Search

Recent evidence suggests that dipeptidyl peptidase-4 (DPP4) inhibition with saxagliptin (Saxa) is renoprotective under comorbid conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS), such as diabetes, obesity, and hypertension, which confer a high cardiovascular risk. Immune system activation is now recognized as a contributor to RAAS-mediated tissue injury, and, importantly, immunomodulatory effects of DPP4 have been reported. Accordingly, we examined the hypothesis that DPP4 inhibition with Saxa attenuates angiotensin II (ANG II)-induced kidney injury and albuminuria via attenuation of immune activation in the kidney. To this end, male mice were infused with either vehicle or ANG II (1,000 ng/kg/min, s.c.) for 3 wk and received either placebo or Saxa (10 mg/kg/day, p.o.) during the final 2 wk. ANG II infusion increased kidney, but not plasma, DPP4 activity in vivo as well as DPP4 activity in cultured proximal tubule cells. The latter was prevented by angiotensin receptor blockade with olmesartan. Further, ANG II induced hypertension and kidney injury characterized by mesangial expansion, mitochondrial damage, reduced brush border megalin expression, and albuminuria. Saxa inhibited DPP4 activity ∼50% in vivo and attenuated ANG II-mediated kidney injury, independent of blood pressure. Further mechanistic experiments revealed mitigation by Saxa of proinflammatory and profibrotic mediators activated by ANG II in the kidney, including CD8(+) T cells, resident macrophages (CD11b(hi)F4/80(lo)Ly6C(−)), and neutrophils. In addition, Saxa improved ANG II suppressed anti-inflammatory regulatory T cell and T helper 2 lymphocyte activity. Taken together, these results demonstrate, for the first time, blood pressure-independent involvement of renal DPP4 activation contributing to RAAS-dependent kidney injury and immune activation. NEW & NOTEWORTHY This work highlights the role of dipeptidyl peptidase-4 (DPP4) in promoting ANG II-mediated kidney inflammation and injury. Specifically, ANG II infusion in mice led to increases in blood pressure and kidney DPP4 activity, which then led to activation of CD8(+) T cells, Ly6C(−) macrophages, and neutrophils and suppression of anti-inflammatory T helper 2 lymphocytes and regulatory T cells. Collectively, this led to kidney injury, characterized by mesangial expansion, mitochondrial damage, and albuminuria, which were mitigated by DPP4 inhibition independent of blood pressure reduction.

Introduction The safety of predicting conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia using apolipoprotein E (APOE) genotyping is unknown. Methods We randomized 114 individuals with MCI to receive estimates of 3‐year risk of conversion to AD dementia informed by APOE genotyping (disclosure arm) or not (non‐disclosure arm) in a non‐inferiority clinical trial. Primary outcomes were anxiety and depression scores. Secondary outcomes included other psychological measures. Results Upper confidence limits for randomization arm differences were 2.3 on the State Trait Anxiety Index and 0.5 on the Geriatric Depression Scale, below non‐inferiority margins of 3.3 and 1.0. Moreover, mean scores were lower in the disclosure arm than non‐disclosure arm for test‐related positive impact (difference: ‐1.9, indicating more positive feelings) and AD concern (difference: ‐0.3). Discussion Providing genetic information to individuals with MCI about imminent risk for AD does not increase risks of anxiety or depression and may provide psychological benefits.

