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FBXW7 mediates high glucose?induced SREBP?1 expression in renal tubular cells of diabetic nephropathy under PI3K/Akt pathway regulation.

ABSTRACT: Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and lipid metabolism abnormality serves a key role in the pathogenesis of DN. Sterol regulatory element?binding protein 1 (SREBP?1) overexpression mediates aberrant lipid accumulation in renal tubular cells of DN. However, the exact mechanism involved in increased SREBP?1 has not been fully elucidated. The aim of the present study was to explore the mechanism involved in SREBP?1 upregulation. Diabetic mice and high glucose?cultured HKC cells were chosen to detect the expression of FBXW7 and SREBP?1 using immunohistochemistry, western blotting and PCR. The present study demonstrated that F?box and WD repeat domain containing 7 (FBXW7) expression was decreased in renal tubular cells of diabetic mice. Moreover, the co?expression of FBXW7 and SREBP?1 was observed in renal tubular cells, but not in the glomeruli. High glucose?induced the downregulation of FBXW7 expression in in vitro cultured HKC cells, which was accompanied by SREBP?1 upregulation. In addition, overexpression of FBXW7 in HKC cells led to SREBP?1 downregulation. By contrast, knockdown of FBXW7 caused SREBP?1 upregulation in HKC cells. It was found that the PI3K/Akt signaling pathway was activated in high glucose?stimulated HKC cells, and inhibition of PI3K/Akt pathway using LY294002 increased FBXW7 expression and decreased SREBP?1 expression. Taken together, the present results suggested that FBXW7 mediated high glucose?induced SREBP?1 expression in renal tubular cells of DN, under the regulation of the PI3K/Akt signaling pathway.

SUBMITTER: Li L

PROVIDER: S-EPMC7893693 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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FBXW7 mediates high glucose‑induced SREBP‑1 expression in renal tubular cells of diabetic nephropathy under PI3K/Akt pathway regulation.

Li Lisha L Yang Juxiang J Li Fan F Gao Fan F Zhu Lin L Hao Jun J

Molecular medicine reports 20210204 4

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and lipid metabolism abnormality serves a key role in the pathogenesis of DN. Sterol regulatory element‑binding protein 1 (SREBP‑1) overexpression mediates aberrant lipid accumulation in renal tubular cells of DN. However, the exact mechanism involved in increased SREBP‑1 has not been fully elucidated. The aim of the present study was to explore the mechanism involved in SREBP‑1 upregulation. Diabetic mice and high glucose‑c ...[more]

PMID: 33537812

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Project description:Hyperglycemia induces p38 MAPK-mediated renal proximal tubular cell (RPTC) apoptosis. The current study hypothesized that alteration of the Akt signaling pathway by hyperglycemia may contribute to p38 MAPK activation and development of diabetic nephropathy. Immunoblot analysis demonstrated a hyperglycemia-induced increase in Akt phosphorylation in diabetic kidneys at 1 mo, peaking at 3 mo, and dropping back to baseline by 6 mo. Immunohistochemical staining with anti-pAkt antisera localized Akt phosphorylation to renal tubules. Maximal p38 MAPK phosphorylation was detected concomitant with increase in terminal uridine deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and caspase-3 activity in 6-mo diabetic kidneys. Exposure of cultured RPTCs to high glucose (HG; 22.5 mM) significantly increased Akt phosphorylation at 3, 6, and 9 h, and decreased thereafter. In contrast, p38 MAPK phosphorylation was detected between 9 and 48 h of HG treatment. Increased p38 MAPK activation at 24 and 48 h coincided with increased apoptosis, demonstrated by increased caspase-3 activity at 24 h and increased TUNEL-positive cells at 48 h of HG exposure. Blockade of p38 cascade with SB203850 inhibited HG-induced caspase-3 activation and TUNEL-positive cells. Overexpression of constitutively active Akt abrogated HG-induced p38 MAPK phosphorylation and RPTC apoptosis. In addition, blockade of the phosphatidylinositol-3 kinase/Akt pathway with LY294002 and silencing of Akt expression with Akt small interfering RNA induced p38 MAPK phosphorylation in the absence of HG. These results collectively suggest that downregulation of Akt activation during long-term hyperglycemia contributes to enhanced p38 MAPK activation and RPTC apoptosis. Mechanism of downregulation of Akt activation in 6-mo streptozotocin diabetic kidneys was attributed to decreased Akt-heat shock protein (Hsp) 25, Akt-p38 interaction, and decreased PTEN activity. Thus PTEN or Hsp25 could serve as potential therapeutic targets to modulate Akt activation and control p38 MAPK-mediated diabetic complications.

Dataset Information

FBXW7 mediates high glucose?induced SREBP?1 expression in renal tubular cells of diabetic nephropathy under PI3K/Akt pathway regulation.

Publications

FBXW7 mediates high glucose‑induced SREBP‑1 expression in renal tubular cells of diabetic nephropathy under PI3K/Akt pathway regulation.

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