Aldosterone-Stimulated SGK1 Activity Mediates Profibrotic Signaling in the Mesangium

Abstract

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-B 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-Bdependent 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-B, effects that may contribute to the progression of aldosteroneinduced mesangial fibrosis and inflammation. Accumulating evidence suggests that angiotensinconverting enzyme (ACE) inhibition or angiotensin II receptor (ATR) blockade attenuates the decline in renal function and structural damage in various kidney diseases. 1-4 These benefits of ACE inhibition and ATR blockade are probably attributed to the suppression of intrarenal angiotensin II concentrations and the changes that follow as a consequence. 4,5 Recent clinical and experimental studies have demonstrated that elevated plasma aldosterone may also contribute to the progression of cardiac and renal disease. 6,7 Greene et al. 8 demonstrated a significant suppression of hyperaldosteronism and a marked attenuation of proteinuria, hypertension, and glomerulosclerosis in a remnant kidney model using rats that were treated with enalapril and losartan. Similarly, Rocha et al. 9 demonstrated the renoprotective effects of eplerenone and spironolactone in an aldosterone-stimulated rat model. Chrysostomou and Becker 7 found that the addition of spironolactone to ACE inhibitors markedly reduced the urinary excretion rate of protein in patients with chronic renal failure without exerting hemodynamic effects. All of these studies strongly suggest that aldosterone is involved in the pathogenesis of renal injury.Our group recently revealed that aldosterone stimulates the mitogen-activated protein kinase

Aldosterone Activates NF-κB in the Collecting Duct

“…Recent studies reported that stimulation of NF-B-dependent luciferase reporter gene activity by aldosterone is dependent on SGK1 in glomerular mesangial cells and in fibroblasts. 11,12 Moreover, SGK1 has been shown to associate physically with and phosphorylate IKK␤, 22 which, once activated, phosphorylates p65/RelA. 33 In agreement with these findings, our results indicate that knockdown or overexpression of SGK1, respectively, inhibited or increased NF-B-targeted gene expression in response to aldosterone.…”

“…Thus, aldosterone-induced NF-B activation is not restricted to nonepithelial cells, such as mesangial cells or fibroblasts, as described previously, 11,12 but is also observed in epithelial CD principal cells.…”

“…To test whether aldosterone-induced NF-B activation in CD cells is mediated by the serine-threonine kinase SGK1, as recently shown in mesangium and heart, 11,12 we transfected mCCD cl1 cells with siRNA targeting SGK1. SGK1 knockdown decreased SGK1 protein abundance by 60% in aldosterone-treated cells ( Figure 7A) and blunted the aldosterone-induced increase of IB␣, IL-6, or PAI-1 mRNA expression ( Figure 7B).…”

“…[5][6][7][8] As outlined by recent reports, mineralocorticoid also mediates inflammation and fibrosis through NF-B activation in liver, heart, and glomerular mesangial cells 9 -13 via a pathway involving the aldosterone early-induced gene, serum and glucocorticoid-induced kinase 1 (SGK1). 11,12 NF-B is a transcription factor composed of dimers of Rel family proteins (p65/RelA, p50/p105, p52/p100, RelB, and c-Rel). Under resting conditions, NF-B is sequestered in the cytoplasm in association with an inhibitory protein of the IB family.…”

Pathophysiological Roles of Aldosterone and Mineralocorticoid Receptor in the Kidney

“…Aldosterone/MR induces phosphorylation of serum and glucocorticoid regulated kinase 1 (SGK1), which in turn phosphorylates and inactivates the nuclear factor of κ light polypeptide B, resulting in the activation of nuclear factor κB (NFκB) (27,30). The activated NFκB then enhances the transcription of inflammatory cytokine genes such as intercellular adhesion molecule 1 and connective tissue growth factor (CTGF) (30).…”