High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAMl), a substrate of the insulin receptor tyrosine kinase, regulates insulin action by promoting insulin clearance. Global null mutation of Ceacam1 gene (Cc1(-/-)) results in features of the metabolic syndrome, including insulin resistance, hyperinsulinemia, visceral adiposity, elevated blood pressure, and albuminuria. It also causes activation of the renal renin-angiotensin system (RAS). In the current study, we tested the hypothesis that high-fat diet enhances the expression of RAS components. Three-month-old wild-type (Cc1(+/+)) and Cc1(-/-) mice were fed either a regular or a high-fat diet for 8 wk. At baseline under regular feeding conditions, Cc1(-/-) mice exhibited higher blood pressure, urine albumin-to-creatinine ratio (UACR), and renal expression of angiotensinogen, renin/prorenin, angiotensin-converting enzyme, (pro)renin receptor, angiotensin subtype AT1 receptor, angiotensin II, and elevated PI3K phosphorylation, as detected by p85α (Tyr(508)) immunostaining, inflammatory response, and the expression of collagen I and collagen III. In Cc1(+/+) mice, high-fat diet increased blood pressure, UACR, the expression of angiotensin-converting enzyme and angiotensin II, PI3K phosphorylation, inflammatory response, and the expression of collagen I and collagen III. In Cc1(-/-) mice, high-fat intake further amplified these parameters. Immunohistochemical staining showed increased p-PI3K p85α (Tyr(508)) expression in renal glomeruli, proximal, distal, and collecting tubules of Cc1(-/-) mice fed a high-fat diet. Together, this demonstrates that high-fat diet amplifies the permissive effect of Ceacam1 deletion on renal expression of all RAS components, PI3K phosphorylation, inflammation, and fibrosis.

Dopamine-Secreting Carotid Body Paraganglioma in a Patient With SDHB Mutation.

Background/Objective: Exclusively dopamine-secreting paragangliomas (PGLs) are rare, and the majority of head and neck PGLs are nonsecretory. Here, we describe a patient with succinate dehydrogenase subunit B (SDHB) mutation and a dopamine-secreting carotid body PGL to highlight the potential importance of screening for dopamine excess in patients with suspected PGL. Case Report: We report a 34-year-old patient who presented with cranial nerve palsy and was found to have a cerebellopontine PGL. Biochemical testing demonstrated increased circulating dopamine levels with normal levels of other catecholamines. Dopamine excess improved with resection of the PGL, and subsequent genetic testing revealed an SDHB mutation. Discussion: Secretory head and neck PGLs and exclusively dopamine-secreting PGLs are both uncommon and rarely present together, although PGLs in patients with SDHB mutations often do produce dopamine. Although current guidelines do not recommend routine evaluation of the dopamine levels in patients at risk for PGL, dopamine-secreting PGLs are frequently locally invasive or metastatic. Conclusion: Screening for dopamine excess in patients with a predisposition to PGL or with suspected PGL may aid in diagnosis and as a marker of successful treatment.

Renal Hypokalemia: An Endocrine Perspective.

The majority of disorders that cause renal potassium wasting present with abnormalities in adrenal hormone secretion. While these findings frequently lead patients to seek endocrine evaluation, clinicians often struggle to accurately diagnose these conditions, delaying treatment and adversely impacting patient care. At the same time, growing insight into the genetic and molecular basis of these disorders continues to improve their diagnosis and management. In this review, we outline a practical integrated approach to the evaluation of renal hypokalemia syndromes that are seen in endocrine practice while highlighting recent advances in understanding of the genetics and pathophysiology behind them.

Nephron specific ATP6AP2 knockout increases urinary excretion of fatty acids and decreases renal cortical megalin expression.

ATP6AP2 knockout in the renal nephron impairs receptor-mediated endocytosis, increasing urinary albumin and glucose excretion and impairing weight gain. Nonesterified fatty acids (NEFA) in urine are bound to albumin and reabsorbed in the proximal tubule through receptor-mediated endocytosis by the megalin-cubilin complex. We hypothesized that ATP6AP2 knockout increases urinary NEFA excretion through a reduction in megalin. Ten-week-old male C57BL/6 mice with nephron specific inducible ATP6AP2 knockout and noninduced controls were fed either normal diet (ND 12% fat) or high fat diet (HFD 45% fat) for 6 months. ATP6AP2 knockout significantly increased urine albumin:creatinine ratio in both ND and HFD fed mice while normalized urine NEFA concentration increased 489% and 259% in ND and HFD knockout mice compared to respective controls. Knockout decreased renal cortical megalin mRNA by 47% on ND and 49% on HFD while megalin protein expression decreased by 36% and 44% respectively. At the same time, markers of mTOR activity were increased while autophagy was impaired. Our results indicate that nephron specific ATP6AP2 knockout increases urinary NEFA excretion in the setting of impaired receptor-mediated endocytosis. Further investigation should determine whether ATP6AP2 contributes to obesity related ectopic lipid deposition in the proximal tubule.

Novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway.

Recent studies suggested that renal gluconeogenesis is substantially stimulated in the kidney in presence of obesity. However, the mechanisms responsible for such stimulation are not well understood. Recently, our laboratory demonstrated that mice fed high fat diet (HFD) exhibited increase in renal Atp6ap2 [also known as (Pro)renin receptor] expression. We hypothesized that HFD upregulates renal gluconeogenesis via Atp6ap2-PGC-1α and AKT pathway. Using real-time polymerase chain reaction, western blot analysis and immunostaining, we evaluated renal expression of the Atp6ap2 and renal gluconeogenic enzymes, PEPCK and G6Pase, in wild type and inducible nephron specific Atp6ap2 knockout mice fed normal diet (ND, 12 kcal% fat) or a high-fat diet (HFD, 45 kcal% fat) for 8 weeks. Compared with ND, HFD mice had significantly higher body weight (23%) (P < 0.05), renal mRNA and protein expression of Atp6ap2 (39 and 35%), PEPCK (44 and 125%) and G6Pase (39 and 44%) respectively. In addition, compared to ND, HFD mice had increased renal protein expression of PGC-1α by 32% (P < 0.05) and downregulated AKT by 33% (P < 0.05) respectively in renal cortex. Atp6ap2-KO abrogated these changes in the mice fed HFD. In conclusion, we identified novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway.

Knockout of Nephron ATP6AP2 Impairs Proximal Tubule Function and Prevents High-Fat Diet-Induced Obesity in Male Mice.

ATP6AP2 expression is increased in the nephron during high-fat diet (HFD) and its knockout (ATP6AP2 KO) reduces body weight (WT) in mice. We evaluated the contribution of ATP6AP2 to urinary glucose (UG) and albumin (Ualb) handling during HFD. We hypothesized that nephron ATP6AP2 KO increases UG and Ualb and minimizes HFD-induced obesity. Eight-week-old male C57BL/6J mice with inducible nephron-specific ATP6AP2 KO and noninduced controls were fed either normal diet (ND, 12% kcal fat) or HFD (45% kcal fat) for 6 months. ATP6AP2 KO mice on ND had 20% (P < 0.01) lower WT compared with controls. HFD-fed mice had 41% (P < 0.05) greater WT than ND-fed control mice. In contrast, ATP6AP2 KO abrogated the increase in WT induced by HFD by 40% (P < 0.05). Mice on HFD had less caloric intake compared with ND controls (P < 0.01). There were no significant differences in metabolic rate between all groups. UG and Ualb was significantly increased in ATP6AP2 KO mice on both ND and HFD. ATP6AP2 KO showed greater levels of proximal tubule apoptosis and histologic evidence of proximal tubule injury. In conclusion, our results demonstrate that nephron-specific ATP6AP2 KO is associated with glucosuria and albuminuria, most likely secondary to renal proximal tubule injury and/or dysfunction. Urinary loss of nutrients may have contributed to the reduced WT of knockout mice on ND and lack of WT gain in response to HFD. Future investigation should elucidate the mechanisms by which loss of renal ATP6AP2 causes proximal tubule injury and dysfunction.

Interaction of the renin angiotensin and cox systems in the kidney.

Cyclooxygenase-2 (COX-2) plays an important role in mediating actions of the renin-angiotensin system (RAS). This review sheds light on the recent developments regarding the complex interactions between components of RAS and COX-2; and their implications on renal function and disease. COX-2 is believed to counter regulate the effects of RAS activation and therefore counter balance the vasoconstriction effect of Ang II. In kidney, under normal conditions, these systems are essential for maintaining a balance between vasodilation and vasoconstriction. However, recent studies suggested a pivotal role for this interplay in pathology. COX-2 increases the renin release and Ang II formation leading to increase in blood pressure. COX-2 is also associated with diabetic nephropathy, where its upregulation in the kidney contributes to glomerular injury and albuminuria. Selective inhibition of COX-2 retards the progression of renal injury. COX-2 also mediates the pathologic effects of the (Pro)renin receptor (PRR) in the kidney. In summary, this review discusses the interaction between the RAS and COX-2 in health and disease.

