THE EFFECT OF THE ER STRESS INHIBITOR, 4-PHENYLBUTYRATE, ON CHRONIC KIDNEY DISEASE IN A MODEL OF SALT SENSITIVE HYPERTENSION

Abstract

<p>ER stress in the kidney is associated with proteinuria. Clinical studies have linked proteinuria with the progression of chronic kidney disease (CKD) at all stages of GFR decline. We hypothesized that treatment with a chemical chaperone, 4-phenylbutyrate (4-PBA), would reduce the severity of CKD and proteinuria in salt sensitive hypertension. The differences in renal pathology between salt sensitive and insensitive hypertension when animals were fed an 8% NaCl (HS) diet were assessed. The Dahl salt sensitive (Dahl S) rat was used as a model of salt sensitive hypertension, while the spontaneously hypertensive rat (SHR) was used as a model of salt insensitive hypertension. The myogenic response of the arcuate artery was studied to determine whether the differences in renal pathology between these models of hypertension was due to an effect of salt on myogenic constriction. Myogenic constriction displayed salt sensitivity in the Dahl S as there was a significant reduction in blood vessel constriction with increasing intralumenal pressures. Myogenic constriction was reduced, but not completely abolished in the SHR with high salt (HS), providing a possible explanation of why this model of hypertension does not develop an equivalent level of renal damage with blood pressure increase as the Dahl S rat. ER stress induction with tunicamycin in arcuate arteries from normotensive animals resulted in an attenuation of the myogenic response. Myogenic constriction was protected from tunicamycin induced ER stress with 4-PBA. 4-PBA treatment (1g/kg/day) in HS fed Dahl S ameliorated proteinuria, renal intratubular protein casts, and renal fibrosis. This correlated with a protection of myogenic constriction and integrity of the glomerular filtration barrier. This suggests that myogenic constriction of the renal vasculature is an important mechanism to protect against salt sensitive hypertension-induced proteinuria. Further, that high salt feeding may inhibit this protective mechanism by inducing ER stress in the renal blood vessels.</p>