Objective Diabetic nephropathy (DN) is characterized by glomerular and tubulointerstitial injury, proteinuria and remodeling. Here we examined whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses renal injury in a pre-clinical model of early DN more effectively than valsartan monotherapy. Methods Sixty-four male Zucker Obese rats (ZO) at 16 weeks of age were distributed into 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val) (68 mg kg−1 day−1; ZOSV); and Group 3: valsartan (val) (31 mg kg−1 day−1; ZOV). Group 4 received hydralazine, an anti-hypertensive drug (30 mg kg−1 day−1, ZOH). Six Zucker Lean (ZL) rats received saline (Group 5) and served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. Results Mean arterial pressure (MAP) increased in ZOC (+ 28%), but not in ZOSV (− 4.2%), ZOV (− 3.9%) or ZOH (− 3.7%), during the 10 week-study period. ZOC were mildly hyperglycemic, hyperinsulinemic and hypercholesterolemic. ZOC exhibited proteinuria, hyperfiltration, elevated renal resistivity index (RRI), glomerular mesangial expansion and podocyte foot process flattening and effacement, reduced nephrin and podocin expression, tubulointerstitial and periarterial fibrosis, increased NOX2, NOX4 and AT1R expression, glomerular and tubular nitroso-oxidative stress, with associated increases in urinary markers of tubular injury. None of the drugs reduced fasting glucose or HbA1c. Hypercholesterolemia was reduced in ZOSV (− 43%) and ZOV (− 34%) (p ZOV > ZOH). Proteinuria was ameliorated in ZOSV (− 47%; p 0.05), but was exacerbated in ZOH (+ 28%; p > 0.05) (ZOSV > ZOV > ZOH). Compared to ZOC, hyperfiltration was improved in ZOSV (p ZOSV > ZOH). Importantly, sac/val was more effective in improving podocyte and tubular mitochondrial ultrastructure than val or hydralazine (ZOSV > ZOV > ZOH) and this was associated with increases in nephrin and podocin gene expression in ZOSV (p ZOV > ZOH). Conclusions Compared to val monotherapy, sac/val was more effective in reducing proteinuria, renal ultrastructure and tubular injury in a clinically relevant animal model of early DN. More importantly, these renoprotective effects were independent of improvements in blood pressure, glycemia and nitroso-oxidative stress. These novel findings warrant future clinical investigations designed to test whether sac/val may offer renoprotection in the setting of DN.

Conventional multisession genetic counseling is currently recommended when disclosing apolipoprotein E (APOE) genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. The objective of this study was to evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD.A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12 months after disclosure.Three hundred and forty-three adults (mean age 58.3, range 33-86 years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n = 115), CP-GC protocol (n = 116), or CP-MD protocol (n = 112). Mean postdisclosure scores on all outcomes were well below cut-offs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P.001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans.These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information.

Therapies to prevent renal injury in obese hypertensive individuals are being actively sought due to the obesity epidemic arising from the Western diet (WD), which is high in fructose and fat. Recently, activation of the immune system and hyperuricemia, observed with high fructose intake, have been linked to the pathophysiology of hypertension and renal injury. Because dipeptidyl peptidase 4 (DPP4) is a driver of maladaptive T-cell/macrophage responses, renal-protective benefits of DPP4 inhibition in the WD-fed mice were examined. Mice fed a WD for 16 weeks were given the DPP4 inhibitor MK0626 in their diet beginning at 4 weeks of age. WD-fed mice were obese, hypertensive, and insulin-resistant and manifested proteinuria and increased plasma DPP4 activity and uric acid levels. WD-fed mice also had elevated kidney DPP4 activity and monocyte chemoattractant protein-1 and IL-12 levels and suppressed IL-10 levels in the kidney, suggesting macrophage-driven inflammation, glomerular and tubulointerstitial injury. WD-induced increases in DPP4 activation in the plasma and kidney and proteinuria in WD mice were abrogated by MK0626, although blood pressure and systemic insulin sensitivity were not improved. Contemporaneously, MK0626 reduced serum uric acid levels, renal oxidative stress, and IL-12 levels and increased IL-10 levels, suggesting that suppression of DPP4 activity leads to suppression of renal immune/inflammatory injury responses to a WD. Taken together, these results demonstrate that DPP4 inhibition prevents high-fructose/high-fat diet-induced glomerular and tubular injury independent of blood pressure/insulin sensitivity and offers a potentially novel therapy for diabetic and obesity-related kidney disease.

Diastolic dysfunction is a prognosticator for future cardiovascular events that demonstrates a strong correlation with obesity. Pharmacological inhibition of dipeptidylpeptidase-4 (DPP-4) to increase the bioavailability of glucagon-like peptide-1 is an emerging therapy for control of glycemia in type 2 diabetes patients. Accumulating evidence suggests that glucagon-like peptide-1 has insulin-independent actions in cardiovascular tissue. However, it is not known whether DPP-4 inhibition improves obesity-related diastolic dysfunction. Eight-week-old Zucker obese (ZO) and Zucker lean rats were fed normal chow diet or diet containing the DPP-4 inhibitor, linagliptin (LGT), for 8 weeks. Plasma DPP-4 activity was 3.3-fold higher in ZO compared with Zucker lean rats and was reduced by 95% with LGT treatment. LGT improved echocardiographic and pressure volume-derived indices of diastolic function that were impaired in ZO control rats, without altering food intake or body weight gain during the study period. LGT also blunted elevated blood pressure progression in ZO rats involving improved skeletal muscle arteriolar function, without reducing left ventricular hypertrophy, fibrosis, or oxidative stress in ZO hearts. Expression of phosphorylated- endothelial nitric oxide synthase (eNOS)(Ser1177), total eNOS, and sarcoplasmic reticulum calcium ATPase 2a protein was elevated in the LGT-treated ZO heart, suggesting improved Ca(2+) handling. The ZO myocardium had an abnormal mitochondrial sarcomeric arrangement and cristae structure that were normalized by LGT. These studies suggest that LGT reduces blood pressure and improves intracellular Cai(2+) mishandling and cardiomyocyte ultrastructure, which collectively result in improvements in diastolic function in the absence of reductions in left ventricular hypertrophy, fibrosis, or oxidative stress in insulin-resistant ZO rats.

