Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

Artunc, Ferruh; Sandulache, Diana; Nasir, Omaima; Boini, Krishna M.; Friedrich, Björn; Beier, Norbert; Dicks, Edith; Pötzsch, Sven; Klingel, Karin; Amann, Kerstin; Blazer‐Yost, Bonnie L.; Scholz, Wolfgang; Risler, T.; Kuhl, Dietmar; Läng, Florian

doi:10.1007/s00424-007-0401-5

Cited by 27 publications

(34 citation statements)

References 54 publications

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“…SGK1 is upregulated by mineralocorticoids and is assumed to participate in the mineralocorticoid regulation of renal sodium excretion (7,9,12,16,22,26,32,33,35,41). It is involved in the volume retention during mineralocorticoid excess (3) or following treatment with the PPAR␥ agonist pioglitazone (4). Our data show that SGK1 protein expression was strongly enhanced in nephrotic wild-type mice suggesting an involvement of the kinase in the observed volume retention.…”

Section: Discussionmentioning

confidence: 77%

Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome

Artunc

Nasir²,

Amann³

et al. 2008

American Journal of Physiology-Renal Physiology

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Doxorubicin-induced nephropathy leads to epithelial sodium channel (ENaC)-dependent volume retention and renal fibrosis. The aldosterone-sensitive serum- and glucocorticoid-inducible kinase SGK1 has been shown to participate in the stimulation of ENaC and to mediate renal fibrosis following mineralocorticoid and salt excess. The present study was performed to elucidate the role of SGK1 in the volume retention and fibrosis during nephrotic syndrome. To this end, doxorubicin (15 μg/g body wt) was injected intravenously into gene-targeted mice lacking SGK1 ( sgk1 −/−) and their wild-type littermates ( sgk1 +/+). Doxorubicin treatment resulted in heavy proteinuria (>100 mg protein/mg crea) in 15/44 of sgk1 +/+ and 15/44 of sgk1 −/− mice leading to severe nephrotic syndrome with ascites, lipidemia, and hypoalbuminemia in both genotypes. Plasma aldosterone levels increased in nephrotic mice of both genotypes and was followed by increased SGK1 protein expression in sgk1 +/+ mice. Urinary sodium excretion reached signficantly lower values in sgk1 +/+ mice (15 ± 5 μmol/mg crea) than in sgk1 −/− mice (35 ± 5 μmol/mg crea) and was associated with a significantly higher body weight gain in sgk1 +/+ compared with sgk1 −/− mice (+6.6 ± 0.7 vs. +4.1 ± 0.8 g). During the course of nephrotic syndrome, serum urea concentrations increased significantly faster in sgk1 −/− mice than in sgk1 +/+ mice leading to uremia and a reduced median survival in sgk1 −/− mice (29 vs. 40 days in sgk1 +/+ mice). In conclusion, gene-targeted mice lacking SGK1 showed blunted volume retention, yet were not protected against renal fibrosis during experimental nephrotic syndrome.

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Section: Discussionmentioning

confidence: 77%

Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome

Artunc

Nasir²,

Amann³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…This approach may overestimate TPV. Previous studies have shown that taking two or more samples within 30 min after EB administration may yield more accurate TPV values of approximately 4 % of total body weight (Morgan et al 2006;Artunc et al 2008;Eisner et al 2012). However, assuming that in our study the clearance rates of EB from the circulation were similar, this should not affect the evaluated differences in TPV between wild-type and LSD1 +/− animals after a HS challenge.…”

Section: Animal Studiesmentioning

confidence: 74%

Lysine-specific demethylase-1 modifies the age effect on blood pressure sensitivity to dietary salt intake

Krug

Tille

Sun

et al. 2012

AGE

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How interactions of an individual's genetic background and environmental factors, such as dietary salt intake, result in age-associated blood pressure elevation is largely unknown. Lysine-specific demethylase-1 (LSD1) is a histone demethylase that mediates epigenetic regulation and modification of gene transcription. We have shown previously that hypertensive African-American minor allele carriers of the LSD1 single nucleotide polymorphism (rs587168) display blood pressure salt sensitivity. Our goal was to further examine the effects of LSD1 genotype variants on interactions between dietary salt intake, age, and blood pressure. We found that LSD1 single nucleotide polymorphism (rs7548692) predisposes to increasing salt sensitivity during aging in normotensive Caucasian subjects. Using a LSD1 heterozygous knockout mouse model, we compared blood pressure values on low (0.02 % Na + ) vs. high (1.6 % Na + ) salt intake. Our results demonstrate significantly increased blood pressure salt sensitivity in LSD1-deficient compared to wild-type animals with age, confirming our findings of salt sensitivity in humans. Elevated blood pressure in LSD1 +/− mice is associated with total plasma volume expansion and altered renal Na + excretion. In summary, our human and animal studies demonstrate that LSD1 is a genetic factor that interacts with dietary salt intake modifying age-associated blood pressure increases and salt sensitivity through alteration of renal Na + handling.

