Stimulation of endoplasmic reticulum stress and inflammation by neuronal (pro)renin receptor is mediated by Toll‐like receptor 4 activation (686.32)

Abstract

Our previous studies demonstrated that brain neuronal prorenin receptor (PRR) contributes to hypertension via NF‐KappB (KB)‐cytokine signaling. This finding coupled with the important role of toll like receptor 4 (TLR4) in inflammation and endoplasmic reticulum (ER) stress suggest that brain neuronal PRR activation, in part, stimulates TLR4 and subsequently induces ER stress and NF‐KB‐cytokine signaling. Therefore blocking TLR4 activation should attenuate the cytokines and ER stress response induced by PRR activation. To test this hypothesis, primary neuronal cultures from rat brain were incubated with 20 nM of renin for 6 hours. Real time PCR was performed to analyze the expression of inflammatory cytokines, NF‐KB and ER stress markers. Renin treatment resulted in significant increases in IL1β (1200‐fold), IL6 (33‐fold), TNFα (17‐fold), NF‐KB (6‐fold) and I‐kappa B kinase (IKK) (7‐fold). In addition, the mRNA levels of ER stress marker Ddit3 and Hspa3 increased by 47%and 41% in renin treated neurons. Quinazoline (10µM), a NF‐KB activation inhibitor, effectively blocked renin‐induced increases in IL1β, IL6, TNFα and NF‐KB, by more than 85%, but failed to inhibit IKK, Ddit3 and Hspa3. In contrast, renin stimulation on all these genes was almost entirely blocked (>90%) by a TLR4 inhibitor TAK‐242 (2 µM), indicating an important role of TRL4 in this newly identified PRR mediated activation of ER stress and inflammation signaling. Further study will probe whether NF‐KB‐inflammation is mediated by ER stress in the context of hypertension.Grant Funding Source: AHA 11SDG7420029