The statistical association between endurance exercise capacity and cardiovascular disease suggests that impaired aerobic metabolism underlies the cardiovascular disease risk in men and women. To explore this connection, we applied divergent artificial selection in rats to develop low-capacity runner (LCR) and high-capacity runner (HCR) rats and found that disease risks segregated strongly with low running capacity. Here, we tested if inborn low aerobic capacity promotes differential sex-related cardiovascular effects. Compared with HCR males (HCR-M), LCR males (LCR-M) were overweight by 34% and had heavier retroperitoneal, epididymal, and omental fat pads; LCR females (LCR-F) were 20% heavier than HCR females (HCR-F), and their retroperitoneal, but not perireproductive or omental, fat pads were heavier as well. Unlike HCR-M, blood pressure was elevated in LCR-M, and this was accompanied by left ventricular (LV) hypertrophy. Like HCR-F, LCR-F exhibited normal blood pressure and LV weight as well as increased spontaneous cage activity compared with males. Despite normal blood pressures, LCR-F exhibited increased myocardial interstitial fibrosis and diastolic dysfunction, as indicated by increased LV stiffness, a decrease in the initial filling rate, and an increase in diastolic relaxation time. Although females exhibited increased arterial stiffness, ejection fraction was normal. Increased interstitial fibrosis and diastolic dysfunction in LCR-F was accompanied by the lowest protein levels of phosphorylated AMP-actived protein kinase [phospho-AMPK (Thr172)] and silent information regulator 1. Thus, the combination of risk factors, including female sex, intrinsic low aerobic capacity, and overweightness, promote myocardial stiffness/fibrosis sufficient to induce diastolic dysfunction in the absence of hypertension and LV hypertrophy.

The aim of this investigation was to evaluate sex differences in baroreflex and heart rate variability (HRV) dysfunction and indexes of end-organ damage in the TG(mRen2)27 (Ren2) rat, a model of renin overexpression and tissue renin-angiotensin-aldosterone system overactivation. Blood pressure (via telemetric monitoring), blood pressure variability [BPV; SD of systolic blood pressure (SBP)], spontaneous baroreflex sensitivity, HRV [HRV Triangular Index (HRV-TI), standard deviation of the average NN interval (SDNN), low and high frequency power (LF and HF, respectively), and Poincaré plot analysis (SD1, SD2)], and cardiovascular function (pressure-volume loop analysis and proteinuria) were evaluated in male and female 10-wk-old Ren2 and Sprague Dawley rats. The severity of hypertension was greater in Ren2 males (R2-M) than in Ren2 females (R2-F). Increased BPV, suppression of baroreflex gain, decreased HRV, and associated end-organ damage manifested as cardiac dysfunction, myocardial remodeling, elevated proteinuria, and tissue oxidative stress were more pronounced in R2-M compared with R2-F. During the dark cycle, HRV-TI and SDNN were negatively correlated with SBP within R2-M and positively correlated within R2-F; within R2-M, these indexes were also negatively correlated with end-organ damage [left ventricular hypertrophy (LVH)]. Furthermore, within R2-M only, LVH was strongly correlated with indexes of HRV representing predominantly vagal (HF, SD1), but not sympathetic (LF, SD2), variability. These data demonstrated relative protection in females from autonomic dysfunction and end-organ damage associated with elevated blood pressure in the Ren2 model of hypertension.

