Alteration of Forkhead Box O (Foxo4) Acetylation Mediates Apoptosis of Podocytes in Diabetes Mellitus

Abstract

The number of kidney podocytes is reduced in diabetic nephropathy. Advanced glycation end products (AGEs) accumulate in patients with diabetes and promote the apoptosis of podocyte by activating the forkhead box O4 (Foxo4) transcription factor to increase the expression of a pro-apoptosis gene, Bcl2l11. Using chromatin immunoprecipitation we demonstrate that AGE-modified bovine serum albumin (AGE-BSA) enhances Foxo4 binding to a forkhead binding element in the promoter of Bcl2lll. AGE-BSA also increases the acetylation of Foxo4. Lysine acetylation of Foxo4 is required for Foxo4 binding and transcription of Bcl2l11 in podocytes treated with AGE-BSA. The expression of a protein deacetylase that targets Foxo4 for deacetylation, sirtuin (Sirt1), is down regulated in cultured podocytes by AGE-BSA treatment and in glomeruli of diabetic patients. SIRT1 over expression in cultured murine podocytes prevents AGE-induced apoptosis. Glomeruli isolated from diabetic db/db mice have increased acetylation of Foxo4, suppressed expression of Sirt1, and increased expression of Bcl2l11 compared to non-diabetic littermates. Together, our data provide evidence that alteration of Foxo4 acetylation and down regulation of Sirt1 expression in diabetes promote podocyte apoptosis. Strategies to preserve Sirt1 expression or reduce Foxo4 acetylation could be used to prevent podocyte loss in diabetes.

Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes

“…We, indeed, observed that SIRT1 expression was increased in GN induced by NTS in vivo and H 2 O 2 -treated podocytes in vitro (Supplemental Figure 8). Chuang et al 35 showed that SIRT1 overexpression in cultured murine podocytes prevents glycative stress-induced apoptosis under diabetic conditions, whereas Yuan et al 36 showed that SIRT1 prevents aldosterone-induced apoptosis of podocytes. Both studies highlight the link between the podocyte-protective effect of SIRT1 and podocyte apoptosis.…”

“…[24][25][26][27][28] In addition, SIRT1 protects the proximal tubular, [29][30][31] medullary, 32 and mesangial cells. 33,34 Several studies have also suggested the possibility of a protective effect of SIRT1 on podocytes [35][36][37] ; however, the molecular mechanism of the function of SIRT1 expressed in podocytes remains unclear.…”

Sirtuin 1: A Target for Kidney Diseases

“…SIRT1 protected renal tubular cells against apoptosis by the bidirectional regulation of catalase expression via deacetylation of FOXO3 (50). In addition, SIRT1 reduced FOXO4 acetylation, preventing podocyte from apoptosis in diabetes (51). Actually, the study by Nemoto et al (62) indicated SIRT1 expression to be regulated in a feed-forward loop by FOXO3a.…”

Hydrogen Rich Water Attenuates Renal Injury and Fibrosis by Regulation Transforming Growth Factor-β Induced Sirt1

“…[12][13][14][15] Silent information regulator (Sir) is a family of genes which participates in the regulation of lifespan. 16) Sirtuins (Sirt), mammalian homologs of Sir2, is a family of nicotinamide adenine dinucleotide-dependent deacetylases.…”

“…[18][19][20] As we all know, increasing evidences have revealed the significant effect of Sirt1 on antifibrosis in DN and AKI. [12][13][14][15] Hydrogen exists virtually everywhere in nature which is found in almost every chemical compound. In this study, we hypothesized that HW is able to alleviate renal fibrosis induced by transforming growth factor-β1 (TGF-β1) by impacting Sirt1.…”