Browsing by Subject "Hypertension"
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Item 2-Methoxyestradiol, a novel pharmacological inhibitor for Angiotensin Type I Receptor(2012-05) Koganti, Sivaramakrishna; Thekkumkara, Thomas; Abbruscato, Thomas J.; Karamyan, Vardan; Liu, XinliDelayed onset of cardiovascular(CVD) disease among females is not well understood, but could be in part due to the protective effect of estrogen before menopause. Experimental studies have identified the angiotensin type I receptor (AT1R) as a key factor in the progression of CVD.In this study, we have examined the effects and mechanism of the estrogen metabolite, 2-Methoxyestradiol (2ME2), on AT1R expression.The study used rat liver epithelial cells as the primary cell model to determine the 2ME2 induced cellular signaling, the overall concept was further confirmed in rat aortic smooth muscle cells and further validated in vivo in an animal model of hypertension. When rat liver epithelial cells were exposed to 2ME2 for 24 hours, cells exhibited significant down-regulation of AngII binding and AT1R mRNA, independent of estrogen receptors (ERĪ±/ERĪ²) with no change in receptor affnity.Significant inhibition of AngII mediated increase in intracellular Ca+2 and increased phopsphorylation of ERK1/2 were also observed.Similar analyses in stably transfected CHO cell lines with a constitutively active cytomegalovirus (CMV) promoter showed no change in AT1R expression suggesting the transcriptional regulation.2ME2 has been shown to bind specifically to endoplasmic reticulum bound G-protein coupled receptor 30(GPR30), activating matrix metalloprpteinases (MMPs) to induce epidermal growth factor receptor (EGFR) activation ultimately leading to AT1R down-regulation.2ME2 treatment showed significant down-regulation of systolic, diastolic and mean arterial blood pressure, as well as a decrease in body weight in spontaneously hypertensive rats (SHR).Consistent with the reduction in blood pressure, we observed AT1R protein and mRNA expression down-regulation in the renal cortical tissue. In summary, as AT1R plays a critical role in the control of cardiovascular diseases, 2ME2 induced changes in receptor expression may provide beneficial effects to the cardiovascular, as well as other systems.Item Effects of dietary sodium chloride on the availability and utilization of proteins in laboratory animals(Texas Tech University, 1983-05) Hussain, HadidahNot availableItem Exercise Pressor Reflex Dysfunction in Hypertension(2009-09-04) Leal, Anna Katherine; Smith, Scott AlanThe exercise pressor reflex and its components, the muscle mechanoreflex and the metaboreflex, are overactive in hypertension. The mechanoreflex and metaboreflex are feedback mechanisms originating in skeletal muscle that increase mean arterial pressure (MAP) and heart rate (HR) during exercise. In hypertensive individuals, mechanoreflex and metaboreflex overactivity can cause dangerous elevations in MAP and HR during physical activity, creating risks for adverse cardiac events. Mechanoreflex (predominantly group III) and metaboreflex (predominantly group IV) afferent fibers, which are activated by mechanical stress and the metabolic byproducts of working muscle, respectively, project to the nucleus tractus solitarius (NTS) in the brainstem. Within this nucleus, nitric oxide (NO) is produced from L-arginine via the enzymatic activity of nitric oxide synthase (NOS). Brainstem NO has been shown to modulate exercise pressor reflex-driven changes in MAP and HR. Therefore, we hypothesized that a decrease in NO production/availability within the NTS is involved in mediating both mechanoreflex and metaboreflex dysfunction in hypertension. To test this, we microdialyzed a NOS inhibitor, L-nitro-arginine methyl ester (L-NAME), and the NO precursor, L-arginine, into the NTS of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats to experimentally alter endogenous NO production during preferential activation of mechanically and metabolically sensitive skeletal muscle afferents. Passive hindlimb muscle stretch was the maneuver used to simulate mechanoreflex activation while metabolically sensitive afferents were activated by hindlimb intra-arterial capsaicin injections. Capsaicin binds to transient potential 1 (TRPv1) receptors, which are primarily localized to group IV afferents. We found that blocking NO production via L-NAME within the NTS of normotensive WKY rats recapitulates the exaggerated cardiovascular response elicited by both mechanically and metabolically sensitive afferent neurons in hypertension. Importantly, we demonstrated that experimentally increasing NO production within the NTS of hypertensive SHR rats partially corrects the enhanced cardiovascular response to activation of both mechanically and metabolically sensitive afferent neurons. These findings provide evidence that a decrease in NO production/availability within the brainstem contributes to mechanoreflex and metaboreflex dysfunction in hypertension. Future utilization of this research could lead to effective treatment options for hypertensive individuals, allowing them to engage in physical activity without the associated hemodynamic risks.Item The hypotensive effects of conventional non-fat dairy products : the role of arterial stiffness(2014-08) Machin, Daniel Robert; Tanaka, Hirofumi, Ph. D.High consumption of dairy products, particularly non-fat dairy, is associated with reduced risk of high blood pressure and vascular dysfunction. Currently, it is not known if the solitary addition of conventional non-fat dairy products to the normal routine diet is capable of reducing blood pressure or improving vascular function. Accordingly, the primary aims of the present study were to determine if the solitary addition of conventional non-fat dairy products to the normal routine diet would reduce blood pressure and improve vascular function in middle-aged and older adults with elevated blood