Background/Aims: Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activation are crucial in the pathogenesis of hypertension, cardiovascular and renal disease. NADPH oxidase-mediated increases in reactive oxygen species (ROS) are an important mediator for RAAS-induced cardiovascular and renal injury. Increased levels of ROS can diminish the bioactivity of nitric oxide (NO), a critical modulator of RAAS effects on the kidney. Thereby, we hypothesized that in vivo nebivolol therapy in a rodent model of activated RAAS would attenuate glomerular damage and proteinuria through its actions to reduce NADPH oxidase activity/ROS and increase bioavailable NO. Methods: We utilized the transgenic Ren2 rat which displays heightened tissue RAAS, hypertension, and proteinuria. Ren2 rats (6–9 weeks of age) and age-matched Sprague-Dawley littermates were treated with nebivolol 10 mg/kg/day (osmotic mini-pump) for 21 days. Results: Ren2 rats exhibited increases in systolic blood pressure, proteinuria, kidney cortical tissue total NADPH oxidase activity and subunits (Rac1, p67phox, and p47phox), ROS and 3-nitrotyrosine, as well as reductions in podocyte protein markers; each of these parameters improved with nebivolol treatment along with increases in renal endothelial NO synthase expression. Conclusions: Our data suggest that nebivolol improves proteinuria through reductions in renal RAAS-mediated increases in NADPH oxidase/ROS and increases in bioavailable NO.

Research clearly shows that, in spite of large-scale social and political changes, women still bear the primary responsibility for housework. Research explaining the unequal division of domestic labor produces mixed results. The authors argue that the “new city” structure of the modern suburbs may be partially responsible for the tenacity of the second shift. The goal of the early suburban movement was to firmly embed women's labor in the private sphere of the isolated suburban home, leaving the public cities to men. The resulting suburban domesticity was marketed through advice literature and wartime propaganda as the ideal way to raise children, sustain better marriages, and fulfill a patriotic duty. With the return of women to the workforce, the iconic 1950s private suburb gave way to a reconstitution of the public and private through the colocation of work, home, and shopping. The authors argue that these new cities take for granted the labor of women and have developed to facilitate the second shift through the commercialization of convenience. The modern urban fringe is built to make the second shift as convenient as possible and in the process continues the social and economic expropriation of women's labor.

Much of our understanding of the effects of diabetes on the peripheral nervous system is derived from models induced by streptozotocin in which hyperglycemia is rapidly caused by pancreatic beta-cell destruction. Here, we have quantified sensory impairments over time in leptin receptor (lepr)–null mutant (−/−) mice, a type 2 model of diabetes in which the absence of leptin receptor signaling leads to obesity and chronic hyperglycemia by 4 weeks of age. To assess these mice as a model for peripheral neuropathy, we quantified the responsiveness of lepr (−/−) mice to mechanical, thermal, and chemogenic stimuli, as well as epidermal and dermal innervation of the hind paw. Compared with wild-type (+/+) and heterozygous (+/−) mice, lepr (−/−) mice displayed reduced sensitivity to mechanical stimuli by 6 weeks of age, and however, responses to noxious heat were normal. Lepr (−/−) mice also devoted less activity to their injected paw during the second phase following formalin administration. However, epidermal and dermal innervation of lepr (−/−) mice was not different from that of lepr (+/+) and (+/−) mice even after 10 weeks of hyperglycemia, suggesting that cutaneous innervation is resistant to chronic hyperglycemia in these mice. These results suggest that certain rodent nocifensive behaviors may be linked to the abundance of cutaneous innervation, while others are not. Finally, these results reveal that the lepr (−/−) mice may not be useful to study neuropathy associated with distal axonal degeneration but may be better suited for studies of hyperglycemia-induced sensory neuron dysfunction without distal nerve loss.

Chronic hyperglycemia in diabetes induces abnormal nerve pathologies, resulting in diabetic neuropathy (DN). Sensory symptoms of DN can manifest as positive (painful), negative (insensate), or both. Streptozotocin (STZ)-induced diabetic C57Bl/6 mice have reduced cutaneous innervation and display reduced behavioral responses to noxious stimuli, reflecting the insensate aspect of the human syndrome. Current studies were undertaken to determine whether the diabetes-induced deficits in pain responses are reflected by changes in spinal activation in this model of DN. Nocifensive responses of nondiabetic and diabetic mice to formalin injection were measured 1, 3, 5, and 7 weeks after STZ, and at each time point formalin-induced spinal Fos expression was quantified. Responses of diabetic mice were significantly reduced during the second phase of the formalin test beginning 3 weeks after STZ and during Phase 1 beginning 5 weeks after STZ. Consistent with the behavioral responses, the number of Fos-positive cells in the dorsal horn of diabetic animals was significantly reduced beginning 3 weeks after STZ and continuing 5 and 7 weeks after STZ. The deficits at 5 weeks after STZ were restored by 2-week treatments with insulin or neurotrophins. These results demonstrate that the reduced sensation occurring from progressive peripheral axon loss results in functional deficits in spinal cord activation. Perspective The reduced expression of the immediate early gene Fos as an indicator of pain transmission supports the diabetes-induced loss of sensation in this Type 1 model of diabetes. This murine model may be better suited to understanding the insensate symptoms of diabetic patients in the absence of chronic pain.

