Role of aldosterone in diabetic nephropathy.
In the last 10 years, many studies have focused on the non-classical action of aldosterone. One of the most important new aspects of aldosterone is its pathogenic role as proinflammatory and profibrotic molecules. It has been reported that aldosterone induces myocardial fibrosis and vascular inflammation through up-regulation of various proinflammatory and profibrotic cytokines. We investigated the effect of aldosterone and spironolactone, which is a non-selective mineralocorticoid receptor antagonist, on monocyte chemoattractant peptide (MCP-1) and collagen synthesis in cultured mesangial and tubular epithelial cells. In addition, to evaluate the effect of spironolactone on diabetic nephropathy, we used Otsuka Long-Evans Tokushima Fatty (OLETF) rats which are known type 2 diabetic animal models. Spironolactone treatment did not induce any significant change in blood glucose levels and blood pressure. However, spironolactone therapy significantly inhibited urinary albumin and MCP-1 excretion. Spironolactone treatment also suppressed renal mRNA expression for MCP-1, macrophage migration inhibitory factor (MIF) as well as intrarenal protein synthesis for ED-1 and MIF. Morphologically, spironolactone treatment significantly prevented glomerulosclerosis, collagen deposition and connective tissue growth factor (CTGF) expression in diabetic rats. In cultured cell experiments, aldosterone directly increased the MCP-1, collagen secretion and spironolactone treatment abolished aldosterone-induced MCP-1 and collagen synthesis. Surprisingly, aldosterone treatment did not induce any significant change in TGFbeta1 gene transcription. Finally, we found that NF-kB activity was increased after stimulation with aldosterone and spironolactone therapy inhibited their activation. In addition, prior treatment with pyrrolidine dithiocarbamate (PDTC), which is a NF-KB inhibitor, inhibited aldosterone-induced MCP-1 protein secretion. These results suggest that aldosterone blockade could play a role in preventing the progression of diabetic nephropathy via anti-inflammatory and antifibrotic mechanisms.
Cha
Dae Ryong
DR
Department of Internal Medicine, Korea University, Ansan City, Kyungki-Do, Korea. cdragn@unitel.co.kr
Kang
Young Sun
YS
Han
Sang Youb
SY
Jee
Yi Hwa
YH
Han
Kum Hyun
KH
Kim
Hyoung Kyu
HK
Han
Jee Young
JY
Kim
Young Sik
YS
D000419:Albuminuria / Q000503:physiopathology; D000450:Aldosterone / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism / Q000652:urine; D003094:Collagen / Q000037:antagonists & inhibitors; D055513:Connective Tissue Growth Factor; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000517:prevention & control; D053331:Ectodysplasins; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D020334:Rats, Inbred OLETF; D013148:Spironolactone / Q000494:pharmacology; D000079424:Tumor Necrosis Factor Inhibitors
C526316:CCN2 protein, rat; D018932:Chemokine CCL2; D053331:Ectodysplasins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; D008565:Membrane Proteins; D000451:Mineralocorticoid Receptor Antagonists; D016328:NF-kappa B; D012333:RNA, Messenger; D000079424:Tumor Necrosis Factor Inhibitors; D055513:Connective Tissue Growth Factor; D013148:Spironolactone; D000450:Aldosterone; D003094:Collagen