Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors.The worldwide prevalence of obesity and associated cardiometabolic diseases have increased dramatically in the past 2-3 decades, rapidly becoming major challenges to the health care systems of most industrialized countries. Current estimates indicate that Ͼ1 billion people in the world are overweight or obese (1). In the United States, at least 65% of adults are overweight, and approximately one-third of adults are obese with a body mass index (defined as kilograms of weight/m 2 of height) of Ͼ30 (2). In children, the prevalence of obesity has also risen rapidly in parallel with increasing obesity in adults; a recent report indicates that 18.4% of 4-year-old children in the United States are obese, with significantly higher rates of obesity in Hispanic, black, and Native American children (3).Associated with obesity is a cascade of metabolic and cardiovascular disorders, including hypertension, a primary mediator of obesity-induced cardiovascular disease. Population studies show that excess weight gain predicts future development of hypertension, and the relationship between body mass index and blood pressure (BP) 2 appears to be nearly linear in diverse populations throughout the world (4). Some studies suggest that excess weight gain may account for 65-75% of human essential hypertension (5). Moreover, clinical studies indicate that weight loss is effective in primary prevention of hypertension and in reducing BP in most hypertensive subjects (6).Although the importance of obesity as a major cause of essential hypertension is well established, the physiological and molecular mechanisms that mediate the BP effects of excess weight gain are only beginning to be elucidated. Excess Weight Gain Increases Renal SodiumReabsorption and Impairs Pressure Natriuresis Table 1 summarizes some of the changes in cardiovascular, neurohormonal, and renal function that occur in obese humans and experimental animals (4,7,8). Notable changes, in addition to increased BP, include increases in cardiac output and heart rate as well as activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS). Rapid weight gain also stimulates renal tubular sodium reabsorption, and obese subjects require higher than normal BP to maintain balance between intake and renal excretion of sodium, indicating impaired renal pressure natriuresis (4).Three factors are especially important in increasing re...

Sestrin2 (SESN2), a highly conserved stress-inducible metabolic protein, is known to repress reactive oxygen species (ROS) and provide cytoprotection against various noxious stimuli including genotoxic and oxidative stress, endoplasmic reticulum (ER) stress, and hypoxia. Studies demonstrate that the upregulation of Sestrin2 under conditions of oxidative stress augments autophagy-directed degradation of Kelch-like ECH-associated protein 1 (Keap1), which targets and breaks down nuclear erythroid-related factor 2 (Nrf2), a key regulator of various antioxidant genes. Moreover, ER stress and hypoxia are shown to induce Sestrins, which ultimately reduce cellular ROS levels. Sestrin2 also plays a pivotal role in metabolic regulation through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Other downstream effects of Sestrins include autophagy activation, antiapoptotic effects in normal cells, and proapoptotic effects in cancer cells. As perturbations in the aforementioned pathways are well documented in multiple diseases, Sestrin2 might serve as a potential therapeutic target for various diseases. Thus, the aim of this review is to discuss the upstream regulators and the downstream effectors of Sestrins and to highlight the significance of Sestrin2 as a biomarker and a therapeutic target in diseases such as metabolic disorders, cardiovascular and neurodegenerative diseases, and cancer.