Randomized clinical trials in patients with hypertension and other cardiovascular disease risk factors have shown that antihypertensive therapy with thiazide diuretics and β-blockers is associated with an increased incidence of new-onset diabetes mellitus and other metabolic abnormalities.1,2 There is growing evidence that those patients with central obesity and other components of the cardiometabolic syndrome are especially prone to new-onset diabetes mellitus.1–5 In persons with abdominal obesity, hypertension, and impaired fasting glucose, there is a 3- to 5-fold increase in the risk for incident diabetes mellitus.4 In this context, there is growing evidence of an association between antihypertensive induced new-onset diabetes mellitus and associated increases in cardiovascular disease morbidity and mortality from stroke and myocardial infarction.6 In the present issue of Hypertension ,7 the impact of abdominal obesity on the incidence of adverse metabolic effects accompanying antihypertensive therapy was examined in a population of hypertensive patients treated with atenolol and/or hydrochlorothiazide (HCTZ). A total of 395 middle-age patients, without diabetes mellitus and/or heart disease (considered low-risk hypertensive patients), participating in the Pharmacogenomic Evaluation of Antihypertensive Responses Study, were included. Patients were randomly assigned to HCTZ or atenolol, and the medication was titrated up to the maximum study dose (25 mg of HCTZ or 100 mg of atenolol). Combination therapy with these 2 agents was instituted if target blood pressure

Objectives: Obesity is an independent risk factor for development and progression of renal injury. High fructose corn syrup consumption has coincided with the obesity epidemic in the United States. High fructose (60%) diets have been demonstrated to be associated with elevation in BP and worsening insulin resistance along with renal injury via increased hepatic production of uric acid. Recently, DPPIV inhibitors have been shown to improve diabetic changes and sodium excretion, effects that are beyond glycemic control. Therefore, the renal protective benefits of DPPIV inhibition in a clinically relevant Western diet fed mouse model were examined. Methods: Mice fed a high fat/high fructose (WD) diet for 16 weeks and given a DPPIV inhibitor MK0626 in their diet were examined for metabolic parameters, inflammation, kidney renin-angiotensin system (RAS) and oxidative stress. Renal injury was assessed by biochemical, immunohistological and electron microscopy techniques. In vitro , angiotensin II (Ang II) effects on OKP-PTCs were assessed for mechanism. Results: MK0626 ameliorated WD-induced increases in serum uric acid, oxidative stress and RAS. WD induced suppression of IL-10 was reversed by MK0626. There was a tendency to improve HOMA-IR by MK0626 but no effect on BP and body weights. Diet induced DPPIV activation in the plasma and kidney of WD mice was abrogated by MK0626 (~80%). WD mice were characterized by increased proteinuria (~3-fold), mesangial expansion and podocyte effacement and these changes were prevented by MK0626. In addition, the PTC endocytosis protein megalin and basilar canalicular network and mitochondrial ultrastructure abnormalities were reversed by MK0626. WD mice had decreased sodium excretion which was improved by MK0626. Ang II directly increased DPPIV activity and sodium hydrogen exchanger activity in PTCs and decreased megalin protein, which was effectively prevented by MK0626. Conclusion: Thus, WD induced increases in DPPIV activity is associated with elevations in uric acid, renal RAS, inflammation and oxidative stress which may result in renal injury. These results suggest that DPPIV inhibitors prevent WD induced renal injury and offer a novel therapy for diabetic and obesity associated renal disease.

Obesity and a nondipping circadian blood pressure (BP) pattern are associated with diastolic dysfunction. Ectopic lipid accumulation is increasingly recognized as an important metabolic abnormality contributing to diastolic dysfunction. However, little is known about the contribution of different lipids and the composition of lipid analytes to diastolic dysfunction. We have performed functional and structural studies and analyzed cardiac lipid profile at two time points during progression to diastolic dysfunction in a genetic model of obesity. Serial cardiac magnetic resonance imaging and telemetric measures of BP between 12 and 15 wk of age in obese male db/db mice indicated a nondipping circadian BP pattern and normal diastolic function at 12 wk that progressed to a deteriorating nondipping pattern and onset of diastolic dysfunction at 15 wk of age. Lipidomic analysis demonstrated elevated fatty acids and ceramides in db/db at 12 wk, but their levels were decreased at 15 wk, and this was accompanied by persistent mitochondrial ultrastructural abnormalities in concert with evidence of increased fatty acid oxidation and enhanced production of reactive oxygen species. Triacylglyceride and diacylglyceride levels were elevated at both 12 and 15 wk, but their composition changed to consist of more saturated and less unsaturated fatty acyl at 15 wk. An increase in the lipid droplets was apparent at both time points, and this was associated with increases in phosphatidycholine. In conclusion, a distinct pattern of myocardial lipid remodeling, accompanied by oxidative stress, is associated with the onset of diastolic dysfunction in obese, insulin-resistant db/db mice.

Myocardial accumulation of fatty acids and lipid intermediates may contribute to cardiac dysfunction, but the interrelationship between different lipid species to diastolic dysfunction is not clearly understood. Herein, we examined changes in levels and composition of different lipid species during the progression to diastolic dysfunction in a clinically relevant model of obese insulin-resistant db/db mice at 12 and 15 wks of age. Obese db/db mice manifested loss of circadian BP dipping and diastolic dysfunction at 15 wks. Myocardial lipidomic analysis demonstrated elevated ceramides and fatty acids in db/db at 12 wks, but their levels were decreased at 15 wk and this was accompanied by increased fatty acid oxidation and enhanced production of reactive oxygen species. Triacylglyceride and diacylglyceride levels remained elevated at both 12 and 15 wk, but their composition changed to consist of more saturated and less unsaturated fatty acyl at 15 wks of age compared to 12 wk. Dysregulation of phospholipid metabolism persisted at 15 wk in db/db. Changes in triacylglyceride and diacylglyceride composition, phospholipid metabolism, β-oxidation, and oxidative stress that are temporally related to non-dipping of BP and diastolic dysfunction suggest a switch in metabolism of lipid intermediates contributes to the development of diastolic dysfunction in over-nutrition.

Publisher Summary This chapter discusses how insulin enhances central nervous system activity and plays an important role in dietary intake-induced sympatho-excitation which, ironically, likely subserves weight maintenance by stimulating thermogenesis at the expense of hypertension. Obesity and insulin resistance (IR) are increasing in prevalence worldwide across gender and ethnicity, especilly in children. IR occurs when peripheral tissues, particularly adipose, liver, and skeletal muscle, are resistant to the metabolic actions of insulin, resulting in reduced insulin-induced intracellular glucose transport. In the kidney, high renal sympathetic tone and excess NE release from renal nerve terminals causes increased renin release from juxtaglomerular cells of the kidney, thereby stimulating the rennin–angiotensin–aldosterone system (RAAS) with inappropriate elevations in angiotensin (Ang) II and aldosterone (Aldo) that impact blood volume and sodium retention. Importantly, both IR and SNS over-activation may also contribute independently to hypertension and end-organ damage via separate pathways involving mitogenic properties (insulin) and reactive oxygen species (ROS) generation in the sympathetic nervous system (SNS).

Telmisartan, an angiotensin receptor blocker, may have unique benefits as it possesses partial peroxisome proliferator-activated receptor (PPAR)-γ agonist activity in addition to antihypertensive effects. In this study, we test whether treatment with telmisartan ameliorates cardiovascular abnormalities to a greater extent than olmesartan, which has little PPAR-γ activity. The hypertensive rodent model of tissue renin-angiotensin system activation, transgenic (mRen2)27 (Ren2) rats and their littermate Sprague-Dawley controls were used. Rats were treated with telmisartan (2 mg·kg−1·day−1), olmesartan (2.5 mg·kg−1·day−1), or vehicle via drinking water for 3 wk; these doses achieved similar blood pressure control, as measured by telemetry. Ren2 rats displayed impaired diastolic and systolic function using left ventricular (LV) pressure-volume (P-V) analysis. Load-independent diastolic indexes, including the time constant of isovolumic relaxation and the slope of the end-diastolic P-V relationship, as well as systolic indexes, including preload recruitable stroke work, the dP/d tmax-end-diastolic volume (EDV) relationship, and the P-V area-EDV relationship, were elevated in Ren2 rats compared with Sprague-Dawley controls ( P < 0.05). The Ren2 myocardium exhibited parallel increases in the oxidant markers NADPH oxidase and 3-nitrotyrosine. The increase in the prohypertrophic protein Jak2 in Ren2 rats was associated with cardiac structural abnormalities using light microscopic and ultrastructural analysis, which included interstitial fibrosis, cardiomyocyte and LV hypertrophy, and mitochondrial derangements. Both angiotensin receptor blockers attenuate these abnormalities to a similar extent. Our data suggest that the beneficial effect of telmisartan and olmesartan on cardiac structure and function may be predominantly pressor-related or angiotensin type 1 receptor dependent in this model of renin-angiotensin system activation.

