The endoplasmic reticulum stress inhibitor, 4‐phenylbutyrate, attenuates chronic kidney disease induced by a model of cardiorenal syndrome (1136.12)
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abstract
Endoplasmic reticulum stress has been identified as a feature of chronic kidney disease and appears to be associated with proteinuria. We have found the endoplasmic reticulum stress inhibitor, 4‐phenylbutyrate (4‐PBA), reduced renal damage in a mouse model of acute kidney injury. Therefore, we hypothesized that inhibition of endoplasmic reticulum stress through augmenting protein folding with a low molecular weight chemical chaperone, 4‐PBA, would attenuate chronic kidney disease. Chronic kidney disease was induced in uninephrectomized wild type mice. After recovery from uninephrectomy, an angiotensin II infusion pump (1.5 ng/min/g) and a deoxycorticosterone (DOCA) pellet were subcutaneously implanted and mice were provided with 1% NaCl in the drinking water for three weeks. Blood pressure was measured and animals were placed in metabolic cages for 24 h urine collection bi‐weekly, starting one week prior to uninephrectomy. Co‐treatment with 4‐PBA (1 g/kg/day) prevented angiotensin II/DOCA/salt‐induced hypertension, cardiac hypertrophy, proteinuria, and kidney injury, as demonstrated by reduced α‐smooth muscle actin expression, protein cast formation and damaged glomeruli. However, 4‐PBA‐treated mice suffered from significantly higher mortality rates. Inhibition of cardiac hypertrophy by 4‐PBA may have been the cause of the increased mortality through congestive heart failure. Despite the higher mortality rate in 4‐PBA‐treated mice, we conclude that 4‐PBA prevents hypertension, proteinuria, cardiac hypertrophy, and chronic kidney disease in this angiotensin II/DOCA/salt model of cardiorenal syndrome.Grant Funding Source: Supported by CIHR OSO‐115895.
