Grape Powder Improves Age-Related Decline in Mitochondrial and Kidney Functions in Fischer 344 Rats

We examined the effects and mechanism of grape powder- (GP-) mediated improvement, if any, on aging kidney function. Adult (3-month) and aged (21-month) Fischer 344 rats were treated without (controls) and with GP (1.5% in drinking water) and kidney parameters were measured. Control aged rats showed higher levels of proteinuria and urinary kidney injury molecule-1 (KIM-1), which decreased with GP treatment in these rats. Renal protein carbonyls (protein oxidation) and gp91phox-NADPH oxidase levels were high in control aged rats, suggesting oxidative stress burden in these rats. GP treatment in aged rats restored these parameters to the levels of adult rats. Moreover, glomerular filtration rate and sodium excretion were low in control aged rats suggesting compromised kidney function, which improved with GP treatment in aged rats. Interestingly, low renal mitochondrial respiration and ATP levels in control aged rats were associated with reduced levels of mitochondrial biogenesis marker MtTFA. Also, Nrf2 proteins levels were reduced in control aged rats. GP treatment increased levels of MtTFA and Nrf2 in aged rats. These results suggest that GP by potentially regulating Nrf2 improves aging mitochondrial and kidney functions

ANGIOTENSIN AT2R ACTIVATION INCREASES ACE2/ANG1-7/MASR AXIS AND PREVENTS FATTY-DIET-INDUCED OBESITY

Purpose: Adipose tissue, the obligatory site of fat accumulation causing obesity, expresses local renin angiotensin system (RAS). RAS is commonly known to regulate blood pressure. However recently, we observed that angiotensin type 2 receptor (AT2R) activation prevents high-fat diet (HFD)-induced adiposity and hyperinsulinemia. Although, the mechanism(s) is(are) not known. There is evidence that other RAS components namely, the angiotensin type 1 receptor (AT1R) positively regulates while the angiotensin converting enzyme 2 (ACE2), which catalyzes the production of Mas receptor (MasR) peptide agonist Ang (1-7), inversely regulates adiposity and hyperinsulinemia. In light of the RAS inter-regulatory features, we hypothesize that AT2R activation causes a decrease in AT1R expression and an increase in the ACE2/Ang (1-7)/MasR expression in adipose tissue exerting beneficial effects on HFD-induced adiposity. Method: Male C57BL/6 mice (12-weeks old) were pretreated with AT2R agonist (C21, 0.3 mg/kg, daily i.p.) for 4 days. Thereafter, the animals were placed on normal chow diet (ND) or HFD with concurrent drug treatment for next 10 days. Results: The HFD increased the epididymal white adipose tissue (eWAT) weight, plasma free fatty acid (FFA), triglyceride (TG) and insulin levels. The increase in these parameters was prevented by C21 treatment. Western blot analysis demonstrated that HFD increased the protein expressions of AT1R and ACE, but decreased Ang (1-7) peptide level as measured by LC/MS analysis in eWAT. The C21 treatment under HFD condition caused a significant decreased in protein expressions of eWAT AT1R and ACE, but an increase in the expressions of MasR, ACE2 and ANG(1-7) peptide level. Conclusions: The pharmacological activation of AT2R with C21 affects adipose RAS components i.e., an increase in ACE2/Ang(1-7)/MasR levels and a decrease in ACE/AT1R expression, improving lipid metabolism and hyperinsulinemia under HFD condition. We propose that the pharmacological activation of AT2R may serve as therapeutic target for controlling obesity and associated metabolic disorders. Supported in part by grant from the NIH (RO1 DK-61578) to Dr. Hussain. Key Words: angiotensin receptors, angiotensin converting enzyme 2, obesit

Role of Angiotensin II Type 2 Receptor in Blood Pressure Regulation in Obese rats

Renin angiotensin system (RAS) consists of enzymes, hormones, proteins and peptides. Angiotensin II (Ang II) is an important peptide of RAS. Ang II acts via AT1 receptor (AT1R) and AT2 receptor (AT2R). While AT1R is known to cause antinatriuresis and increase in blood pressure, the role of AT2R in renal function and long-term BP regulation is not well defined. Recently our laboratory showed that AT2R are upregulated in the kidney of obese rats and selective activation of these receptors stimulates nitric oxide/cGMP pathway, inhibits proximal tubules Na+/K+-ATPase (NKA) activity and increases urinary sodium excretion. In light of those findings, we undertook this project to investigate the role of AT2R in renal function, long-term blood pressure control and interaction with renal AT1R function in obese Zucker rats, an animal model exhibiting hyperinsulinemia, hyperglycemia and hypertension. Also, we studied the mechanism associated with hyperglycemia induced AT2R upregulation in proximal tubule cells. First, we designed experiment to determine whether AT2R has a protective role in blood pressure increase in obese rats. We treated obese Zucker rats with AT2R antagonist PD123319 (PD) for two weeks and BP was measured. Treatment with PD significantly increased the blood pressure, which was associated with increased renal renin expression in obese rats. This suggested that AT2R protect against increase in blood pressure by keeping renal renin expression low. Then, we designed experiments to determine whether chronic AT2R activation affects Na-balance and lowers BP in obese rats. We treated lean and obese Zucker rats with AT2R agonist CGP42112A (CGP) for two weeks. Two weeks treatment caused a decrease in BP by 19 mmHg and in Na-balance in obese but not in lean rats. The plasma renin activity was significantly decreased in both lean and obese CGP-treated rats. The expression of AT2R, AT1R, angiotensin converting enzyme (ACE) and renin in the kidney cortex was not affected by the CGP-treatment of obese or lean rats. However, ACE2 expression and activity was significantly increased in CGP-treated obese rats and not in lean rats. These studies suggest that long-term activation of AT2R decreases BP in obese rats. The reduction in BP by AT2R agonist treatment may have been contributed by a decrease in Na-balance and an enhanced expression and activity of ACE2 in renal cortex. In order to determine whether the reduction in BP and decrease in Na-balance might have been contributed by the ability of AT2R to antagonize renal AT1R function in CGP-treated obese rats, we again treated the obese Zucker rats with CGP for two weeks. We performed the renal function study after two weeks under anesthesia. We found that CGP-treatment of obese rats caused reduction in Ang II pressor response and blunted the candesartan-induced natriuresis/diuresis in these rats suggesting that chronic activation of AT2R antagonizes the function of AT1R. Earlier studies from our laboratory suggest that AT2R promote Na-excretion but the contribution of different nephron segments in AT2R-induced natriuresis is not known. We investigated the involvement of proximal tubule AT2R in natriuresis by blocking the two important distal tubule Na-transporters (NaCl cotransporter and ENaC). We found that selective activation of AT2R with a novel AT2R agonist C21 promoted natriuresis predominantly via proximal tubules. We also performed in vitro experiments (HK2 cells) to elucidate the potential signaling mechanism involved in the proximal tubule AT2R upregulation in diabetes/hyperglycemia. In this experiment, we exposed HK2 cells with high glucose with and without IRF-1 siRNA. High glucose increased AT2R expression in HK2 cells and is mediated via transcriptional mechanism involving the transcription factor IRF-1. Collectively, the data suggest that long-term treatment with AT2R agonist attenuates positive Na-balance, lowers renal renin expression, antagonizes the function of AT1R and decreases blood pressure in obese Zucker rats. Moreover AT2R upregulation in response to hyperglycemia may be compensatory mechanism to exert a beneficial role in kidney function. These findings highlight the therapeutic potential of AT2R for treating obesity/diabetes related hypertension.Pharmacological and Pharmaceutical Sciences, Department o

Proactive Personality as Mediating variable between Career Skills, Servant Leadership and Subjective Career Success of Working Women: A Study from Private Sector Universities of Pakistan