Hypertension and type 2 diabetes mellitus (T2DM) are powerful risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), both of which are leading causes of morbidity and mortality worldwide. Research into the pathophysiology of CVD and CKD risk factors has identified salt sensitivity and insulin resistance as key elements underlying the relationship between hypertension and T2DM. Excess dietary salt and caloric intake, as commonly found in westernized diets, is linked not only to increased blood pressure, but also to defective insulin sensitivity and impaired glucose homeostasis. In this setting, activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS), as well as increased signaling through the mineralocorticoid receptor (MR), result in increased production of reactive oxygen species and oxidative stress, which in turn contribute to insulin resistance and impaired vascular function. In addition, insulin resistance is not limited to classic insulin-sensitive tissues such as skeletal muscle, but it also affects the cardiovascular system, where it participates in the development of CVD and CKD. Current clinical knowledge points towards an impact of salt restriction, RAAS blockade, and MR antagonism on cardiovascular and renal protection, but also on improved insulin sensitivity and glucose homeostasis.

The cardiometabolic syndrome comprises a cluster of risk factors, including abdominal obesity, dyslipidemia, hypertension, insulin resistance/glucose intolerance, and proteinuria. This syndrome is due, in part, to the accumulation of visceral fat, which promotes synthesis of proinflammatory adipokines resulting in a visceral adipose tissue-specific increase in reactive oxygen species derived from NADPH oxidase. Adipose tissue oxidative stress results in the development of systemic oxidative stress and inflammation, which further lead to development of metabolic dyslipidemia, impaired glucose metabolism, renal disease, and hypertension. Importantly, visceral—not subcutaneous—fat is the significant source of the circulating adipokines that promote these systemic abnormalities. Chronic low-grade inflammation develops within adipose tissue because of the additional infiltration and accumulation of inflammatory macrophages. There is evidence that lifestyle changes, bariatric surgery, and/or administration of insulin-sensitizing, anti-inflammatory, or antihypertensive drugs that address the risk factors promoting the cardiometabolic syndrome act, in part, by promoting an anti-inflammatory adipokine profile in visceral fat.

Background/Aims: The impact of nebivolol therapy on the renal proximal tubular cell (PTC) structure and function was investigated in a transgenic (TG) rodent model of hypertension and the cardiometabolic syndrome. The TG Ren2 rat develops nephropathy with proteinuria, increased renal angiotensin II levels and oxidative stress, and PTC remodeling. Nebivolol, a β1-antagonist, has recently been shown to reduce albuminuria, in part, through reductions in renal oxidative stress. Accordingly, we hypothesized that nebivolol therapy would attenuate PTC damage and tubulointerstitial fibrosis. Methods: Young Ren2 (R2-N) and SD (SD-N) rats were treated with nebivolol (10 mg/kg/day) or vehicle (R2-C; SD-C) for 3 weeks. PTC structure and function were tested using transmission electron microscopy and functional measurements. Results: Nebivolol treatment decreased urinary N-acetyl-β-D-glucosaminidase, tubulointerstitial ultrastructural remodeling and fibrosis, NADPH oxidase activity, 3-nitrotyrosine levels, and increased megalin and lysosomal-associated membrane protein-2 immunostaining in PTCs. Ultrastructural abnormalities that were improved with therapy included altered canalicular structure, reduced endosomes/lysosomes and PTC vacuoles, basement membrane thickening, and mitochondrial remodeling/fragmentation. Conclusion: These observations support the notion that nebivolol may improve PTC reabsorption of albumin and other glomerular filtered small molecular weight proteins in association with the attenuation of oxidative stress, tubulointerstitial injury and fibrosis in this rat model of metabolic kidney disease.

