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Podocytes are the key target for injury in proteinuric glomerular diseases that result in podocyte loss, progressive focal segmental glomerular sclerosis (FSGS), and renal failure. Current evidence suggests that the initiation of podocyte injury and associated proteinuria can be separated from factors that drive and maintain these pathogenic processes leading to FSGS. In nephrotic urine aberrant glomerular filtration of plasminogen (Plg) is activated to the biologically active serine protease plasmin by urokinase-type plasminogen activator (uPA). In vivo inhibition of uPA mitigates Plg activation and development of FSGS in several proteinuric models of renal disease including 5/6 nephrectomy. Here, we show that Plg is markedly increased in the urine in two murine models of proteinuric kidney disease associated with podocyte injury: Tg26 HIV-associated nephropathy and the Cd2ap-/- model of FSGS. We show that human podocytes express uPA and three Plg receptors: uPAR, tPA, and Plg-RKT. We demonstrate that Plg treatment of podocytes specifically upregulates NADPH oxidase isoforms NOX2/NOX4 and increases production of mitochondrialdependent superoxide anion (O2 -) that promotes endothelin-1 synthesis. Plg via O2 - also promotes expression of the B scavenger receptor CD36 and subsequent increased intracellular cholesterol uptake resulting in podocyte apoptosis. Taken together, our findings suggest that following disruption of the glomerular filtration barrier at the onset of proteinuric disease, podocytes are exposed to Plg resulting in further injury mediated by oxidative stress. We suggest that chronic exposure to Plg could serve as a "second hit" in glomerular disease and that Plg is potentially an attractive target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking (CS) adversely affect the progression of DN. The effects of CS on DN progression have been attributed to combustion-generated molecules without consideration to the role of nicotine (NIC), responsible for the addictive properties of both CS and electronic cigarettes (ECs). Podocytes are essential to preserve the structure and function of the glomerular filtration barrier, and strong evidence indicates that early podocyte loss promotes DN progression. We performed experiments in human podocytes and in a mouse model of diabetes that develops nephropathy resembling human DN. We determined that NIC binding to podocytes in concentrations achieved with CS and ECs activated NADPH oxidase, which sets in motion a dysfunctional molecular network integrated by cyclooxygenase 2, known to induce podocyte injury; downregulation of AMP-activated protein kinase, important for maintaining cellular energy stores and antioxidation; and upregulation of CD36, which increased lipid uptake and promoted apoptosis. In diabetic mice, NIC increased proteinuria, a recognized marker of chronic kidney disease progression, accompanied by reduced glomerular podocyte synaptopodin, a crucial stabilizer of the podocyte cytoskeleton, and increased fibronectin expression. This novel study critically implicates NIC itself as a contributor to DN progression in CS and EC users. NEW & NOTEWORTHY In this study, we demonstrate that nicotine increases the production of reactive oxygen species, increases cyclooxygenase-2 expression, and upregulates Cd36 while inducing downregulation of AMP-activated protein kinase. In vivo nicotine increases proteinuria and fibronectin expression in diabetic mice. This study demonstrates that effects of nicotine on podocytes are responsible, at least in part, for the deleterious effects of smoking in the progression of chronic kidney disease, including diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Urinary plasminogen/plasmin, or plasmin (ogen) uria, has been demonstrated in proteinuric patients and exposure of cultured podocytes to plasminogen results in injury via oxidative stress pathways. A causative role for plasmin (ogen) as a "second hit" in kidney disease progression has yet to have been demonstrated in vivo. Additionally, association between plasmin (ogen) uria and kidney function in glomerular diseases remains unclear. We performed comparative studies in a puromycin aminonucleoside (PAN) nephropathy rat model treated with amiloride, an inhibitor of plasminogen activation, and measured changes in plasmin (ogen) uria. In a glomerular disease biorepository cohort (n = 128), we measured time‐of‐biopsy albuminuria, proteinuria, and plasmin (ogen) uria for correlations with kidney outcomes. In cultured human podocytes, plasminogen treatment was associated with decreased focal adhesion marker expression with rescue by amiloride. Increased glomerular plasmin (ogen) was found in PAN rats and focal segmental glomerulosclerosis (FSGS) patients. PAN nephropathy was associated with increases in plasmin (ogen) uria and proteinuria. Amiloride was protective against PAN‐induced glomerular injury, reducing CD36 scavenger receptor expression and oxidative stress. In patients, we found associations between plasmin (ogen) uria and edema status as well as eGFR. Our study demonstrates a role for plasmin (ogen)‐induced podocyte injury in the PAN nephropathy model, with amiloride having podocyte‐protective properties. In one of the largest glomerular disease cohorts to study plasminogen, we validated previous findings while suggesting a potentially novel relationship between plasmin (ogen) uria and estimated glomerular filtration rate (eGFR). Together, these findings suggest a role for plasmin (ogen) in mediating glomerular injury and as a viable targetable biomarker for podocyte‐sparing treatments. [ABSTRACT FROM AUTHOR]

