Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats.
Aldosterone induces myocardial fibrosis and vascular inflammation via proinflammatory and profibrotic cytokines. The effect of spironolactone on renal inflammation and renal function was investigated in type 2 diabetic rats. For define the molecular mechanism of spironolactone, the effect of spironolactone on the synthesis of monocyte chemotactic peptide-1 (MCP-1) and its upstream transcription factor, NF-kappaB, was evaluated in cultured mesangial cells and proximal tubular cells. There were no changes in blood glucose concentration or BP after spironolactone treatment. Spironolactone treatment significantly reduced urinary albumin excretion and ameliorated glomerulosclerosis. Urinary levels of MCP-1 were significantly increased concurrently with renal expression of MCP-1, macrophage migration inhibitory factor, and macrophage infiltration. Spironolactone treatment significantly inhibited urinary excretion of MCP-1 as well as renal MCP-1 and migration inhibitory factor expression and macrophage infiltration. In addition, aldosterone induced upregulation of MCP-1 expression and NF-kappaB transcriptional activity in cultured cells, and spironolactone reduced both NF-kappaB activation and MCP-1 synthesis. Furthermore, NF-kappaB inhibition abolished aldosterone-induced MCP-1 production. Overall, these findings suggest that aldosterone-induced NF-kappaB activation leads to activation of proinflammatory cytokines, ultimately leading to renal injury in this model. These data suggest that mineralocorticoid blockade may be a potential therapeutic target in diabetic nephropathy.
Department of Internal Medicine, Korea University Ansan Hospital, 516 Kojan-Dong, Ansan City, Kyungki-Do 425-020, Korea.
Sang-Youb
SY
Han
Cy-Hyun
CH
Kim
Han-Seong
HS
Kim
Yi-Hwa
YH
Jee
Hye-Kyoung
HK
Song
Mi-Hwa
MH
Lee
Kum-Hyun
KH
Han
Hyoung-Kyu
HK
Kim
Young-Sun
YS
Kang
Jee-Young
JY
Han
Young-Sik
YS
Kim
Dae-Ryong
DR
Cha
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage; D016328:NF-kappa B / Q000276:immunology; D051381:Rats; D013148:Spironolactone / Q000008:administration & dosage*
D000893:Anti-Inflammatory Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D000451:Mineralocorticoid Receptor Antagonists; D016328:NF-kappa B; D013148:Spironolactone