Type-2 diabetes prevalence is continuing to rise worldwide due to physical inactivity and obesity epidemic. Diabetes and fluctuations of blood sugar are related to multiple micro- and macrovascular complications, that are attributed to oxidative stress, endoplasmic reticulum (ER) activation and inflammatory processes, which lead to endothelial dysfunction characterized, among other features, by reduced availability of nitric oxide (NO) and aberrant angiogenic capacity. Several enzymatic anti-oxidant and anti-inflammatory agents have been found to play protective roles against oxidative stress and its downstream signaling pathways. Of particular interest, heme oxygenase (HO) isoforms, specifically HO-1, have attracted much attention as major cytoprotective players in conditions associated with inflammation and oxidative stress. HO operates as a key rate-limiting enzyme in the process of degradation of the iron-containing molecule, heme, yielding the following byproducts: carbon monoxide (CO), iron, and biliverdin. Because HO-1 induction was linked to pro-oxidant states, it has been regarded as a marker of oxidative stress; however, accumulating evidence has established multiple cytoprotective roles of the enzyme in metabolic and cardiovascular disorders. The cytoprotective effects of HO-1 depend on several cellular mechanisms including the generation of bilirubin, an anti-oxidant molecule, from the degradation of heme; the induction of ferritin, a strong chelator of free iron; and the release of CO, that displays multiple anti-inflammatory and anti-apoptotic actions. The current review article describes the major molecular mechanisms contributing to endothelial dysfunction and altered angiogenesis in diabetes with a special focus on the interplay between oxidative stress and ER stress response. The review summarizes the key cytoprotective roles of HO-1 against hyperglycemia-induced endothelial dysfunction and aberrant angiogenesis and discusses the major underlying cellular mechanisms associated with its protective effects.

Metformin, a well-known anti-diabetic agent, is very effective in lowering blood glucose in patients with type 2 diabetes with minimal side-effects. Metformin is also being recommended in the treatment of obesity and polycystic ovary syndrome. Metformin elicits its therapeutic effects mainly via activation of AMP-activated kinase (AMPK) pathway. Renal cells under hyperglycemic or proteinuric conditions exhibit inactivation of cell defense mechanisms such as AMPK and autophagy, and activation of pathologic pathways such as mammalian target of rapamycin (mTOR), endoplasmic reticulum (ER) stress, epithelial-to-mesenchymal transition (EMT), oxidative stress, and hypoxia. As these pathologic pathways are intertwined with AMPK signaling, the potential benefits of metformin therapy in patients with type 2 diabetes would extend beyond its anti-hyperglycemic effects. However, since metformin is eliminated unchanged through the kidneys and some studies have shown the incidence of lactic acidosis with its use during severe renal dysfunction, the use of metformin was contraindicated in patients with renal disease until recently. With more studies indicating the relatively low incidence of lactic acidosis and revealing the additional benefits with metformin therapy, the US FDA has now approved metformin to be administered in patients with established renal disease based on their renal function. The purpose of this review is to highlight the various mechanisms by which metformin protects renal cells that have lost its functionality in a diabetic or non-diabetic setting and to enlighten the advantages and therapeutic potential of metformin as a nephroprotectant for patients with diabetic nephropathy and other non-diabetic forms of chronic kidney disease. J. Cell. Physiol. 232: 731-742, 2017. © 2016 Wiley Periodicals, Inc.

Renal ischemia/reperfusion (I/R) injury often occurs as a result of vascular surgery, organ procurement, or transplantation. We previously showed that renal I/R results in ATP depletion, oxidant production, and manganese superoxide dismutase (MnSOD) inactivation. There have been several reports that overexpression of MnSOD protects tissues/organs from I/R related damage, thus a loss of MnSOD activity during I/R likely contributes to tissue injury. The present study examined the therapeutic benefit of a catalytic antioxidant Mn(III) meso-tetrakis(N-hexylpyridinium-2-yl) porphyrin, (MnTnHex-2-PyP 5+ ) using the rat renal I/R model. This was the first study to examine the effects of MnTnHex-2-PyP 5+ in an animal model of oxidative stress injury. Our results showed that porphyrin pretreatment of rats for 24 hr protected against ATP depletion, MnSOD inactivation, nitrotyrosine formation, and renal dysfunction. The dose (50 μg/kg) used in this study is lower than doses of various types of antioxidants commonly used in animal models of oxidative stress injuries. In addition, using novel proteomic techniques, we identified ATP synthase-beta subunit as a key protein induced by MnTnHex-2-PyP 5+ treatment alone, and complex V (ATP synthase) as a target of injury during renal I/R. These results showed that MnTnHex-2-PyP 5+ protected against renal I/R injury via induction of key mitochondrial proteins that may be capable of blunting oxidative injury.