Sirtuin1 (SIRT1) Regulates Tumor Necrosis Factor-alpha (TNF-α-Induced) Aquaporin-2 (AQP2) Expression in Renal Medullary Collecting Duct Cells Through Inhibiting the NF-κB Pathway

Abstract

BackgroundAquaporin-2 (AQP2) plays a major role in water reabsorption in the renal collecting duct, and is involved in a variety of renal disease. Recent studies have indicate that sirtuin1 (SIRT1) exerts renoprotective properties against kidney diseases. This study aimed to determine the potential role of SIRT1 in AQP2 expression induced by tumor necrosis factor-alpha (TNF-α) and to disclose the underlying mechanism in renal inner medullary collecting duct (IMCD) cells.Material/MethodsQuantitative real-time PCR and Western blotting were respectively identified mRNA and protein expression. Immunofluorescence staining was used to detect the localization of AQP2. Small-interfering RNA (siRNA) was carried out for mechanism study.ResultsResults showed that AQP2 was clearly increased in the plasma membrane and decreased in the cytoplasm of IMCD cells treated with AVP. TNF-α treatment in IMCD cells significantly reduced SIRT1 and AQP2 expression, and increased acetylated NF-κBp65 protein level in time- and concentration-dependent manners. Moreover, SIRT1 overexpression or the activator SRT1720 augmented AQP2 expression and reduced the acetylation of NF-κBp65, which was reversed by SIRT1 siRNA or the inhibitors Ex527 and sirtinol in TNF-α-induced IMCD cells. Knockdown of NF-κBp65 or NF-κBp65 inhibition by pyrrolidine dithiocarbamate (PDTC) enhanced AQP2 expression in IMCD cells exposed to TNF-α. Importantly, knockdown of NF-κBp65 augmented the up-regulation of SIRT1 on AQP2 expression in IMCD cells induced by TNF-α.ConclusionsThese findings indicate that SIRT1 increases AQP2 expression in TNF-α-induced IMCD cells via the NF-κB-dependent signalling pathway, which might provide novel insight to understanding the renoprotective effects of SIRT1 in kidney diseases.

Inhibiting the urokinase‐type plasminogen activator receptor system recovers STZ‐induced diabetic nephropathy

“…In addition, NF‐κB regulation of ICAM‐1 positively correlates with nephropathy by influencing mesangial cell proliferation . Moreover, NF‐κB participates to iNOS accumulation and, together with CREB, regulates AQP2 gene transcription . Whether UPARANT‐induced inhibition of HIF‐1α accumulation ameliorates kidney disease remains unclear as to some extent the activation of HIF‐1, but not its inhibition, seems to exert a beneficial role in the progression of DN .…”

“…58 Moreover, NF-κB participates to iNOS accumulation 59 and, together with CREB, regulates AQP2 gene transcription. 60 Whether UPARANT-induced inhibition of HIF-1α accumulation ameliorates kidney disease remains unclear as to some extent the activation of HIF-1, but not its inhibition, seems to exert a beneficial role in the progression of DN. 61 Suppression of inflammatory processes and ameliorated renal fibrosis results in recovered renal morphology as shown here by the reduction of glomerular hypertrophy and mesangial area increase.…”

Biological Effects and Properties of Eukaryotic Sirtuins

“…Енергетична депривація також збільшує вміст НАД + , що в свою чергу, призводить до активації НАД + -залежної дезацетилазної активності SIRT1. Активовані AMПK і SIRT1 через фосфорилю-вання і деацетилювання активізують PGC-1α, що, в свою чергу, індукує мітохондріальний біогенез і окиснення жирних кислот (рис.3) [1,6,21,[35][36][37][38][39]. Також було показано, що SIRT3 активує такі центральні регулятори циклу трикарбонових кислот, як глутаматде-гідрогенази й ізоцитратдегідрогенази.…”

“…Амілоїди в клітинах людей, які страждають на хворобу Альцгеймера, підсилюють ацетилювання RELA-субодиниці в мікроглії мозку, акти-вуючи NF-κB. При цьому SIRT1 деацетилює NF-κB, захищаючи таким чином нейрони [15,38,51].…”

Endogenous factors and mechanisms of renoprotection and renal repair

“…For example, landmark studies by Brenner et al identified the activity of the renin-angiotensin system as a key player in the loss of GFR, and consequently, agents that block the system have successfully been introduced in clinical practice. 12,13 Clusterin (CLU) is discussed as molecule exerting its renoprotective properties by counteracting hypoxia/ischaemia-mediated injury via activation of prosurvival autophagy. 7 Research also identified acute kidney injury (AKI) as risk factor for the development of CKD, which also affects injury and repair mechanisms.…”