Aldosterone-stimulated SGK1 activity mediates profibrotic signaling in the mesangium.
Several recent reports support the hypothesis that aldosterone contributes to the progression of renal injury. Mineralocorticoids increase the expression of serum- and glucocorticoid-inducible protein kinase 1 (SGK1), which is upregulated in several fibrotic diseases. It was hypothesized that SGK1 may mediate the effects of aldosterone on glomerular fibrosis and inflammation. In primary cultures of rat mesangial cells, aldosterone stimulated the expression, phosphorylation, and kinase activity of SGK1, as well as SGK1-dependent NF-kappaB activity. Furthermore, aldosterone augmented the promoter activity and protein expression of intercellular adhesion molecule-1 (ICAM-1), which modulates the inflammatory response, and the profibrotic cytokine connective tissue growth factor (CTGF) in an SGK1- and NF-kappaB-dependent manner. Similar to the in vitro results, uninephrectomized rats that were treated with aldosterone demonstrated increased glomerular expression of SGK1, ICAM-1, and CTGF proteins than untreated rats; these changes were accompanied by hypertension, glomerulosclerosis, and inflammation. In conclusion, these findings suggest that aldosterone stimulates ICAM-1 and CTGF transcription via the activation of SGK1 and NF-kappaB, effects that may contribute to the progression of aldosterone-induced mesangial fibrosis and inflammation.
Terada
Yoshio
Y
Department of Blood Purification and Nephrology, Tokyo Medical and Dental University, 5-45, Yushima 1-chome, Bunkyo-ku, Tokyo 113-8519, Japan. yterada.kid@tmd.ac.jp
Kuwana
Hitoshi
H
Kobayashi
Takahiko
T
Okado
Tomokazu
T
Suzuki
Noriko
N
Yoshimoto
Takanobu
T
Hirata
Yukio
Y
Sasaki
Sei
S
D000450:Aldosterone / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000918:Antibody Specificity; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D005355:Fibrosis; D005920:Glomerular Mesangium / Q000201:enzymology / Q000473:pathology; D051550:I-kappa B Kinase / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D000906:Antibodies; D055513:Connective Tissue Growth Factor; D051550:I-kappa B Kinase; D017874:Immediate-Early Proteins; D018799:Intercellular Adhesion Molecule-1; D036341:Intercellular Signaling Peptides and Proteins; D048369:MAP Kinase Kinase 1; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000099184:Serum-Glucocorticoid Regulated Kinases; C526316:CCN2 protein, rat