Mineralocorticoid receptor-dependent proximal tubule injury is mediated by a redox-sensitive mTOR/S6K1 pathway.
OBJECTIVE
The mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics.


METHODS
Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks.


RESULTS
Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-β-aminoglycosidase (β-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and β-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)-catenin, T- and N-cadherin.


CONCLUSIONS
Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure.
Harry S. Truman VA Medical Center, Columbia, MO, USA. whaleyconnella@health.missouri.edu
Adam T
AT
Whaley-Connell
Javad
J
Habibi
Ravi
R
Nistala
Vincent G
VG
DeMarco
Lakshmi
L
Pulakat
Melvin R
MR
Hayden
Tejaswini
T
Joginpally
Carlos M
CM
Ferrario
Alan R
AR
Parrish
James R
JR
Sowers
D000419:Albuminuria / Q000378:metabolism / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure; D007150:Immunohistochemistry / Q000379:methods; D007684:Kidney Tubules / Q000187:drug effects*; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D013148:Spironolactone / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases