Endothelial cell serum and glucocorticoid regulated kinase 1 (SGK1) mediates vascular stiffening.

BACKGROUND: Excessive dietary salt intake increases vascular stiffness in humans, especially in salt-sensitive populations. While we recently suggested that the endothelial sodium channel (EnNaC) contributes to salt-sensitivity related endothelial cell (EC) and arterial stiffening, mechanistic understanding remains incomplete. This study therefore aimed to explore the role of EC-serum and glucocorticoid regulated kinase 1 (SGK1), as a reported regulator of sodium channels, in EC and arterial stiffening. METHODS AND RESULTS: A mouse model of salt sensitivity-associated vascular stiffening was produced by subcutaneous implantation of slow-release deoxycorticosterone acetate (DOCA) pellets, with salt (1 % NaCl, 0.2 % KCl) administered via drinking water. Preliminary data showed that global SGK1 deletion caused significantly decreased blood pressure (BP), EnNaC activity and aortic endothelium stiffness as compared to control mice following DOCA-salt treatment. To probe EC signaling pathways, selective deletion of EC-SGK1 was performed by cross-breeding cadherin 5-Cre mice with sgk1flox/flox mice. DOCA-salt treated control mice had significantly increased BP, EC and aortic stiffness in vivo and ex vivo, which were attenuated by EC-SGK1 deficiency. To demonstrate relevance to humans, human aortic ECs were cultured in the absence or presence of aldosterone and high salt with or without the SGK1 inhibitor, EMD638683 (10uM or 25uM). Treatment with aldosterone and high salt increased intrinsic stiffness of ECs, which was prevented by SGK1 inhibition. Further, the SGK1 inhibitor prevented aldosterone and high salt induced actin polymerization, a key mechanism in cellular stiffening. CONCLUSION: EC-SGK1 contributes to salt-sensitivity related EC and aortic stiffening by mechanisms appearing to involve regulation of actin polymerization.

Diabetic Vasculopathy: Molecular Mechanisms and Clinical Insights.

Clinical and basic studies have documented that both hyperglycemia and insulin-resistance/hyperinsulinemia not only constitute metabolic disorders contributing to cardiometabolic syndrome, but also predispose to diabetic vasculopathy, which refers to diabetes-mellitus-induced microvascular and macrovascular complications, including retinopathy, neuropathy, atherosclerosis, coronary artery disease, hypertension, and peripheral artery disease. The underlying molecular and cellular mechanisms include inappropriate activation of the renin angiotensin-aldosterone system, mitochondrial dysfunction, excessive oxidative stress, inflammation, dyslipidemia, and thrombosis. These abnormalities collectively promote metabolic disorders and further promote diabetic vasculopathy. Recent evidence has revealed that endothelial progenitor cell dysfunction, gut dysbiosis, and the abnormal release of extracellular vesicles and their carried microRNAs also contribute to the development and progression of diabetic vasculopathy. Therefore, clinical control and treatment of diabetes mellitus, as well as the development of novel therapeutic strategies are crucial in preventing cardiometabolic syndrome and related diabetic vasculopathy. The present review focuses on the relationship between insulin resistance and diabetes mellitus in diabetic vasculopathy and related cardiovascular disease, highlighting epidemiology and clinical characteristics, pathophysiology, and molecular mechanisms, as well as management strategies.

Vascular endothelial mineralocorticoid receptors and epithelial sodium channels in metabolic syndrome and related cardiovascular disease.

Metabolic syndrome is a group of risk factors that increase the risk of developing metabolic and cardiovascular disease (CVD) and include obesity, dyslipidemia, insulin resistance, atherosclerosis, hypertension, coronary artery disease, and heart failure. Recent research indicates that excessive production of aldosterone and associated activation of mineralocorticoid receptors (MR) impair insulin metabolic signaling, promote insulin resistance, and increase the risk of developing metabolic syndrome and CVD. Moreover, activation of specific epithelial sodium channels (ENaC) in endothelial cells (EnNaC), which are downstream targets of endothelial-specific MR (ECMR) signaling, are also believed to play a crucial role in the development of metabolic syndrome and CVD. These adverse effects of ECMR/EnNaC activation are mediated by increased oxidative stress, inflammation, and lipid metabolic disorders. It is worth noting that ECMR/EnNaC activation and the pathophysiology underlying metabolic syndrome and CVD appears to exhibit sexual dimorphism. Targeting ECMR/EnNaC signaling may have a beneficial effect in preventing insulin resistance, diabetes, metabolic syndrome, and related CVD. This review aims to examine our current understanding of the relationship between MR activation and increased metabolic syndrome and CVD, with particular emphasis placed on the role for endothelial-specific ECMR/EnNaC signaling in these pathological processes.

Endothelial MRs Mediate Western Diet-Induced Lipid Disorders and Skeletal Muscle Insulin Resistance in Females.

Consumption of a Western diet (WD) consisting of excess fat and carbohydrates activates the renin-angiotensin-aldosterone system, which has emerged as an important risk factor for systemic and tissue insulin resistance. We recently discovered that activated mineralocorticoid receptors (MRs) in diet-induced obesity induce CD36 expression, increase ectopic lipid accumulation, and result in systemic and tissue insulin resistance. Here, we have further investigated whether endothelial cell (EC)-specific MR (ECMR) activation participates in WD-induced ectopic skeletal muscle lipid accumulation, insulin resistance, and dysfunction. Six-week-old female ECMR knockout (ECMR-/-) and wild-type (ECMR+/+) mice were fed either a WD or a chow diet for 16 weeks. ECMR-/- mice were found to have decreased WD-induced in vivo glucose intolerance and insulin resistance at 16 weeks. Improved insulin sensitivity was accompanied by increased glucose transporter type 4 expression in conjunction with improved soleus insulin metabolic signaling in phosphoinositide 3-kinases/protein kinase B and endothelial nitric oxide synthase activation. Additionally, ECMR-/- also blunted WD-induced increases in CD36 expression and associated elevations in soleus free fatty acid, total intramyocellular lipid content, oxidative stress, and soleus fibrosis. Moreover, in vitro and in vivo activation of ECMR increased EC-derived exosomal CD36 that was further taken up by skeletal muscle cells, leading to increased skeletal muscle CD36 levels. These findings indicate that in the context of an obesogenic WD, enhanced ECMR signaling increases EC-derived exosomal CD36 resulting in increased uptake and elevated concentrations of CD36 in skeletal muscle cells, contributing to increased lipid metabolic disorders and soleus insulin resistance.

Endothelial cell-specific mineralocorticoid receptor activation promotes diastolic dysfunction in diet-induced obese male mice.

Widespread consumption of diets high in fat and fructose (Western diet, WD) has led to increased prevalence of obesity and diastolic dysfunction (DD). DD is a prominent feature of heart failure with preserved ejection fraction (HFpEF). However, the underlying mechanisms of DD are poorly understood, and treatment options are still limited. We have previously shown that deletion of the cell-specific mineralocorticoid receptor in endothelial cells (ECMR) abrogates DD induced by WD feeding in female mice. However, the specific role of ECMR activation in the pathogenesis of DD in male mice has not been clarified. Therefore, we fed 4-wk-old ECMR knockout (ECMRKO) male mice and littermates (LM) with either a WD or chow diet (CD) for 16 wk. WD feeding resulted in DD characterized by increased left ventricle (LV) filling pressure (E/e') and diastolic stiffness [E/e'/LV inner diameter at end diastole (LVIDd)]. Compared with CD, WD in LM resulted in increased myocardial macrophage infiltration, oxidative stress, and increased myocardial phosphorylation of Akt, in concert with decreased phospholamban phosphorylation. WD also resulted in focal cardiomyocyte remodeling, characterized by areas of sarcomeric disorganization, loss of mitochondrial electron density, and mitochondrial fragmentation. Conversely, WD-induced DD and associated biochemical and structural abnormalities were prevented by ECMR deletion. In contrast with our previously reported observations in females, WD-fed male mice exhibited enhanced Akt signaling and a lower magnitude of cardiac injury. Collectively, our data support a critical role for ECMR in obesity-induced DD and suggest critical mechanistic differences in the genesis of DD between males and females.

Targeting DNA damage response in cardiovascular diseases: from pathophysiology to therapeutic implications.

Cardiovascular diseases (CVDs) arise from a complex interplay among genomic, proteomic, and metabolomic abnormalities. Emerging evidence has recently consolidated the presence of robust DNA damage in a variety of cardiovascular disorders. DNA damage triggers a series of cellular responses termed DNA damage response (DDR) including detection of DNA lesions, cell cycle arrest, DNA repair, cellular senescence, and apoptosis, in all organ systems including hearts and vasculature. Although transient DDR in response to temporary DNA damage can be beneficial for cardiovascular function, persistent activation of DDR promotes the onset and development of CVDs. Moreover, therapeutic interventions that target DNA damage and DDR have the potential to attenuate cardiovascular dysfunction and improve disease outcome. In this review, we will discuss molecular mechanisms of DNA damage and repair in the onset and development of CVDs, and explore how DDR in specific cardiac cell types contributes to CVDs. Moreover, we will highlight the latest advances regarding the potential therapeutic strategies targeting DNA damage signalling in CVDs.

Parkin Insufficiency Accentuates High-Fat Diet-Induced Cardiac Remodeling and Contractile Dysfunction Through VDAC1-Mediated Mitochondrial Ca2+ Overload.

Mitochondrial Ca2+ overload contributes to obesity cardiomyopathy, yet mechanisms that directly regulate it remain elusive. The authors investigated the role of Parkin on obesity-induced cardiac remodeling and dysfunction in human hearts and a mouse model of 24-week high-fat diet (HFD) feeding. Parkin knockout aggravated HFD-induced cardiac remodeling and dysfunction, mitochondrial Ca2+ overload, and apoptosis without affecting global metabolism, blood pressure, and aortic stiffness. Parkin deficiency unmasked HFD-induced decline in voltage-dependent anion channel (VDAC) type 1 degradation through the ubiquitin-proteasome system but not other VDAC isoforms or mitochondrial Ca2+ uniporter complex. These data suggest that Parkin-mediated proteolysis of VDAC type 1 is a promising therapeutic target for obesity cardiomyopathy.

Mineralocorticoid Receptors Mediate Diet-Induced Lipid Infiltration of Skeletal Muscle and Insulin Resistance.

Excess circulating lipids increase total intramyocellular (IMC) lipid content and ectopic fat storage, resulting in lipotoxicity and insulin resistance in skeletal muscle. Consumption of a diet high in fat and refined sugars-a Western diet (WD)-has been shown to activate mineralocorticoid receptors (MRs) and promote insulin resistance. However, our understanding of the precise mechanisms by which enhanced MR activation promotes skeletal muscle insulin resistance remains unclear. In this study, we investigated the mechanisms by which enhanced MR signaling in soleus muscle promotes ectopic skeletal muscle lipid accumulation and related insulin resistance. Six-week-old C57BL/6J mice were fed either a mouse chow diet or a WD with or without spironolactone (1 mg/kg/day) for 16 weeks. Spironolactone attenuated 16 weeks of WD-induced in vivo glucose intolerance and insulin resistance, and improved soleus insulin metabolic signaling. Improved insulin sensitivity was accompanied by increased glucose transporter 4 (Glut4) expression in conjunction with decreased soleus free fatty acid and IMC lipid content, as well as CD36 expression. Additionally, spironolactone prevented WD-induced soleus mitochondria dysfunction. Furthermore, MR signaling also mediated WD/aldosterone-induced reductions in soleus microRNA (miR)-99a, which was identified to negatively target CD36 and prevented palmitic acid-induced increases in CD36 expression, lipid droplet formation, mitochondria dysfunction, and insulin resistance in C2C12 cells. These data indicate that inhibition of MR activation with spironolactone prevented diet-induced abnormal expression of miR-99a, which had the capacity to reduce CD36, leading to reduced IMC lipid content and improved soleus mitochondria function and insulin sensitivity.

Mineralocorticoid Receptor Activation in Vascular Insulin Resistance and Dysfunction.

Systemic insulin resistance is characterized by reduced insulin metabolic signaling and glucose intolerance. Mineralocorticoid receptors (MRs), the principal receptors for the hormone aldosterone, play an important role in regulating renal sodium handling and blood pressure. Recent studies suggest that MRs also exist in tissues outside the kidney, including vascular endothelial cells, smooth muscle cells, fibroblasts, perivascular adipose tissue, and immune cells. Risk factors, including excessive salt intake/salt sensitivity, hypertension, and obesity, can lead to the activation of vascular MRs to promote inflammation, oxidative stress, remodeling, and fibrosis, as well as cardiovascular stiffening and microcirculatory impairment. These pathophysiological changes are associated with a diminished ability of insulin to initiate appropriate intracellular signaling events, resulting in a reduced glucose uptake within the microcirculation and related vascular insulin resistance. Therefore, the pharmacological inhibition of MR activation provides a potential therapeutic option for improving vascular function, glucose uptake, and vascular insulin sensitivity. This review highlights recent experimental and clinical data that support the contribution of abnormal MR activation to the development of vascular insulin resistance and dysfunction.

THIRSTY FOR FRUCTOSE: Arginine Vasopressin, Fructose, and the Pathogenesis of Metabolic and Renal Disease.

We review the pathways by which arginine vasopressin (AVP) and hydration influence the sequelae of the metabolic syndrome induced by high fructose consumption. AVP and inadequate hydration have been shown to worsen the severity of two phenotypes associated with metabolic syndrome induced by high fructose intake-enhanced lipogenesis and insulin resistance. These findings have implications for those who frequently consume sweeteners such as high fructose corn syrup (HFCS). Patients with metabolic syndrome are at higher risk for microalbuminuria and/or chronic kidney disease; however, it is difficult to discriminate the detrimental renal effects of the metabolic syndrome from those of hypertension, impaired glucose metabolism, and obesity. It is not surprising the prevalence of chronic renal insufficiency is growing hand in hand with obesity, insulin resistance, and metabolic syndrome in those who consume large amounts of fructose. Higher AVP levels and low hydration status worsen the renal insufficiency found in patients with metabolic syndrome. This inter-relationship has public health consequences, especially among underserved populations who perform physical labor in environments that place them at risk for dehydration. MesoAmerican endemic nephropathy is a type of chronic kidney disease highly prevalent in hot ambient climates from southwest Mexico through Latin America. There is growing evidence that this public health crisis is being spurred by greater fructose consumption in the face of dehydration and increased dehydration-dependent vasopressin secretion. Work is needed at unraveling the mechanism(s) by which fructose consumption and increased AVP levels can worsen the renal disease associated with components of the metabolic syndrome.

Cell death regulation by MAMs: from molecular mechanisms to therapeutic implications in cardiovascular diseases.

The endoplasmic reticulum (ER) and mitochondria are interconnected intracellular organelles with vital roles in the regulation of cell signaling and function. While the ER participates in a number of biological processes including lipid biosynthesis, Ca2+ storage and protein folding and processing, mitochondria are highly dynamic organelles governing ATP synthesis, free radical production, innate immunity and apoptosis. Interplay between the ER and mitochondria plays a crucial role in regulating energy metabolism and cell fate control under stress. The mitochondria-associated membranes (MAMs) denote physical contact sites between ER and mitochondria that mediate bidirectional communications between the two organelles. Although Ca2+ transport from ER to mitochondria is vital for mitochondrial homeostasis and energy metabolism, unrestrained Ca2+ transfer may result in mitochondrial Ca2+ overload, mitochondrial damage and cell death. Here we summarize the roles of MAMs in cell physiology and its impact in pathological conditions with a focus on cardiovascular disease. The possibility of manipulating ER-mitochondria contacts as potential therapeutic approaches is also discussed.

Heart failure with preserved ejection fraction (HFpEF) in type 2 diabetes mellitus: from pathophysiology to therapeutics.

Type 2 diabetes mellitus (T2DM or T2D) is a devastating metabolic abnormality featured by insulin resistance, hyperglycemia, and hyperlipidemia. T2D provokes unique metabolic changes and compromises cardiovascular geometry and function. Meanwhile, T2D increases the overall risk for heart failure (HF) and acts independent of classical risk factors including coronary artery disease, hypertension, and valvular heart diseases. The incidence of HF is extremely high in patients with T2D and is manifested as HF with preserved, reduced, and midrange ejection fraction (HFpEF, HFrEF, and HFmrEF, respectively), all of which significantly worsen the prognosis for T2D. HFpEF is seen in approximately half of the HF cases and is defined as a heterogenous syndrome with discrete phenotypes, particularly in close association with metabolic syndrome. Nonetheless, management of HFpEF in T2D remains unclear, largely due to the poorly defined pathophysiology behind HFpEF. Here, in this review, we will summarize findings from multiple preclinical and clinical studies as well as recent clinical trials, mainly focusing on the pathophysiology, potential mechanisms, and therapies of HFpEF in T2D.

