Mineralocorticoid receptor blockade enhances the antiproteinuric effect of an angiotensin II blocker through inhibiting podocyte injury in type 2 diabetic rats.
Treatment with angiotensin II type 1 receptor blockers (ARBs) is the first-line therapy for hypertensive patients with diabetic nephropathy. However, emerging clinical evidence indicates that mineralocorticoid receptor (MR) blockers have blood pressure-independent antiproteinuric effects. We sought to determine whether treatment with an MR blocker, eplerenone, enhances the effects of an ARB, telmisartan, on podocyte injury and proteinuria in type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats. From 20 to 50 weeks old, diabetic OLETF rats showed higher systolic blood pressure (SBP) and urinary protein excretion (U(protein)V) than nondiabetic control Long-Evans-Tokushima-Otsuka rats. At 50 weeks old, OLETF rats also showed glomerular sclerosis and podocyte injury, whereas nephrin and podocin mRNA levels in isolated glomeruli were significantly decreased. Treatment with telmisartan (3 mg/kg/day p.o.) decreased SBP and U(protein)V, increased nephrin and podocin mRNA levels, and attenuated glomerular sclerosis and podocyte injury. Eplerenone (100 mg/kg/day p.o.) did not alter SBP but elicited similar changes in renal parameters. However, greater reductions in U(protein)V and podocyte injury and greater increases in nephrin and podocin mRNA levels were observed in the combination treatment group. Hydralazine (25 mg/kg/day p.o.) decreased SBP but did not alter any renal parameters. These data indicate that MR blockade enhances the SBP-independent antiproteinuric effect of an ARB through inhibiting podocyte injury in type 2 diabetic rats.
Nishiyama
Akira
A
Department of Pharmacology, Kagawa University Medical School, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. akira@kms.ac.jp
Kobori
Hiroyuki
H
Konishi
Yoshio
Y
Morikawa
Takashi
T
Maeda
Isseki
I
Okumura
Michiaki
M
Kishida
Masatsugu
M
Hamada
Masahiro
M
Nagai
Yukiko
Y
Nakagawa
Toshitaka
T
Ohashi
Naro
N
Nakano
Daisuke
D
Hitomi
Hirofumi
H
Imanishi
Masahito
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D000077545:Eplerenone; D047908:Intracellular Signaling Peptides and Proteins; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D000451:Mineralocorticoid Receptor Antagonists; D050199:Podocytes / Q000187:drug effects* / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D020334:Rats, Inbred OLETF; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000451:Mineralocorticoid Receptor Antagonists; C407223:NPHS2 protein; C113267:nephrin; D013148:Spironolactone; D000077545:Eplerenone; D000077333:Telmisartan