2.2.4. Endoplasmic Reticulum Stress

There is experimental evidence that the accumulation of unfolded proteins in the endoplasmic reticulum of renal tubular epithelial cells may play a role in their death and associated interstitial fibrosis [55]. This accumulation causes endoplasmic reticulum stress, thereby activating the unfolded protein response, which is an evolutionarily conserved cellular response primarily regulated by the endoplasmic reticulum-resident chaperone glucose-regulated protein 78 (GRP78). Misfolded proteins cause GRP78 to dissociate from endoplasmic reticulum transmembrane proteins (PKR-like endoplasmic reticulum kinase, inositol-required enzyme 1, and activating transcription factor 6), thereby activating the cell survival unfolded protein response signaling pathways. This response attempts to maintain proteostasis by reducing general protein translation and increasing the production of molecular chaperones. Severe endoplasmic reticulum stress leads to apoptosis of renal epithelial cells. Endoplasmic reticulum stress also increases the expression of T-cell deathassociated gene 51 (TDAG51), also known as pleckstrin homology-like domain, family A member 1. This increases the expression of TGF-β (transforming growth factor) receptor 1, which leads to the splicing of the *xbp1* (X box protein) gene. Spliced XBP1 protein leads to the activation of pro-fibrotic genes, and the development of renal interstitial fibrosis [55].

Acute kidney injury superimposed on CKD may accelerate the progression to kidney failure. One of the ways it may do this is by impairing nicotinamide adenine dinucleotide (NAD+) production, by repressing transcription of the gene for quinolinate phosphoribosyl transferase (QPRT, a bottleneck enzyme of de novo NAD+ biosynthesis), as part of the endoplasmic reticulum stress response [56]. A high urinary quinolinate-to-tryptophan ratio can serve as an indirect indicator of impaired QPRT activity and reduced de novo NAD+ biosynthesis in the kidney [56].
