Aldosterone-induced TGF-β₁Expression is Regulated by Mitogen-Activated Protein Kinases and Activator Protein-1 in Mesangial Cells

Abstract

Aldosterone has been shown to stimulate renal TGF-β1 expression. However, the mechanisms for aldosterone-induced TGF-β1 expression have not been clearly determined in mesangial cells. We examined the role of extracellular-signal regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) in the aldosterone-induced TGF-β1 expression in rat mesangial cells. TGF-β1 protein in the conditioned medium released from rat mesangial cells was measured by sandwich ELISA, TGF-β1 mRNA expression was analyzed by Northern blotting, AP-1 DNA binding activity was measured by EMSA and the ERK1/2, JNK activity was analyzed by western blotting. Aldosterone significantly stimulated TGF-β1 protein production and TGF-β1 mRNA expression in mesangial cells in a dose-dependent manner. Aldosterone significantly increased AP-1 DNA binding activity in mesangial cells. Pre-treatment of cells with AP-1 inhibitor, curcumin, blocked aldosterone-induced AP-1 DNA binding activity as well as aldosterone-induced TGF-β1 production. Aldosterone increased phosphorylation of ERK1/2 and JNK in mesangial cells. Pre-treatment of cells with ERK1/2 inhibitor, PD98059, or JNK inhibitor, SP600125 significantly inhibited aldosterone-induced ERK1/2 and JNK activity and subsequently TGF-β1 production, respectively. We conclude that aldosterone-induced TGF-β1 expression in mesangial cells is regulated by the ERK1/2, JNK and AP-1 intracellular signaling pathways.

The aldosterone receptor antagonist spironolactone prevents peritoneal inflammation and fibrosis

“…38,39 Irbesartan and spironolactone seem to decrease the extent of peritoneal injury caused by bacterial peritonitis. 40 Aldosterone stimulates the MAPK pathway and cell-cycle progression in mesangial cells mainly via MR. 41 Another study demonstrated that aldosterone rapidly induced phosphorylation of JNK and spironolactone abolished aldosterone-induced phosphorylation of JNK, 42 which is in agreement with our findings. Spironolactone was shown to downregulate ED1, MCP-1, p-c-Jun, TGF-b1 and FN in the visceral peritoneum.…”

“…Aldosterone-induced TGF-b1 expression in mesangial cells is regulated by the ERK1/2, JNK and AP-1 intracellular signaling pathways. 15 In this study, we investigated the hypothesis that aldosterone could promote peritoneal inflammation and fibrosis by stimulating the secretion of macrophages in the peritoneum, activating the JNK pathway, and further upregulating the expression of TGF-b1.…”

Regulation of WNK1 Expression by miR-192 and Aldosterone

“…9 Aldosterone promotes renal fibrosis by stimulating collagen synthesis via ERK1/2 phosphorylation and TGF-␤ induction. 34 miR-192 could thus participate in the multiple roles of aldosterone in health and diseases. The mechanisms by which aldosterone regulates miR-192 expression remain to be defined.…”

Molecular Diagnostics of Calcineurin-Related Pathologies

“…Another pathologic hallmark is arteriolar vasoconstriction, which leads to glomerular ischemia (76 ). Both angiotensin II and aldosterone may independently aggravate these pathologic effects because of their stimulating effects on TGF-␤ production (75,77,78 ). Tacrolimus has a similar nephrotoxic profile, although it is seemingly somewhat less severe (79 ).…”