are unclear. Previously, we have identified cross-talk between mineralocorticoid receptor (MR), a nuclear transcription factor regulated by the steroid aldosterone, and the small GTPase Rac1, which is implicated in proteinuric kidney disease. We here show that high-salt loading activates Rac1 in the kidneys in rodent models of salt-sensitive hypertension, leading to blood pressure elevation and renal injury via an MR-dependent pathway. We found that a high-salt diet caused renal Rac1 upregulation in salt-sensitive Dahl (Dahl-S) rats and downregulation in salt-insensitive Dahl (Dahl-R) rats. Despite a reduction of serum aldosterone levels, salt-loaded Dahl-S rats showed increased MR signaling in the kidneys, and Rac1 inhibition prevented hypertension and renal damage with MR repression. We further demonstrated in aldosterone-infused rats as well as adrenalectomized Dahl-S rats with aldosterone supplementation that salt-induced Rac1 and aldosterone acted interdependently to cause MR overactivity and hypertension. Finally, we confirmed the key role of Rac1 in modulating salt susceptibility in mice lacking Rho GDP–dissociation inhibitor α. Therefore, our data identify Rac1 as a determinant of salt sensitivity and provide insights into the mechanism of salt-induced hypertension and kidney injury.

Authors

Shigeru Shibata, ShengYu Mu, Hiroo Kawarazaki, Kazuhiko Muraoka, Ken-ichi Ishizawa, Shigetaka Yoshida, Wakako Kawarazaki, Maki Takeuchi, Nobuhiro Ayuzawa, Jun Miyoshi, Yoshimi Takai, Akira Ishikawa, Tatsuo Shimosawa, Katsuyuki Ando, Miki Nagase, Toshiro Fujita

×
Problems with a PDF?

This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.

Having trouble reading a PDF?

PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.

Having trouble saving a PDF?

Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.

Having trouble printing a PDF?

  1. Try printing one page at a time or to a newer printer.
  2. Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
  3. Make sure you are using the latest version of Adobe's Acrobat Reader.

Supplemental data - Download (1.40 MB)

Advertisement