Obesity and cigarette smoke are major cardiovascular (CV) risk factors and, when coexisting in the same individuals, have additive/synergistic effects upon CVD. We studied the mechanisms involved in nicotine enhancement of CVD in Sprague Dawley rats with diet–induced obesity. The rats were fed either a high fat (HFD) or normal rat chow diet with or without nicotine (100 mg/L in drinking water) for 20 weeks. HFD rats developed central obesity, increased systolic blood pressure (SBP), aortic superoxide (O2-) production, and impaired endothelial nitric oxide synthase (eNOS) and endothelium-dependent relaxation to acetylcholine (EDR). Nicotine further increased SBP, O2- and impaired eNOS and EDR in obese rats. In the peritoneal macrophages from obese rats, tumor necrosis factor (TNF) α, interleukin 1β and CD36 were increased, and were further increased in nicotine-treated obese rats. Using PCR array we found that 3 of 84 target proinflammatory genes were increased by 2–4 fold in the aorta of obese rats, 11 of the target genes were further increased in nicotine-treated obese rats. HUVECs, incubated with conditioned medium from the peritoneal macrophages of nicotine treated-obese rats, exhibited reduced eNOS and increased NADPH oxidase subunits gp91phox and p22phox expression. Those effects were partially prevented by adding anti-TNFα antibody to the conditioned medium. Our results suggest that nicotine aggravates the CV effects of diet–induced obesity including the oxidative stress, vascular inflammation and endothelial dysfunction. The underlying mechanisms may involve in targeting endothelium by enhancement of macrophage-derived TNFα. [ABSTRACT FROM AUTHOR]

Introduction: Excess sodium intake is common across all age, sex, racial, and ethnic groups in the US and remains an important modifiable risk factor for elevated blood pressure (BP), a leading contributor to cardiovascular disease. While multiple 24 -hour urinary measures of sodium excretion are the preferred objective measure of sodium intake, multiple standardized, interviewer-administered 24 hour dietary recalls offer a useful surrogate measure for longitudinal group comparisons, especially unique among US Hispanics/Latinos of diverse backgrounds. Objectives: To assess whether dietary sodium intake was associated with change in systolic blood pressure (SBP) over six years, overall and by use of BP lowering medication. Methods: The Hispanic Community Health Study/Study of Latinos is an ongoing prospective population-based study of 16,415 diverse Hispanics/Latinos aged 18-74 yr from four US communities. Visit 1 (baseline) was conducted in 2008-2011, and visit 2 is currently ongoing (2014-2017). Dietary sodium intake was averaged from two interviewer-administered 24-hour diet recalls collected at visit 1. Likewise, SBP was the average from three seated measurements in visit 1 and about six years later in visit 2. Change in SBP from visit 1 to visit 2 was calculated. Using linear regression models adjusted for age, sex, study site, follow-up years, Hispanic/Latino background, education, income, nativity, diabetes, chronic kidney disease, dyslipidemia, family history of CVD, BMI, smoking, alcohol use, physical activity, and energy intake, we estimated the association of a 500 mg/day increment of sodium intake on change in SBP. Models were further stratified by self-reported use of BP lowering medication at visit 2. Results: The sample includes 7,904 adults who attended visit 2 by September 2016; average follow-up time was 5.8 years (SE: 0.02). At visit 1 mean age was 44.5 years (SE: 0.05); 57% were female (SE: 0.86). Overall, mean sodium intake was 3171 mg/day (SE: 33); a 500 mg/day higher sodium intake was associated with a 0.33 mmHg increase in SBP (95% CI: 0.07, 0.60). Among individuals not reporting taking BP lowering medication, mean sodium was 3,181 (SE: 34) and a 500 mg higher sodium intake was associated with a non-significant 0.29 mmHg increase in SBP (95% CI: -0.00, 0.58). Among individuals on BP lowering medication, mean sodium intake was 2,966 (SE: 50) and a 500 mg higher sodium intake was significantly associated with a 0.61 mmHg increase in SBP (95% CI: 0.11, 1.11). Conclusions: Among a large sample of diverse US Hispanics/Latinos, higher sodium intake was associated with small SBP increases in approximately six years. The effect of sodium on elevated SBP was stronger among individuals on BP lowering medications. [ABSTRACT FROM AUTHOR]