Purpose: To examine the effect of career skills and servant-leadership on intrinsic career success with surrogating effect of proactive personality traits. Design/method/approach: Structural equation modeling has been applied to extract the statistical finding by applying MPlus Software. Findings: Proactive personality traits mediates between the relationship of career skills, servant-leadership, and intrinsic career success. Research implications: The model have a look at providing the suggestion for policy makers to hire and train highly educated faculty to participate in servant-leadership for the betterment of career skills and intrinsic career success, which improves institutional performance. Originality: The research study examined the P-E fit theory and the model in this particular context of Pakistan is unique and constructed to suggest policy makers the techniques for advancing the career success of working women in academia

Mediating Role of Perceived Fairness between Organizational Commitment, Organizational Trust and Work Engagement of Female Faculty Members of Public Sector Universities in Punjab, Pakistan

Purpose: Ensuring the competitive advantages for female faculty members and to attain sustainable progress in rapidly transforming educational environment in the current era.   Design/Methodology/Approach: Structural Equation Modeling (SEM) has been applied by using MPlus Software. The construct in the Context of Pakistan is exploratory in nature. Findings: The study has examined the mediating relationship of fairness between organizational trust, organizational commitment and work engagement of female faculty members working in public sector universities of Punjab, Pakistan.   Implications/Originality/Value: It is necessary to explore the other suitable attributes of the relevant construct in the context of Pakistan. As the results remained not satisfactory and generalizability of the results is not possible

Antecedents of Intrapreneurship with Mediating Effect of Career Adaptability: A Study from Pakistan

Purpose: The study emphasized on exploring the antecedes of intrapreneurship by testing the career construction theory and perceived personality study from the context of Pakistan’s private sector universities. Design/Methodology/Approach: A Total of 270 male and female academicians working in private sector universities had participated in this cross-sectional research study. The survey questionnaire was adopted from different authentic sources and evaluated for validity and reliability. MPlus software has been used for statistical findings. Findings: It has been estimated statistically that career adaptability overall mediates between the relationship of perceived personality traits and Intrapreneurship. Implications/Originality/Value: It might be established that all the public/private sector universities might follow almost the same policies and laws but there are some differences like payment of salaries / remuneration of the faculty members working in government sector universities and private sector universities of Punjab, Pakistan. The study highlighted such issues of personality directly and indirectly with career adaptability and intrapreneurship

Role of the angiotensin II AT2 receptor in inflammation and oxidative stress: opposing effects in lean and obese Zucker rats

Inflammation and oxidative stress are believed to contribute to hypertension in obesity/diabetes. Recently, we reported a role for the AT2 receptor in blood pressure control in obese Zucker rats. However, the role of AT2 receptors in inflammation and oxidative stress in obesity is not known. Therefore, in the present study, we tested the effects of the AT2 receptor agonist CGP-42112A on inflammation and oxidative stress in obese Zucker rats and compared them in their lean counterparts. Rats were systemically treated with either vehicle (control) or CGP-42112A (1 μg·kg−1·min−1; osmotic pump) for 2 wk. Markers of inflammation (CRP, MCP-1, TNF-α, and IL-6) and oxidative stress (HO-1, gp-91phox) as well as an antioxidant (SOD) were determined. Control obese rats had higher plasma levels of CRP, MCP-1, TNF-α, IL-6, and HO-1 compared with control lean rats. Conversely, plasma SOD activity was lower in control obese than in control lean rats. Furthermore, the protein levels of TNF-α and gp-91phox were higher in the kidney cortex of control obese rats. Interestingly, CGP-42112A treatment in obese rats reduced the plasma and kidney cortex inflammatory (TNF-α, IL-6) and oxidative stress (gp-91phox) markers and increased plasma SOD activity to the levels seen in lean control rats. However, CGP-42112A treatment in lean rats increased inflammatory (TNF-α, IL-6) and oxidative stress (gp-91phox) markers in the plasma and kidney cortex. Our present studies suggest anti-inflammatory and antioxidative functions of AT2 receptor in obese Zucker rats but proinflammatory and prooxidative functions in lean Zucker rats