XBP‐1: A Key Transcriptional Regulator of Lipid Synthesis in Renal Epithelial Cells

Abstract

Renal medullary collecting duct cells are physiologically exposed to high and variable concentrations of NaCl involved in urinary concentrating mechanism. Despite such adverse environment, renal cells activate protective and survival mechanisms. In these sense, our lab demonstrated that hyperosmolarity increased lipid biosynthesis to protect membrane integrity. It is also known that the transcription of osmoprotective genes such as organic osmolyte and urea transporters, COX2, and AQPs, are induced. Such a massive protein synthesis could cause endoplasmic reticulum (ER) stress and trigger unfolded‐protein response (UPR) signalling pathways, among them the Ire1‐ XBP1 pathway. The active form of XBP‐1 is a transcription factor that activates the expression of lipogenic genes which, in turn, activate membrane biogenesis and ER stress alleviation. Thus, it could exist a relationship between osmotic‐increased lipid metabolism and UPR activation. In the present work, we explore such a possibility. To do that, MDCK cells were subjected to iso (298 mOsm/kg H2O) or hyper osmolarity (512 mOsm/kg H2O) for different periods of time and then, lipid synthesis, UPR activation, and the relationship between both processes were studied. 24 and 48 h of hypertonic treatment significantly increased the levels of 14C‐glycerol labelled‐phospholipids (PLs) and triglycerides (TGs). Such increase was consistent with the increased mRNA levels of Lipin2, FAS, DGAT2 and SCD. ER stress markers mRNA XBP1 and CHOP were also increased. XBP1 silencing reduced the levels 1,2 DAG and TAG formed. This finding was consistent with the decrease in the levels of Lipin2 and DGAT2 mRNA. Interestingly, neither PL synthesis nor Kennedy pathway enzymes mRNA levels were affected. We also found that XBP1 silencing causes SREBP (a master lipogenic transcription factor) downregulation. These results clearly evidence a major role of XBP1 in the regulation of lipid synthesis in renal epithelial cells and cell protection against osmotic stress.Support or Funding InformationFONCyT. Prestamo BID‐PICT2013‐1132.