PPARγ-Induced Stimulation of Amiloride-Sensitive Sodium Current in Renal Collecting Duct Principal Cells is Serum and Insulin Dependent

Abstract

Background/Aims: Thiazolidinediones (TZDs), such as rosiglitazone or pioglitazone, are peroxisome proliferator-activated receptor gamma (PPARγ) agonists currently used in the treatment of type 2 diabetes. However, their clinical applicability is limited by common and severe side effects including strong water retention, edema and cardiac stroke. The precise mechanisms leading to these disorders are not clearly understood and remain controversial. While the nature of the disorders due to TZDs points to an increase in ENaC-mediated sodium reabsorption in the aldosterone-sensitive distal nephron, some studies suggested that this channel was not targeted by PPARγ agonists. Methods: Mouse cortical collecting duct cells were incubated in different types of culture medium and treated with or without rosiglitazone. Transepithelial Na⁺ current was measured and the changes in SGK and Nedd4 expression were determined by immunoblotting. Results: Herein we demonstrate that rosiglitazone stimulates the amiloride-sensitive transepithelial sodium current in Collecting Duct Principal Cells after 3h and 24h treatment. This activation was dependent of both serum and insulin in culture medium and was mediated by SGK1/Nedd4-2 pathway stimulation. In these conditions, rosiglitazone induced SGK1 expression, Nedd4-2 phosphorylation and thus abolished ubiquitylation and internalization of ENaC channels. This mechanism explains most of the side effects of thiazolidinediones previously observed in humans and animals. Conclusion: Our data show an increase in transepithelial sodium amiloride-sensitive current induced by a PPARγ agonist in presence of serum and insulin, thus confirming some in-vitro and in-vivo experiments while providing explanations for previous conflicting findings.

Serum and Glucocorticoid Regulated Kinase 1 in Sodium Homeostasis

“…The kidneys play a pivotal role in the maintenance of Na + homeostasis [62,173]. Urinary Na + reabsorption is regulated tightly to maintain a constant extracellular volume as limiting extrarenal Na + loss during dietary Na + restriction [47].…”

“…As illustrated above, SGK1 regulates ENaC [62,85,173] in the apical membrane and the Na + /K + -ATPase in the basolateral membrane, thereby coordinating Na + transport at both sides of epithelial cells [177]. In early distal tubules, the chlorothiazide-sensitive NCC mediates Na + uptake [178,179].…”

“…This Na + retention in nephrons may contribute to the development of edema and promote secondary hypertension in patients with type 2 diabetes mellitus, as a side effect of PPARγ treatment [62]. PPARγ agonists promote the activation of SGK1, the phosphorylation of Nedd4-2 and abolish ubiquitination and internalization of ENaC, leading to sodium and fluid retention [62]. Moreover, PPARγ stimulates Na + transport in the distal tubular epithelia and proximal tubule cells via SGK1-dependent regulation of NHE3 [184,237,239].…”

“…Both its expression levels and activities are regulated by hormonal and non-hormonal factors [50], including glucocorticoids [51,52], mineralocorticoids [16,42], androgen [53,54,55,56], gonadotropin-releasing hormone (GnRH) [57], excessive extracellular glucose concentrations [58,59], memory consolidation and reconsolidation [60], hypertonic and hypotonic stimuli [61], chronic stress [52], and peroxisome proliferator-activated receptor γ (PPARγ) [62]. SGK1 is also induced by lipopolysaccharides [63], tumor necrosis factor (TNF)-α [63,64], angiotensin [65], resistin [66], granulocyte-macrophage colony-stimulating factor (GM-CSF) [67], fibroblast growth factor-23 (FGF23) [68], as well as miR-27a [24], miR-424 [69], miR-155 [70] and miR-133b [71].…”

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“…Change in allergenicity and potency: Metal binding may alter potency and allergenicity of antibiotics. Some are notorious for side effects, e.g., water retention and heart failure upon sodium penicillin administration 11…”