ER stress and a chronic inflammatory response are induced in an Angiotensin II/DOCA salt model of chronic kidney disease.

We have developed a C57BL/6 mouse model of Chronic Kidney Disease (CKD). The mice underwent a uninephrectomy (Unx) or a sham operation. Unx mice received 1% NaCl in the drinking water and a 50 mg 21‐day release deoxycorticosterone (DOCA) pellet with Angiotensin II (AngII) infusion (1.5 ng Ang II/minute/g). Mice were sacrificed at day 21. This model produced CKD characterized by hypertensive proteinuria. We hypothesized that hypertension‐induced proteinuria results in endoplasmic reticulum (ER) stress as microarray studies in patients with established proteinuria showed upregulation of unfolded protein response (UPR) genes. In the model, electron microscopy showed disruption of the podocyte filtration barrier. Light microscopy revealed an increase in PAS‐positive intratubular protein casts. RT‐PCR analysis showed increased ER stress markers: GRP78, spliced XBP1, CHOP and TDAG51. TUNEL staining showed increased apoptosis in the tubular epithelium of Unx animals. An increase in T‐cell and macrophage infiltration confirmed an inflammatory response to CKD accompanied by renal interstitial fibrosis as shown by de novo α‐smooth muscle actin and collagen staining. This response may be due to ER stress induced pro‐inflammatory mediators such as NFκB. Future studies will assess whether the therapeutic inhibition of ER stress could alter the progression of chronic inflammation in CKD. Funding, CIHR OSO‐115895.