Sgk1 sensitivity of Na+/H+ exchanger activity and cardiac remodeling following pressure overload

Abstract

Sustained increase of cardiac workload is known to trigger cardiac remodeling with eventual development of cardiac failure. Compelling evidence points to a critical role of enhanced cardiac Na(+)/H(+) exchanger (NHE1) activity in the underlying pathophysiology. The signaling triggering up-regulation of NHE1 remained, however, ill defined. The present study explored the involvement of the serum- and glucocorticoid-inducible kinase Sgk1 in cardiac remodeling due to transverse aortic constriction (TAC). To this end, experiments were performed in gene targeted mice lacking functional Sgk1 (sgk1 (-/-)) and their wild-type controls (sgk1 (+/+)). Transcript levels have been determined by RT-PCR, cytosolic pH (pH( i )) utilizing 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence, Na(+)/H(+) exchanger activity by the Na(+)-dependent realkalinization after an ammonium pulse, ejection fraction (%) utilizing cardiac cine magnetic resonance imaging and cardiac glucose uptake by PET imaging. As a result, TAC increased the mRNA expression of Sgk1 in sgk1 (+/+) mice, paralleled by an increase in Nhe1 transcript levels as well as Na(+)/H(+) exchanger activity, all effects virtually abrogated in sgk1 (-/-) mice. In sgk1 (+/+) mice, TAC induced a decrease in Pgc1a mRNA expression, while Spp1 mRNA expression was increased, both effects diminished in the sgk1 (-/-) mice. TAC was followed by a significant increase of heart and lung weight in sgk1 (+/+) mice, an effect significantly blunted in sgk1 (-/-) mice. TAC increased the transcript levels of Anp and Bnp, effects again significantly blunted in sgk1 (-/-) mice. TAC increased transcript levels of Collagen I and III as well as Ctgf mRNA and CTGF protein abundance, effects significantly blunted in sgk1 (-/-) mice. TAC further decreased the ejection fraction in sgk1 (+/+) mice, an effect again attenuated in sgk1 (-/-) mice. Also, cardiac FDG-glucose uptake was increased to a larger extent in sgk1 (+/+) mice than in sgk1 (-/-) mice after TAC. These observations point to an important role for SGK1 in cardiac remodeling and development of heart failure following an excessive work load.

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

“…Quantitative RT-PCR was performed as described previously (72). Briefly, after sacrificing the animals, tissues were immediately snap frozen in liquid nitrogen.…”

Sgk1-Dependent Stimulation of Cardiac Na+/H+Exchanger Nhe1 by Dexamethasone

“…Lack of Sgk1 reduced the cardiac remodeling induced by pressure overload [11,12]. Similarly, lack of Sgk1 significantly blunted the cardiac hypertrophy and fibrosis by mineralocorticoid excess [34] and angiotensin II infusion [41].…”

“…Altered expression of Sgk1 is associated with cardiac remodeling [10,11,12]. Lack of Sgk1 reduced the cardiac remodeling induced by pressure overload [11,12].…”

“…SGK1 abundance is particularly high in fibrosing tissue [22,23,33,34]. SGK1 upregulates a wide variety of transporters [8,9,35,36] including the Na + /H + exchangers Nhe1 [11] and Nhe3 [37,38,39,40]. …”

“…Sgk1 is further stimulated by cardiac pressure overload [10,11,12] and genomically upregulated by a variety of further hormones [13] including mineralocorticoids [14,15,16], 1,25-dyhydroxyvitamin D 3 (1,25(OH) 2 D 3 ) [17], gonadotropins [18,19,20,21] and TGFβ [22,23]. The expressed kinase is activated by Phosphoinositide 3-kinase (PI3K) through phosphoinositide-dependent kinase PDK1 [24,25,26,27,28,29,30,31] and by the mammalian target of rapamycin TORC2 protein complex [32].…”