Fang Bai

Oxidative stress has been shown to cause an alteration of intracellular signaling in adipocytes that may lead to various comorbidities of obesity and cardiovascular complications. Evidence suggests that dysregulation of Na, K-ATPase signaling can contribute to systemic inflammation and redox signaling that leads to various metabolic disturbances. Hence the present study aims to explore the specific role of adipocyte Na, K-ATPase signaling in the amelioration of pathophysiological alterations of experimental uremic cardiomyopathy. Experimental uremic cardiomyopathy was induced by partial nephrectomy (PNx), and adipocyte-specific expression of NaKtide, a peptide that inhibits Na, K-ATPase signaling, was achieved using a lentivirus construct with NaKtide expression driven by an adiponectin promoter. Cardiomyopathy and anemia induced in partial nephrectomy mice were accompanied by an altered molecular phenotype of adipocytes, increased systemic inflammatory cytokines and oxidant stress within 4 weeks. These changes were significantly worsened by the addition of a Western diet (enriched in fat and fructose contents) but were prevented with specific expression of NaKtide in adipocytes. The skeletal muscle-specific expression of NaKtide did not ameliorate the disease phenotype. Adipocyte dysfunction and uremic cardiomyopathy developed in PNx mice, both were significantly ameliorated by the adipocyte-specific expression of NaKtide. These findings suggest that oxidative milieu in the adipocyte has a pivotal role in the development and progression of uremic cardiomyopathy in mice subjected to partial nephrectomy. If confirmed in humans, this may be a lead for future research to explore novel therapeutic targets in chronic renal failure.

In recent years, Na/K-ATPase signaling has been implicated in different physiological and pathophysiological conditions, including cardiac hypertrophy and uremic cardiomyopathy. Cardiotonic steroids (CTS), specific ligands of Na/K-ATPase, regulate its enzymatic activity (at higher concentrations) and signaling function (at lower concentrations without significantly affecting its enzymatic activity) and increase reactive oxygen species (ROS) generation. On the other hand, an increase in ROS alone also regulates the Na/K-ATPase enzymatic activity and signaling function. We termed this phenomenon the Na/K-ATPase-mediated oxidant-amplification loop, in which oxidative stress regulates both the Na/K-ATPase activity and signaling. Most recently, we also demonstrated that this amplification loop is involved in the development of uremic cardiomyopathy. This review aims to evaluate the redox-sensitive Na/K-ATPase-mediated oxidant amplification loop and uremic cardiomyopathy.

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.