Background. Intermittent smoking is prevalent amongHispanics, but little is known about whether this smoking pattern associates with increased chronic kidney disease (CKD) risk in this population. The objective of the present study is to identify patterns of exposure associated with CKD in US Hispanics. Methods. We used cross-sectional data on 15 410 participants of the Hispanics Community Health Study/the Study of Latinos, a population-based study of individuals aged 18-74 years, recruited in 2008 to 2011 from four US field centers (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA). Smoking exposure was obtained through a questionnaire. CKD was defined by an estimated glomerular filtration rate of <60 mL/min/ 1.73 m² or a urine albumin-to-creatinine ratio of ≥30 mg/g. Results. Approximately 14% of individuals were daily and 7% were intermittent smokers, and 16% were past smokers. There was a significant interaction between smoking status and packyears of exposure (P = 0.0003). In adjusted models, therewas an increased odds of CKD among daily, intermittent and past smokers by pack-years compared with never smokers. The association of intermittent smokers was significant at 10 pack-years [odds ratio (OR) = 1.38, 95% confidence intervals (CI) 1.06, 1.81], whereas for daily smokers this association was observed at 40 pack-years (OR = 1.43, 95% CI 1.09, 1.89). Conclusions. Our findings of increased risk of CKD among Hispanics who are intermittent smokers support screening and smoking cessation interventions targeted to this population for the prevention of CKD. It also suggests novel mechanistic pathways for kidney toxicity that should be further explored in future studies. [ABSTRACT FROM AUTHOR]

Background: We have previously shown that in hypertensive Dahl salt-sensitive (DS) rats, impaired endotheliumdependent relaxation to acetylcholine and to insulin is mechanistically linked to up-regulation of angiotensin (Ang) II actions and the production of reactive oxygen species (ROS) and to activation of the proinflammatory transcription factor (NF)κB. Here we investigated whether Ang II activation of NFκB contributed to insulin resistance in the skeletal muscle of this animal model. Methods: DS rats were fed either a normal (NS, 0.5% NaCl) or high (HS, 4% NaCl) salt diet for 6 weeks. In addition, 3 separate groups of HS rats were given angiotensin receptor 1 blocker candesartan (ARB, 10 mg/kg/day in drinking water), antioxidant tempol (1 mmol/L in drinking water) or NFκB inhibitor PDTC (150 mg/kg in drinking water). Results: DS rats manifested an increase in soleus muscle Ang II content, ROS production and phosopho-IκBα/IκBα ratio, ARB or tempol reduced ROS and phospho-IκBα/IκBα ratio. Hypertensive DS rats also manifested a reduction in glucose infusion rate, impaired insulin-induced Akt phosphorylation and Glut-4 translocation in the soleus muscle, which were prevented with treatment of either ARB, tempol, or PDTC. Data from the rat diabetes signaling pathway PCR array showed that 8 genes among 84 target genes were altered in the muscle of hypertensive rats with the increase in gene expression of ACE1 and 5 proinflammatory genes, and decrease of 2 glucose metabolic genes. Incubation of the muscle with NFκB SN50 (a specific peptide inhibitor of NFκB) ex vivo reversed changes in hypertension-induced gene expression. Conclusion: The current findings strongly suggest that the activation of NFκB inflammatory pathway by Ang II play a critical role in skeletal muscle insulin resistance in salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Introduction: Experimental evidence suggests sedentary time (ST), in part, contributes to cardiovascular disease risk by eliciting detrimental hemodynamic changes (blood pooling, turbulent blood flow) in the lower limbs. However, few studies have examined the association of ST and peripheral artery disease (PAD). Hypothesis: We hypothesized that longer daily ST is associated with higher odds of PAD, independent of moderate-to-vigorous physical activity (MVPA). Methods: We examined cross-sectional associations of accelerometer-measured ST (measured over 7 days) and the ankle brachial index (ABI) among 7,677 Hispanic adults (ages 45-74) who were enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). ST (<100 counts/min) was standardized to 16 hours/d of wear time. Using multivariable logistic regression accounting for the complex survey design, we analyzed quartiles of ST then used restricted cubic splines (RCS) to assess non-linear associations of ST with odds of PAD (ABI ≤ 0.9), all models controlled for claudication, MVPA, and traditional cardiovascular risk factors. Results: Median ST was 12.2 hours/day (76% of wear time) and 366 (5%) participants had PAD. Using RCS with 3 knots (10th, 50th & 90th percentile), ST had a significant non-linear association with PAD (p= 0.004). As seen in the dose-response figure, a threshold effect was seen such that time spent above median ST was associated with significantly higher odds of PAD. For example, compared to median ST, 2 hours above median ST (14.2 hours/day) was associated with 1.60 times the odds of PAD (OR 1.60, 1.24-2.07). Conclusions: Among Hispanic/Latino adults, higher ST is associated with higher odds of PAD, independent of claudication, MVPA, and traditional cardiovascular risk factors. Importantly, this effect was only observed at higher levels of ST. Further study is warranted to determine if reducing high levels of ST may reduce risk of PAD or prevent progression of the disease. [ABSTRACT FROM AUTHOR]