PI3K/Akt pathway mediates high glucose‐induced lipid accumulation in human renal proximal tubular cells via spliced XBP‐1

Abstract

In the present study, we investigated the effect of X-box-binding protein-1 (XBP-1) splicing on lipogenesis in high glucose-stimulated human renal proximal tubular cell line (HKC). The results revealed that high glucose promoted the splicing of XBP-1, concomitant with up-regulation of lipogenic genes including fatty acid synthase, acetyl-CoA carboxylase, adipocyte differentiation-related protein, and cellular triglyceride. Again, silence of XBP-1 with shRNA vector inhibited high glucose-caused increased lipogenesis. Furthermore, we confirmed that the inhibition of phosphotidyl inositol 3-kinase (PI3K)/Akt pathway with LY294002 or Akt shRNA vector blocked the effect of high glucose on XBP-1 splicing and cellular triglyceride. These above data suggest that spliced XBP-1 mediates high glucose-induced lipid accumulation in HKC cells and PI3K/Akt pathway may be involved in high glucose-caused XBP-1 splicing.

Intermittent injections of osteocalcin reverse autophagic dysfunction and endoplasmic reticulum stress resulting from diet-induced obesity in the vascular tissue via the NFκB-p65-dependent mechanism

“…40 However, the possibility that Gprc6a could be a specific receptor for osteocalcin has never been tested through biochemical or genetic means, and it is still hard to clearly define the early stages of osteocalcin-mediated signaling from the plasma membrane. Blockade of Akt pathway effectively prevented increased XBP-1 and lipid droplet formation in human renal proximal tubular cells under stimulation of high glucose, 41 indicating that Akt pathway mediated high glucoseinduced XBP-1 expression. In our study, osteocalcin could reduce ER stress and improve insulin signaling in multiple cell types in an XBP-1-independent manner.…”

Effect of Qufengtongluo Decoction on PI3K/Akt Signaling Pathway in the Kidney of Type 2 Diabetes Mellitus Rat (GK Rat) with Diabetic Nephropathy

“…P-PI3K and p-Akt activate PI3K/Akt signaling pathway, while PTEN can inhibit PI3K/Akt signaling pathway [ 14 ]. PI3K/Akt signaling pathway closely contacts with the expansion of mesangial cell (MC) [ 8 , 15 , 16 ], podocyte apoptosis [ 17 ], and renal tubule injury [ 18 , 19 ]. Moreover, several studies [ 8 , 15 , 20 , 21 ] have shown that many inflammatory and immune factors, transforming growth factor- β 1 (TGF- β 1) [ 8 , 15 , 20 ] and tumor necrosis factor-a (TNF-a) [ 21 ], for example, contribute to DN formation through PI3K/Akt signaling pathway.…”

Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly

“…In human proximal tubular cells (HK-2) palmitic acid (a FFA) induces ER stress and this can be blocked with a cannabinoid receptor antagonist [88]. In a human renal tubular cell line (HKC), high glucose conditions increase splicing of XBP-1 and transfection of spliced XBP-1 increases expression of fatty acid synthase and acetyl-CoA carboxlase to promote lipid synthesis [89]. In contrast, in mesangial cells, high glucose conditions reduce spliced XBP-1 expression.…”