Renal endoplasmic reticulum stress is induced via endothelin A receptor activation (857.7)

Abstract

The endothelin (ET‐1) system has been recently implicated in renal endoplasmic reticulum (ER) stress development, a type of cellular stress caused by misfolded protein accumulation within this organelle. To clarify the role of the ETA receptor in renal ER stress, we hypothesized that pharmacological blockade of this receptor via ABT‐627 leads to reduced renal response to the ER stress inducer tunicamycin (TM). WT and ETB deficient (sl/sl) rats (n=3‐4/group) were pre‐treated with ABT‐627 (5mg/kg/day; drinking water) for 1 week and given a single injection of TM (2ug/g bwt; i.p.). Kidneys, plasma and urine were collected 24h later. ER stress markers in renal cortical and medullary regions were determined by qRT‐PCR. Treatment of WT animals with ABT‐627 significantly reduced the ER stress response to TM in cortex and outer medulla (fold change/WT+H2O; GRP78 (0.12±0.02 and 0.04± 0.01, respectively), ATF‐4 (0.20± 0.02 and 0.15± 0.02), ATF‐6 (0.28± 0.08 and 0.18± 0.04), spliced XBP‐1 (0.03+0.01 and 0.05± 0.01) and CHOP (0.02± 0.01 and 0.04± 0.01). On the contrary, ABT‐627 pre‐treatment failed to decrease cortical and medullary ER stress development in sl/sl rats. These results indicate that ETA receptor activation leads to induction of renal ER stress genes, while ETB receptor activation has protective effects. Modulation of the ET system may have therapeutic value in protecting against ER stress‐induced renal injury.Grant Funding Source: Supported by NIH and AHA