Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

• Main Authors: Yanling Yan, Jiayan Wang, Muhammad A. Chaudhry, Ying Nie, Shuyan Sun, Jazmin Carmon, Preeya T. Shah, Fang Bai, Rebecca Pratt, Cameron Brickman, Komal Sodhi, Jung Han Kim, Sandrine Pierre, Deepak Malhotra, Gary O. Rankin, Zi-jian Xie, Joseph I. Shapiro, Jiang Liu
• Format: Article
• Language: English
• Published: MDPI AG 2019-07-01
• Series: International Journal of Molecular Sciences
• Subjects: Na/K-ATPase; salt-sensitive hypertension; obesity; metabolic syndrome; pressure-natriuresis curve; reactive oxygen species
• Online Access: https://www.mdpi.com/1422-0067/20/14/3495

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na⁺ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na⁺ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na⁺ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.