Crosstalk between the Unfolded Protein Response and NF-κB-Mediated Inflammation in the Progression of Chronic Kidney Disease

Table 1

Pharmacological manipulation of the UPR. To study the various pathways of the UPR, pharmacological manipulations to the specific pathways can be utilized. To examine the PERK pathway, salubrinal is an inhibitor of the dephosphorylation of eIF2. To investigate the IRE1 pathway, STF-083010 and Irestatin are inhibitors of IRE1 endonuclease activity. The ATF6 pathway can be inhibited with 4-(2-aminoetheryl) benzenesulfonyl fluoride (AEBSF) to prevent cleavage of ATF6. The role of protein folding chaperones can be determined by utilizing artificial chaperones including 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), which aid in the folding of proteins. Further, to investigate sustained activation of the unfolded protein response, classic ER stress inducers, tunicamycin and thapsigargin, can be used as well as disease-related inducers including indoxyl sulfate.

UPR gene	Pharmacological manipulation	Description
PERK	Salubrinal	Phosphatase inhibitor prevents dephosphorylation of eIF2
	GSK2606414	Potent and selective PERK inhibitor
IRE1	STF083010	Specifically inhibits IRE1 endonuclease activity during ER stress without affecting its kinase activity
	Irestatin	Specific inhibitor of IRE1
ATF6	4-(2-Aminoethyl) benzenesulfonyl fluoride (AEBSF)	Serine protease inhibitor inhibits site 1 and site 2 proteases preventing ATF6 cleavage and inhibits transcription of ATF6 target genes
Small chemical protein folding chaperones	4-Phenylbutyrate (4-PBA)	4-PBA and TUDCA aid in protein folding reducing misfolded protein accumulation in the ER
	Tauroursodeoxycholic acid (TUDCA)
UPR activating agents	Tunicamycin	Inhibitor of N-linked protein glycosylation hinders a process required for proper protein folding
	Thapsigargin	Inhibitor of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump causes ER stress
	Indoxyl sulfate	Uremic toxin that causes ER stress via oxidative stress