Hypertension induces proteinuria and renal fibrosis associated with endoplasmic reticulum (ER) stress in the Dahl salt sensitive rat

Abstract

Hypertension and proteinuria are associated with the progression of chronic kidney disease (CKD). CKD occurs via a process of kidney fibrosis and nephron loss. The Dahl salt sensitive hypertensive rat (Dahl SS) is a model of hypertension caused by high salt, resulting in proteinuria and CKD. We hypothesized that hypertension‐induced proteinuria in the Dahl SS leads to renal fibrosis through the initiation of ER stress and the unfolded protein response (UPR). The UPR is an important modulator in the differentiation of various cell types, including myofibroblasts. We tested this using two models of hypertension, the Dahl SS rat and the spontaneously hypertensive rat (SHR) treated with a high salt (8% NaCl) or maintained on a low salt (0.4% NaCl) diet for 14 days. Kidneys from these animals were processed for histology and immunohistochemistry for markers of both ER stress and fibrosis. In the high salt treated Dahl SS rat, intratubular protein casts were observed. These rats also displayed renal fibrosis as shown by trichrome and α‐smooth‐muscle actin staining, and ER stress, shown by GRP78 and CHOP staining. Contrarily, the SHR developed no significant proteinuria or interstitial fibrosis in response to high salt despite malignant hypertension. These results suggest that hypertension‐induced proteinuria is associated with an ER stress response and renal interstitial fibrosis. Supported by CIHR – OSO‐115895.