Inhibition of sphingomyelinase attenuates diet - Induced increases in aortic stiffness.

Sphingomyelinases ensure ceramide production and play an integral role in cell turnover, inward budding of vesicles and outward release of exosomes. Recent data indicate a unique role for neutral sphingomyelinase (nSMase) in the control of ceramide-dependent exosome release and inflammatory pathways. Further, while inhibition of nSMase in vascular tissue attenuates the progression of atherosclerosis, little is known regarding its role on metabolic signaling and arterial vasomotor function. Accordingly, we hypothesized that nSMase inhibition with GW4869, would attenuate Western diet (WD) - induced increases in aortic stiffness through alterations in pathways which lead to oxidative stress, inflammation and vascular remodeling. Six week-old female C57BL/6L mice were fed either a WD containing excess fat (46%) and fructose (17.5%) for 16 weeks or a standard chow diet (CD). Mice were variably treated with GW4869 (2.0 µg/g body weight, intraperitoneal injection every 48 h for 12 weeks). WD feeding increased nSMase2 expression and activation while causing aortic stiffening and impaired vasorelaxation as determined by pulse wave velocity (PWV) and wire myography, respectively. Moreover, these functional abnormalities were associated with aortic remodeling and attenuated AMP-activated protein kinase, Sirtuin 1, and endothelial nitric oxide synthase activation. GW4869 treatment prevented the WD-induced increases in nSMase activation, PWV, and impaired endothelium dependent/independent vascular relaxation. GW4869 also inhibited WD-induced aortic CD36 expression, lipid accumulation, oxidative stress, inflammatory responses, as well as aortic remodeling. These findings indicate that targeting nSMase prevents diet - induced aortic stiffening and impaired vascular relaxation by attenuating oxidative stress, inflammation and adverse vascular remodeling.

Targeting mineralocorticoid receptors in diet-induced hepatic steatosis and insulin resistance.

Mineralocorticoid receptor (MR) activation plays an important role in hepatic insulin resistance. However, the precise mechanisms by which MR activation promotes hepatic insulin resistance remains unclear. Therefore, we sought to investigate the roles and mechanisms by which MR activation promotes Western diet (WD)-induced hepatic steatosis and insulin resistance. Six-week-old C57BL6J mice were fed either mouse chow or a WD, high in saturated fat and refined carbohydrates, with or without the MR antagonist spironolactone (1 mg/kg/day) for 16 wk. WD feeding resulted in systemic insulin resistance at 8 and 16 wk. WD also induced impaired hepatic insulin metabolic signaling via phosphoinositide 3-kinases/protein kinase B pathways, which was associated with increased hepatic CD36, fatty acid transport proteins, fatty acid-binding protein-1, and hepatic steatosis. Meanwhile, consumption of a WD-induced hepatic mitochondria dysfunction, oxidative stress, and inflammatory responses. These abnormalities occurring in response to WD feeding were blunted with spironolactone treatment. Moreover, spironolactone promoted white adipose tissue browning and hepatic glucose transporter type 4 expression. These data suggest that enhanced hepatic MR signaling mediates diet-induced hepatic steatosis and dysregulation of adipose tissue browning, and subsequent hepatic mitochondria dysfunction, oxidative stress, inflammation, as well as hepatic insulin resistance.

Endothelial sodium channel activation mediates DOCA-salt-induced endothelial cell and arterial stiffening.

INTRODUCTION: High salt intake and aldosterone are both associated with vascular stiffening in humans. However, our preliminary work showed that high dietary salt alone did not increase endothelial cell (EC) or vascular stiffness or endothelial sodium channel (EnNaC) activation in mice, presumably because aldosterone production was significantly suppressed as a result of the high salt diet. We thus hypothesized that high salt consumption along with an exogenous mineralocorticoid would substantially increase EC and vascular stiffness via activation of the EnNaC. METHODS AND RESULTS: Mice were implanted with slow-release DOCA pellets and given salt in their drinking water for 21 days. Mice with either specific deletion of the alpha subunit of EnNaC or treated with a pharmacological inhibitor of mTOR, a downstream signaling molecule involved in mineralocorticoid receptor activation of EnNaC, were studied. DOCA-salt treated control mice had increased blood pressure, EC Na+ transport activity, EC and arterial stiffness, which were attenuated in both the αEnNaC-/- and mTOR inhibitor treated groups. Further, depletion of αEnNaC prevented DOCA-salt-induced impairment in EC-dependent vascular relaxation. CONCLUSION: While high salt consumption alone does not cause EC or vascular stiffening, the combination of EC MR activation and high salt causes activation of EnNaC which increases EC and arterial stiffness and impairs vascular relaxation. Underlying mechanisms appear to include mTOR signaling.

