Diabetes mellitus and hypertension are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. In this study, we assessed interactions of hypertension and diabetes in causing kidney dysfunction and injury and the role of endoplasmic reticulum (ER) stress. Hypertension was induced by aorta constriction (AC) between the renal arteries in 6-month old male Goto-Kakizaki (GK) type 2 diabetic and control Wistar rats. Fasting plasma glucose averaged 162±11 and 87±2 mg/dL in GK and Wistar rats, respectively. AC produced hypertension in the right kidney (above AC) and near normal blood pressure (BP) in the left kidney (below AC), with both kidneys exposed to the same levels of glucose, circulating hormones, and neural influences. After 8 wks of AC, BP above the AC (and in the right kidney) increased from 109±1 to 152±5 mmHg in GK rats and from 106±4 to 141±5 mmHg in Wistar rats. The diabetic-hypertensive right kidneys in GK-AC rats had much greater increases in albumin excretion and histological injury compared to left kidneys (diabetes only) of GK rats or right kidneys (hypertension only) of Wistar-AC rats. Marked increases in ER stress and oxidative stress indicators were observed in diabetic-hypertensive kidneys of GK-AC rats. Inhibition of ER stress with tauroursodeoxycholic acid (TUDCA) for 6 wks reduced BP (135±4 vs 151±4 mmHg), albumin excretion, ER and oxidative stress, glomerular injury, while increasing GFR in hypertensive-diabetic kidneys. These results suggest that diabetes and hypertension interact synergistically to promote kidney dysfunction and injury via ER stress.

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Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review high-lights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension.

Melanocortins play an important role in regulating blood pressure (BP) and sympathetic nervous system (SNS) activity as well as energy balance, glucose and other metabolic functions in humans and experimental animals. In experimental models of hypertension with high SNS activity, blockade of the melanocortin-4 receptor (MC4R) reduces BP despite causing marked hyperphagia and obesity. Activation of the central nervous system (CNS) pro-opiomelanocortin (POMC)–MC4R pathway appears to be an important link between obesity, SNS activation and hypertension. Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, urinary catecholamine excretion and SNS responses to cold stimuli compared to obese subjects with normal MC4R function. In this review we discuss the importance of the brain POMC-MC4R system in regulating SNS activity and BP in obesity and other forms of hypertension. We also highlight potential mechanisms and brain circuitry by which the melanocortin system regulates cardiovascular function.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin receptor signaling and may contribute to leptin resistance in diet-induced obesity. Although PTP1B inhibition has been suggested as a potential weight loss therapy, the role of specific neuronal PTP1B signaling in cardiovascular and metabolic regulation and the importance of sex differences in this regulation are still unclear. In this study, we investigated the impact of proopiomelanocortin (POMC) neuronal PTP1B deficiency in cardiometabolic regulation in male and female mice fed a high-fat diet (HFD). When compared with control mice (PTP1B ), male and female mice deficient in POMC neuronal PTP1B (PTP1B/POMC-Cre) had attenuated body weight gain (males: -18%; females: -16%) and fat mass (males: -33%; female: -29%) in response to HFD. Glucose tolerance was improved by 40%, and liver lipid accumulation was reduced by 40% in PTP1B/POMC-Cre males but not in females. When compared with control mice, deficiency of POMC neuronal PTP1B did not alter mean arterial pressure (MAP) in male or female mice (males: 112 ± 1 vs. 112 ± 1 mmHg in controls; females: 106 ± 3 vs. 109 ± 3 mmHg in controls). Deficiency of POMC neuronal PTP1B also did not alter MAP response to acute stress in males or females compared with control mice (males: Δ32 ± 0 vs. Δ29 ± 4 mmHg; females: Δ22 ± 2 vs. Δ27 ± 4 mmHg). These data demonstrate that POMC-specific PTP1B deficiency improved glucose tolerance and attenuated diet-induced fatty liver only in male mice and attenuated weight gain in males and females but did not enhance the MAP and HR responses to a HFD or to acute stress.