A Case for Conservative Management: Characterizing the Natural History of Radiographically Diagnosed Rathke Cleft Cysts.

CONTEXT: Rathke cleft cysts (RCCs) are benign embryonic remnants of the Rathke's pouch found in 13% to 33% of the general population. When symptomatic, they manifest themselves by compressing adjacent structures, causing pressure effects such as headache, visual disturbance, or pituitary hormone deficits. Most RCCs are asymptomatic, and their management remains controversial. Surgical resection has generally been indicated to treat symptomatic RCCs but carries the risk of complications. OBJECTIVE: Our objective was to better characterize the outcomes for patients with presumed RCCs undergoing conservative management. DESIGN: This was a retrospective cohort study. SETTING: The setting was a pituitary program at a university medical center. PARTICIPANTS: The participants were 75 patients with radiographically diagnosed RCCs. METHODS: All brain magnetic resonance imaging (MRI) scans performed at the University of Virginia from 2006 through 2013 were searched for the words "Rathke cleft cyst," and pituitary clinic notes from 2007 to 2012 were reviewed for patients identified as probably having an RCC. Images for all patients were reviewed by the interpreting neuroradiologist, and those patients with at least 2 MRI scans were included. The dimensions of each cyst were assessed by the same neuroradiologist, and the volume of each cyst was analyzed as a function of the time from the first image obtained. RESULTS: A total of 75 patients (4-76 years old) met our inclusion criteria. The length of follow-up was 1 to 126 months (median 24 months). In 43 patients (57%) no detectable change in the size of their cysts was seen, in 21 patients (28%) cysts increased in size, and in 11 patients (15%) cysts decreased in size. The predicted mean cyst growth rate was not significantly different from 0. CONCLUSION: The increasingly prevalent use of brain imaging modalities such as MRI has resulted in an increase in the incidental discovery of pituitary lesions. Our study demonstrates that the majority of radiologically diagnosed RCCs remain unchanged or decrease in size over time. These results suggest that, in the absence of pressure symptoms, it is reasonable to manage patients with RCCs conservatively.

Barriers encountered during enrollment in an internet-mediated randomized controlled trial.

BACKGROUND: Online technology is a promising resource for conducting clinical research. While the internet may improve a study's reach, as well as the efficiency of data collection, it may also introduce a number of challenges for participants and investigators. The objective of this research was to determine the challenges that potential participants faced during the enrollment phase of a randomized controlled intervention trial of Stepping Up to Health, an internet-mediated walking program that utilized a multi-step online enrollment process. METHODS: We conducted a quantitative content analysis of 623 help tickets logged in a participant management database during the enrollment phase of a clinical trial investigating the effect of an automated internet-mediated walking intervention. Qualitative coding was performed by two trained coders, and 10% of the sample was coded by both coders to determine inter-coder reliability. Quantitative analyses included standard descriptive statistics on ticket characteristics and theme frequency, and a Poisson regression analysis identified characteristics of potential participants who reported more frequent problems during enrollment. RESULTS: In total, 880 potential participants visited the study website and 80% completed the enrollment screening. Of the potential participants who visited the study website, 38% had help tickets logged in the participant management database. The total number of help tickets associated with individual potential participants ranged from 0 to 7 (M = .71). Overall, 46% of help tickets were initiated by email and 54% were initiated by phone. The most common help ticket theme was issues related to the study process (48%). The next most prominent theme was discussion related to obtaining medical clearance (34%), followed by issues related to pedometers and uploading (31%). Older individuals, women, and those with lower self-rated internet ability were more likely to report problems during the enrollment process. CONCLUSION: Prospective participants in an online clinical trial encountered a number of barriers to enrollment that led them to request help from study staff. Questions about the complex enrollment process itself were common. In a complex multi-step enrollment process, providing personalized feedback to potential participants indicating their status within the enrollment process may be beneficial. TRIAL REGISTRATION: ClinicalTrials.gov NCT00729040.