Hyperaldosteronemia and Activation of the Epithelial Sodium Channel Are Not Required for Sodium Retention in Puromycin-Induced Nephrosis

Lourdel, Stéphane; Loffing, Johannes; Favrè, Guillaume; Paulais, Marc; Nissant, Antoine; Fakitsas, Panos; Créminon, Christophe; Féraille, Eric; Verrey, François; Teulon, Jacques; Doucet, Alain; Deschênes, Georges

doi:10.1681/asn.2005040363

Cited by 66 publications

(108 citation statements)

References 21 publications

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“…The reason, however, remains elusive. Up to now, the majority of studies in rats focused only on the first 6 days after induction of nephrotic syndrome and could not contribute to the elucidation of the underlying mechanisms (8,13,27,34,51). The increased potassium excretion observed in nephrotic mice over time might be a consequence of increased plasma K ϩ levels and hyperaldosteronism.…”

Section: Discussionmentioning

confidence: 99%

“…Nephrotic syndrome can be induced by treatment with adriamycin (doxorubicin) (6,8,14,27,34,51). Due to the absence of immune-mediated injury and the lack of immune deposits, doxorubicin-induced nephrotic syndrome resembles human minimal change disease and focal segmental glomerulosclerosis (FSGS) (6).…”

mentioning

confidence: 99%

“…In susceptible mice doxorubicin-induced nephrotic syndrome is followed by volume retention which is accounted for by enhanced activity of epithelial sodium channels (ENaC) and Na-K-ATPase in the collecting duct (15,34). The volume retention and ascites formation in rats could not be prevented by blockade of the mineralocorticoid receptor but were completely abrogated by the ENaC inhibitor amiloride (15).…”

mentioning

confidence: 99%

“…SGK1 is expressed in the aldosterone-sensitive distal nephron (33) and stimulates the ENaC (7,9,12,16,22,26,32,33,35,41), the renal outer medullary K ϩ channel ROMK (52), and the Na ϩ -K ϩ -ATPase (40,44,53). As a matter of fact, nephrotic syndrome has previously been shown by some (8,34) but not all (51) experimentators to upregulate SGK1 protein and mRNA expression. Even if SGK1 transcript levels remained constant, SGK1-dependent stimulation of ENaC could still play a permissive role in fluid retention.…”

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confidence: 99%

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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: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Kidneys of both groups were removed from the anesthetized rats and cut into 5-mm slices. To identify Na transporters, membrane fractions from the cortex and the outer medulla (inner stripe) were prepared, and Western blot analysis was performed as previously described (20,21) (primary antibodies used were anti-NHE3, 1:1,000; anti-NCC, 1:50,000; anti-BSC1, 1:5,000; anti-␣ ENaC, 1:3,000; anti-␤ENaC, 1:20,000; anti-␥ ENaC, 1:2,000; and anti-Na ϩ /K ϩ ATPase, 1:20,000). After incubation with the appropriate peroxidase-conjugated secondary antibodies, blots were washed, and luminol-enhanced chemiluminescence (ECL; Perkin Elmer Life Science Products, Boston, MA) was used to visualize bound antibodies before exposure to Hyperfilm ECL (Amersham, Arlington Heights, IL).…”

Section: Methodsmentioning

confidence: 99%

Exposure to Maternal Diabetes Induces Salt-Sensitive Hypertension and Impairs Renal Function in Adult Rat Offspring

et al. 2008

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OBJECTIVE— Epidemiological and experimental studies have led to the hypothesis of fetal origin of adult diseases, suggesting that some adult diseases might be determined before birth by altered fetal development. We have previously demonstrated in the rat that in utero exposure to maternal diabetes impairs renal development leading to a reduction in nephron number. Little is known on the long-term consequences of in utero exposure to maternal diabetes. The aim of the study was to assess, in the rat, long-term effects of in utero exposure to maternal diabetes on blood pressure and renal function in adulthood. RESEARCH DESIGN AND METHODS— Diabetes was induced in Sprague-Dawley pregnant rats by streptozotocin on day 0 of gestation. Systolic blood pressure, plasma renin activity, and renal function were measured in the offspring from 1 to 18 months of age. High-salt diet experiments were performed at the prehypertensive stage, and the abundance of tubular sodium transporters was evaluated by Western blot analysis. Kidney tissues were processed for histopathology and glomerular computer-assisted histomorphometry. RESULTS AND CONCLUSIONS— We demonstrated that in utero exposure to maternal diabetes induces a salt-sensitive hypertension in the offspring associated with a decrease in renal function in adulthood. High-salt diet experiments show an alteration of renal sodium handling that may be explained by a fetal reprogramming of tubular functions in association or as a result of the inborn nephron deficit induced by in utero exposure to maternal diabetes.

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Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC)

Loffing

Korbmacher

2009

Pflugers Arch - Eur J Physiol

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147

141

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The aldosterone-sensitive distal nephron (ASDN) includes the late distal convoluted tubule 2, the connecting tubule (CNT) and the collecting duct. The appropriate regulation of sodium (Na + ) absorption in the ASDN is essential to precisely match urinary Na + excretion to dietary Na + intake whilst taking extra-renal Na + losses into account. There is increasing evidence that Na + transport in the CNT is of particular importance for the maintenance of body Na + balance and for the long-term control of extracellular fluid volume and arterial blood pressure. Na + transport in the CNT critically depends on the activity and abundance of the amiloride-sensitive epithelial sodium channel (ENaC) in the luminal membrane of the CNT cells. As a rate-limiting step for transepithelial Na + transport, ENaC is the main target of hormones (e.g. aldosterone, angiotensin II, vasopressin and insulin/insulinlike growth factor 1) to adjust transepithelial Na + transport in this tubular segment. In this review, we highlight the structural and functional properties of the CNT that contribute to the high Na + transport capacity of this segment. Moreover, we discuss some aspects of the complex pathways and molecular mechanisms involved in ENaC regulation by hormones, kinases, proteases and associated proteins that control its function. Whilst cultured cells and heterologous expression systems have greatly advanced our knowledge about some of these regulatory mechanisms, future studies will have to determine the relative importance of the various pathways in the native tubule and in particular in the CNT.

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Hyperaldosteronemia and Activation of the Epithelial Sodium Channel Are Not Required for Sodium Retention in Puromycin-Induced Nephrosis

Cited by 66 publications

References 21 publications

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

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

Exposure to Maternal Diabetes Induces Salt-Sensitive Hypertension and Impairs Renal Function in Adult Rat Offspring

Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC)

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