title: Endoplasmic reticulum stress inhibition limits the progression of chronic kidney disease in the Dahl salt-sensitive rat.
abstract: Proteinuria is one of the primary risk factors for the progression of chronic kidney disease (CKD) and has been implicated in the induction of endoplasmic reticulum (ER) stress. We hypothesized that the suppression of ER stress with a low molecular weight chemical chaperone, 4-phenylbutyric acid (4-PBA), would reduce the severity of CKD and proteinuria in the Dahl salt-sensitive (SS) hypertensive rat. To induce hypertension and CKD, 12-wk-old male rats were placed on a high-salt (HS) diet for 4 wk with or without 4-PBA treatment. We assessed blood pressure and markers of CKD, including proteinuria, albuminuria, and renal pathology. Furthermore, we determined if HS feeding resulted in an impaired myogenic response, subsequent to ER stress. 4-PBA treatment reduced salt-induced hypertension, proteinuria, and albuminuria and preserved myogenic constriction. Furthermore, renal pathology was reduced with 4-PBA treatment, as indicated by lowered expression of profibrotic markers and fewer intratubular protein casts. In addition, ER stress in the glomerulus was reduced, and the integrity of the glomerular filtration barrier was preserved. These results suggest that 4-PBA treatment protects against proteinuria in the SS rat by preserving the myogenic response and by preventing ER stress, which led to a breakdown in the glomerular filtration barrier. As such, alleviating ER stress serves as a viable therapeutic strategy to preserve kidney function and to delay the progression of CKD in the animal model under study.
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; and.
authors.forename: Victoria
authors.initials: V
authors.lastname: Yum
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; and.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Carlisle
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; and.
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; and.
authors.forename: Elise
authors.initials: E
authors.lastname: Brimble
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; and.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Chahal
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; and.
authors.forename: Chandak
authors.initials: C
authors.lastname: Upagupta
authors.affiliation: Department of Medicine, Division of Respirology, McMaster University, St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Ask
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; and jdickhou@stjosham.on.ca.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Dickhout
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology*; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000473:pathology; D012965:Sodium Chloride / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*
chemical_list: D010654:Phenylbutyrates; D017673:Sodium Chloride, Dietary; D012965:Sodium Chloride; C075773:4-phenylbutyric acid
keywords: 4-phenylbutyric acid; endoplasmic reticulum stress; myogenic response; proteinuria; salt-sensitive hypertension