Aldosterone promotes fibronectin production through a Smad2-dependent TGF-beta1 pathway in mesangial cells.
Accumulating evidence demonstrates that aldosterone can cause extra-cellular matrix (ECM) accumulation, in addition to regulating sodium and potassium homeostasis. Increased extra-cellular matrix production by renal glomerular mesangial cells has been suggested to be involved in pathogenesis of glomerular sclerosis. The present studies examine whether aldosterone is also produced in renal mesangial cells, and the effect of aldosterone on ECM accumulation in these cells. In cultured renal mesangial cells, aldosterone synthase (CYP11B2), mineralocorticoid receptor (MR), and 11beta-HSD2 mRNA expressions were detected by RT-PCR. The ability of renal mesangial cells to produce aldosterone was confirmed by directly detecting aldosterone in culture medium via radioimmunoassay. Real-time RT-PCR showed that the expression of CYP11B2 mRNA in mesangial cells was significantly enhanced by AngII (P<0.001) and by potassium (P<0.05). Exposure of the cultured mesangial cells to aldosterone significantly increased fibronectin production from 12.4+/-1.9 to 74.6+/-16.8ng/ml (P<0.05). The aldosterone induced fibronectin production was abolished by aldosterone receptor antagonist spironolactone. Aldosterone also increased the TGF-beta1 reporter luciferase activity from 0.8+/-0.1 to 1.7+/-0.1 (P<0.05). Immunoblot showed TGF-beta1 protein expression was increased following aldosterone treatment. Blocking TGF-beta1 signaling pathway by knocking down Smad2 significantly blunted the aldosterone induced fibronectin production. The present studies indicate that renal mesangial cell is a target of local aldosterone action, which promotes ECM protein fibronectin production via TGF-beta1/Smad2 signaling pathway.
Lai
Lingyun
L
Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, PR China.
Chen
Jing
J
Hao
Chuan-Ming
CM
Lin
Shanyan
S
Gu
Yong
Y
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis / Q000235:genetics; D000450:Aldosterone / Q000096:biosynthesis* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis / Q000235:genetics; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis*; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism*; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D005353:Fibronectins; D018161:Receptors, Mineralocorticoid; D051899:Smad2 Protein; C497784:Smad2 protein, rat; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000450:Aldosterone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D019405:Cytochrome P-450 CYP11B2