<p><b><i>Background/Aims:</i></b> Obesity and diabetes are intimately
interrelated, and are independent risk factors for kidney disease.
Overactivation of mineralocorticoid receptor (MR) is implicated in end
organ damage of both pathologies. But the underlying mechanism of MR
activation in kidney remains uncertain. We explored the involvement of
Rac1, which we previously identified as a ligand-independent MR
activator, in renal MR activation in vitro and in vivo. <b><i>Methods:</i></b>
We evaluated the MR activity and Rac1 activity under high-glucose
stimulation using luciferase reporter system and glutathione
S-transferase pull-down assay in cultured mesangial cells. To elucidate
the role of Rac1 in vivo, we employed KKA<sup>y</sup>, a mouse model of
obesity-related type 2 diabetes, which spontaneously developed massive
albuminuria and distinct glomerular lesions accompanied by increased
plasma aldosterone concentration. <b><i>Results:</i></b> High-glucose
stimulation increased Rac1 activity and MR transcriptional activity in
cultured mesangial cells. Overexpression of constitutively active Rac1
activated MR, and glucose-induced MR activation was suppressed by
overexpression of dominant negative Rac1 or Rac inhibitor EHT1864. In
KKA<sup>y</sup>, renal Rac1 was activated, and nuclear MR was increased.
EHT1864 treatment suppressed renal Rac1 and MR activity and mitigated
renal pathology of KKA<sup>y</sup> without changing plasma aldosterone concentration. <b><i>Conclusion:</i></b> Our results suggest that MR activation plays an important role in the nephropathy of KKA<sup>y</sup>
mice, and that glucose-induced Rac1 activation, in addition to
hyperaldosteronemia, contributes to their renal MR activation. Along
with MR blockade, Rac inhibition may potentially be a preferred option
in the treatment of nephropathy in obesity-related diabetic patients.</p