The prevalence of diabetes, hypertension, and cardiovascular disease (CVD) and chronic kidney disease (CKD) is increasing in concert with obesity. Insulin resistance, metabolic dyslipidemia, central obesity, albuminuria and hypertension commonly cluster to comprise the cardiometabolic syndrome. Emerging evidence supports a shift in our understanding of the crucial role of elevated serum aldosterone in promoting insulin resistance and resistant hypertension. Aldosterone enhances tissue generation of oxygen free radicals and systemic inflammation. This increase in oxidative stress and inflammation, in turn, contributes to impaired insulin metabolic signaling, reduced endothelial-mediated vasorelaxation and associated cardiovascular and renal structural and functional abnormalities. In this context, recent investigation indicates that hyperaldosteronism, which is often associated with obesity, contributes to impaired pancreatic beta-cell function as well as diminished skeletal muscle insulin metabolic signaling. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated, in part, by aldosterone's non-genomic as well as genomic signaling through the mineralocorticoid receptor (MR). In the cardiometabolic syndrome there are increased circulating levels of glucocorticoids, which can also activate MR signaling in cardiovascular, adipose, skeletal muscle, neuronal, and liver tissue. Further, there is increasing evidence that fat tissue produces a lipid soluble factor that stimulates aldosterone production from the adrenal zona glomerulosa. Recently, have we learned that MR blockade improves pancreatic insulin release, insulin-mediated glucose utilization, endothelium-dependent vasorelaxation as well as reducing the progression of CVD and CKD. In summary, aldosterone excess exerts detrimental metabolic effects that contribute to the development of the CMS and resistant hypertension as well as CVD and CKD.

Renin-angiotensin system (RAS) activation contributes to kidney injury through oxidative stress. Renin is the rate-limiting step in angiotensin (ANG II) generation. Recent work suggests renin inhibition improves proteinuria comparable to ANG type 1 receptor (AT1R) blockade (ARB). Thereby, we investigated the relative impact of treatment with a renin inhibitor vs. an ARB on renal oxidative stress and associated glomerular structural and functional changes in the transgenic Ren2 rat, which manifests hypertension, albuminuria, and increased tissue RAS activity. Young Ren2 and age-matched Sprague-Dawley (SD) controls (age 6–9 wk) were treated with a renin inhibitor (aliskiren), an ARB (irbesartan), or vehicle for 21 days. Ren2 rats exhibited increases in systolic pressure (SBP), albuminuria, and renal 3-nitrotyrosine content as well as ultrastructural podocyte foot-process effacement and diminution of the podocyte-specific protein nephrin. Structural and functional alterations were accompanied by increased renal cortical ANG II, AT1R, as well as NADPH oxidase subunit (Nox2) expression compared with SD controls. Abnormalities were attenuated to a similar extent with both aliskiren and irbesartan treatment. Despite the fact the dose of irbesartan used caused a greater reduction in SBP than aliskerin treatment ( P < 0.05), the effects on proteinuria, nephrin, and oxidative stress were similar between the two treatments. Our results highlight both the importance of pressor-related reductions on podocyte integrity and albuminuria as well as RAS-mediated oxidant stress largely comparable between ARB and renin inhibition treatment.

Human diabetic patients often lose touch and vibratory sensations, but to date, most studies on diabetes-induced sensory nerve degeneration have focused on epidermal C-fibers. Here, we explored the effects of diabetes on cutaneous myelinated fibers in relation to the behavioral responses to tactile stimuli from diabetic mice. Weekly behavioral testing began prior to streptozotocin (STZ) administration and continued until 8 weeks, at which time myelinated fiber innervation was examined in the footpad by immunohistochemistry using antiserum to neurofilament heavy chain (NF-H) and myelin basic protein (MBP). Diabetic mice developed reduced behavioral responses to non-noxious (monofilaments) and noxious (pinprick) stimuli. In addition, diabetic mice displayed a 50% reduction in NF-H-positive myelinated innervation of the dermal footpad compared with non-diabetic mice. To test whether two neurotrophins nerve growth factor (NGF) and/or neurotrophin-3 (NT-3) known to support myelinated cutaneous fibers could influence myelinated innervation, diabetic mice were treated intrathecally for 2 weeks with NGF, NT-3, NGF and NT-3. Neurotrophin-treated mice were then compared with diabetic mice treated with insulin for 2 weeks. NGF and insulin treatment both increased paw withdrawal to mechanical stimulation in diabetic mice, whereas NT-3 or a combination of NGF and NT-3 failed to alter paw withdrawal responses. Surprisingly, all treatments significantly increased myelinated innervation compared with control-treated diabetic mice, demonstrating that myelinated cutaneous fibers damaged by hyperglycemia respond to intrathecal administration of neurotrophins. Moreover, NT-3 treatment increased epidermal Merkel cell numbers associated with nerve fibers, consistent with increased numbers of NT-3-responsive slowly adapting A-fibers. These studies suggest that myelinated fiber loss may contribute as significantly as unmyelinated epidermal loss in diabetic neuropathy, and the contradiction between neurotrophin-induced increases in dermal innervation and behavior emphasizes the need for multiple approaches to accurately assess sensory improvements in diabetic neuropathy.