The IRE1/JNK signaling pathway regulates inflammation cytokines and production of glomerular extracellular matrix in the acute kidney injury to chronic kidney disease transition.

Abstract

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is extremely complex. Incomplete renal tubule repair, inflammation, and endoplasmic reticulum (ER) stress all play major roles. AKI activates ER stress, and the sensor protein inositol-requiring kinase-1 (IRE1) mediates inflammation by promoting the phosphorylation of C-jun NH2-terminal kinase (JNK). The interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway is associated with the secretion of renal extracellular matrix (ECM) and fibrosis. It remains unclear whether these signaling pathways play a role in the AKI-CKD transition. In this study, a mouse model of ischemia-reperfusion (I/R) with bilateral renal artery clipping was used. IRE1 or JNK inhibitors were also injected to confirm their roles in the AKI-CKD transition. The renal function of the mice was determined by observing the pathology of the renal tubules and glomeruli through electron microscopy, immunohistochemistry, western blotting and quantitative real-time PCR. I/R stimulates ER stress and the IRE1/JNK pathway in the renal tubules in a short period of time, leading to continuous inflammation. Long-term I/R injury activates the STAT3 pathway in the glomeruli, activates mesangial cells proliferation, causes secretion of large amounts of glomerular ECM, and promotes glomerular sclerosis. This damage to the renal tubules and glomeruli is significantly reduced in I/R model mice pretreated with IRE1 or JNK inhibitors. These findings suggested that the IRE1/JNK pathway regulates the inflammatory cytokines caused by AKI and continues to activate the STAT3 pathway and production of ECM in the glomeruli at late stages, suggesting the feasibility of targeted therapy for the AKI-CKD transition.