title: Endothelin receptor-specific control of endoplasmic reticulum stress and apoptosis in the kidney.
abstract: Endothelin-1 (ET-1) promotes renal damage during cardiovascular disease; yet, the molecular mechanisms involved remain unknown. Endoplasmic reticulum (ER) stress, triggered by unfolded protein accumulation in the ER, contributes to apoptosis and organ injury. These studies aimed to determine whether the ET-1 system promotes renal ER stress development in response to tunicamycin. ETBdeficient (ETBdef) or transgenic control (TG-con) rats were used in the presence or absence of ETAreceptor antagonism. Tunicamycin treatment similarly increased cortical ER stress markers in both rat genotypes; however, only ETBdef rats showed a 14-24 fold increase from baseline for medullary GRP78, sXBP-1, and CHOP. Pre-treatment of TG-con rats with the ETAblocker ABT-627 for 1 week prior to tunicamycin injection significantly reduced the ER stress response in cortex and medulla, and also inhibited renal apoptosis. Pre-treatment with ABT-627 failed to decrease renal ER stress and apoptosis in ETBdef rats. In conclusion, the ET-1 system is important for the development of tunicamycin-induced renal ER stress and apoptosis. ETAreceptor activation induces renal ER stress genes and apoptosis, while functional activation of the ETBreceptor has protective effects. These results highlight targeting the ETAreceptor as a therapeutic approach against ER stress-induced kidney injury.
authors.affiliation: Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: De Miguel
authors.affiliation: Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hamrick
authors.affiliation: Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Hobbs
authors.affiliation: Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Pollock
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Carmines
authors.affiliation: Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pollock
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D059865:Endoplasmic Reticulum Stress; D007668:Kidney / Q000473:pathology*; D051381:Rats; D017466:Receptors, Endothelin / Q000378:metabolism*; D014415:Tunicamycin / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D017466:Receptors, Endothelin; D014415:Tunicamycin