Role of the vascular endothelial sodium channel activation in the genesis of pathologically increased cardiovascular stiffness.

Cardiovascular (CV) stiffening represents a complex series of events evolving from pathological changes in individual cells of the vasculature and heart which leads to overt tissue fibrosis. While vascular stiffening occurs naturally with ageing it is accelerated in states of insulin (INS) resistance, such as obesity and type 2 diabetes. CV stiffening is clinically manifested as increased arterial pulse wave velocity and myocardial fibrosis-induced diastolic dysfunction. A key question that remains is how are these events mechanistically linked. In this regard, heightened activation of vascular mineralocorticoid receptors (MR) and hyperinsulinaemia occur in obesity and INS resistance states. Further, a downstream mediator of MR and INS receptor activation, the endothelial cell Na+ channel (EnNaC), has recently been identified as a key molecular determinant of endothelial dysfunction and CV fibrosis and stiffening. Increased activity of the EnNaC results in a number of negative consequences including stiffening of the cortical actin cytoskeleton in endothelial cells, impaired endothelial NO release, increased oxidative stress-meditated NO destruction, increased vascular permeability, and stimulation of an inflammatory environment. Such endothelial alterations impact vascular function and stiffening through regulation of vascular tone and stimulation of tissue remodelling including fibrosis. In the case of the heart, obesity and INS resistance are associated with coronary vascular endothelial stiffening and associated reductions in bioavailable NO leading to heart failure with preserved systolic function (HFpEF). After a brief discussion on mechanisms leading to vascular stiffness per se, this review then focuses on recent findings regarding the role of INS and aldosterone to enhance EnNaC activity and associated CV stiffness in obesity/INS resistance states. Finally, we discuss how coronary artery-mediated EnNaC activation may lead to cardiac fibrosis and HFpEF, a condition that is especially pronounced in obese and diabetic females.

Traumatic brain injury induces region-specific glutamate metabolism changes as measured by multiple mass spectrometry methods.

The release of excess glutamate following traumatic brain injury (TBI) results in glutamate excitotoxicity and metabolic energy failure. Endogenous mechanisms for reducing glutamate concentration in the brain parenchyma following TBI are poorly understood. Using multiple mass spectrometry approaches, we examined TBI-induced changes to glutamate metabolism. We present evidence that glutamate concentration can be reduced by glutamate oxidation via a "truncated" tricarboxylic acid cycle coupled to the urea cycle. This process reduces glutamate levels, generates carbon for energy metabolism, leads to citrulline accumulation, and produces nitric oxide. Several key metabolites are identified by metabolomics in support of this mechanism and the locations of these metabolites in the injured hemisphere are demonstrated by MALDI-MS imaging. The results of this study establish the advantages of multiple mass spectrometry approaches and provide insights into glutamate metabolism following TBI that could lead to improved treatment approaches.

Hypertension in Diabetes: An Update of Basic Mechanisms and Clinical Disease.

Epidemiological studies have documented that insulin resistance and diabetes not only constitute metabolic abnormalities but also predispose to hypertension, vascular stiffness, and associated cardiovascular disease. Meanwhile, excessive arterial stiffness and impaired vasorelaxation, in turn, contribute to worsening insulin resistance and the development of diabetes. Molecular mechanisms promoting hypertension in diabetes include inappropriate activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, mitochondria dysfunction, excessive oxidative stress, and systemic inflammation. This review highlights recent studies which have uncovered new underlying mechanisms for the increased propensity for the development of hypertension in association with diabetes. These include enhanced activation of epithelial sodium channels, alterations in extracellular vesicles and their microRNAs, abnormal gut microbiota, and increased renal sodium-glucose cotransporter activity, which collectively predispose to hypertension in association with diabetes. This review also covers socioeconomic factors and currently recommended blood pressure targets and related treatment strategies in diabetic patients with hypertension.