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“…8,11,15 Indeed, several studies suggested that increased salt and water reabsorption by the kidney plays an important role in generation of TZD-induced edema and implicated the collecting duct as the major site of TZD-induced sodium retention. 19,20,22 These studies led to the notion that TZD-induced fluid retention is mediated primarily by the action of the PPAR␥ agonist on ENaC in the collecting duct, either directly or by an aldosterone-dependent manner. 5 However, data contradicting this notion are also found in the literature.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma volume was measured using the dye dilution technique with Evans blue 22 in additional groups of CHF rats and control rats (nϭ7 to 10 each) that were treated with RGZ for 4 weeks as discussed above.…”

Section: Plasma Volume Measurementsmentioning

confidence: 99%

Effects of Chronic Rosiglitazone Treatment on Renal Handling of Salt and Water in Rats With Volume-Overload Congestive Heart Failure

Goltsman

Wang

LaVallie

et al. 2011

Circ: Heart Failure

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Background-The side effects of fluid retention and edema of the thiazolidinedione (TZD) class of peroxisome proliferator-activated receptor-␥ agonists limit their use in patients with congestive heart failure (CHF). The present study aims to explore whether chronic treatment with the TZD compound rosiglitazone (RGZ) is associated with worsening of salt and water retention in male Sprague-Dawley rats with aorto-caval fistula, an experimental model of volume-overload CHF. Methods and Results-The effects of oral RGZ (30 mg/kg per day for 4 weeks) in CHF rats on plasma volume, cumulative sodium excretion, renal expression of Na ϩ channels and transporters, and selected biomarkers of CHF were compared with those in CHF rats and sham-operated control rats treated with vehicle only (nϭ7 to 10). Additionally, the response to acute saline loading (3.5% of body weight) was evaluated after 2 weeks of treatment by renal clearance methodology. Chronic RGZ treatment caused no further increase in plasma volume compared with vehicle-treated CHF rats. Moreover, no increase in renal expression of Na ϩ transport-linked channels/transporters was observed in response to RGZ. Cumulative sodium excretion was enhanced in CHF rats after RGZ and by another TZD compound, pioglitazone. In response to saline loading, RGZ-treated animals displayed a higher natriuretic/diuretic response than did vehicle-treated rats. Chronic RGZ treatment was not associated with any deterioration in selected biomarkers of CHF, whereas indices of cardiac hypertrophy and blood pressure were improved. Conclusions-Chronic RGZ treatment was not associated with worsening of fluid retention or cardiac status in rats with experimental volume-overload CHF. Rather, RGZ appeared to improve renal handling of salt and water in rats with CHF. (Circ Heart Fail. 2011;4:345-354.)Key Words: thiazolidinedione Ⅲ aorto-caval fistula Ⅲ renal sodium excretion Ⅲ ECF volume expansion Ⅲ rat R osiglitazone (RGZ) is a member of the thiazolidinedione (TZD) class of compounds that act as agonists of peroxisome proliferator-activated receptor-gamma (PPAR-␥). 1 Activation of PPAR-␥ exerts important metabolic effects by regulating the expression of genes involved in glucose and lipid metabolism. 2 Oral RGZ is highly effective in improving insulin sensitivity and the metabolic abnormalities of type 2 diabetes mellitus (T2DM). 1 However, the clinical benefits of TZDs are hampered by the concomitant adverse effects of fluid retention and peripheral edema. These were reported in 4% to 7% of TZD-treated patients and in up to 15% in those who receive concurrent insulin therapy. [3][4][5] Moreover, the overall cardiovascular safety of these drugs has been questioned on the basis of observations of increased incidence of heart failure and cardiac ischemic events in RGZ-treated patients. 6 -8 In particular, the increase in cardiac events led recently to more restrictive measures on RGZ use in patients with T2DM. 9,10 Indeed, the original guidelines of the American Heart Association (AHA) prohibit th...

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Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

Cited by 27 publications

References 54 publications

Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome

Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome

Lysine-specific demethylase-1 modifies the age effect on blood pressure sensitivity to dietary salt intake

Effects of Chronic Rosiglitazone Treatment on Renal Handling of Salt and Water in Rats With Volume-Overload Congestive Heart Failure

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