pressure. Using a randomized, crossover intervention study design, forty-nine adults with elevated blood pressure underwent a High Dairy condition (+4 servings/day of conventional non-fat dairy products) and isocaloric No Dairy condition (+4 servings/day fruit products) in which all dairy products were removed. Both dietary conditions lasted 4 weeks with a 2-week washout before crossing over into the alternate condition. In Study 1, the High Dairy condition produced reductions in brachial systolic blood pressure and pulse pressure. The hypotensive effects were observed within three weeks after the initiation of dietary intervention and in both casual seated and ambulatory (24-hour) measurements. On the contrary, pulse pressure was increased after removal of all dairy products in the No Dairy condition compared to baseline and after in the High Dairy condition. There were no changes in diastolic blood pressure after either dietary condition. In Study 2, the High Dairy condition produced reductions in carotid systolic blood pressure, pulse pressure, and carotid-femoral pulse wave velocity with a concomitant increase in brachial flow-mediated dilation and cardiovagal baroreflex sensitivity. Brachial flow-mediated dilation decreased and carotid pulse pressure increased after removal of all dairy products in the No Dairy condition. Furthermore, [delta] carotid systolic blood pressure and carotid-femoral pulse wave velocity were highly related. Taken together, we concluded that the solitary manipulation of conventional dairy products, particularly non-fat dairy, in the normal routine diet would modulate levels of blood pressure and vascular function in middle-aged and older adults with pre-hypertension and hypertension.Item Identification of Substrates and Pathways Regulated by WNK1(2004-12-15) Lee, Byung-Hoon; Cobb, Melanie H.WNK (With No lysine (K)), a serine/threonine protein kinase, is a unique molecule not belonging to any other canonical protein kinase family including mitogen-activated protein (MAP) kinases. The name of the WNK protein kinase family reflects the fact that a catalytic lysine lies in a position different in WNKs from that in all other protein kinases. The urgency of a mechanistic examination of the WNK family protein kinase was heightened by the discovery that mutations in at least two of the four human WNKs, WNK1 and 4, caused a heritable form of hypertension. My study focused on unveiling WNK1 substrates and interactors for a better understanding of the molecular pathways served by WNK kinases. Yeast two-hybrid screening was performed to identify the binding partners of WNK1 and yielded genuine interactors including synaptotagmin (Syt) isoforms, Smad2, and dynein light chain (LC8/PIN). WNK1, not WNK4, selectively binds to and phosphorylates Syt2 within its calcium binding C2 domains. Calcium strongly enhanced their binding in vitro. Essential Ca2+-binding residues in the Syt2 C2 domains were critical for formation of a WNK1-Syt2 complex and for Syt2 phosphorylation. WNK1 displayed specificity among Syt isoforms and mutational analysis implicated a hydrophobic residue on the WNK1 kinase domain surface as essential for the high affinity WNK1-Syt2 interaction and phosphorylation. Endogenous WNK1 and Syt2 coimmunoprecipitated and colocalized on a subset of secretory granules in the INS-1 cell line, a pancreatic beta cell model system. Importantly, phosphorylation by WNK1 increased the amount of Ca2+ required for Syt2 binding to phospholipid vesicles; mutation of Thr202, a WNK1 phosphorylation site identified from mass spectrometric analysis, partially prevented this change. These findings provide a biochemical scenario that could lead to the retention or insertion of proteins in the plasma membrane. WNK1 may serve as a molecular switch for vesicle trafficking and other membrane events that regulate ion balance. The interaction with and phosphorylation of other molecules by WNK1 were also investigated here.Item Implications of electromyographic feedback for essential hypertensive patients.(Texas Tech University, 1975-05) Fray, John MichaelThe general purpose of the present study was to investigate hypothesized therapeutic aspects of biofeedback relaxation techniques in controlling diastolic blood pressure. There have been reports from the Far East for several hundred years of yogis who have been able to control bodily functions normally not under the control of the autonomic nervous system, such as heartbeat, body temperature, and amount of oxygen taken in. These early reports indicated the possibility of gaining voluntary control over internal bodily functions (Kamiya, Barber, DiCara, Miller, Shapiro, & Stoyva, 1971). However, these reports did not suggest techniques by which voluntary control could be taught to a sample of selected individuals. To be widely applied, some feasible techniques had to be developed for the control of internal bodily functions (Kamiya et al., 1971).Item Mechanisms of Intradialytic Hypertension(2012-08-15) Kim, Bohyun Catherine; Inrig, JulaIntradialytic Hypertension and Its Association with Endothelial Cell Dysfunction Background: Intradialytic hypertension is associated with adverse outcomes, yet the mechanism is uncertain. Patients with intradialytic hypertension exhibit imbalances in endothelial-derived vasoregulators nitric oxide and endothelin-1, indirectly suggesting endothelial cell dysfunction. We hypothesized that intradialytic hypertension is associated in vivo with endothelial cell dysfunction, a novel predictor of adverse cardiovascular outcomes. Design, settings, participants, & measurements: We performed a case-control cohort study including 25 hemodialysis (HD) subjects without (controls) and 25 with intradialytic hypertension (an increase in systolic BP pre- to postdialysis greater than or equal to 10 mmHg greater than or equal to 4/6 consecutive HD sessions). The primary outcome was peripheral blood endothelial progenitor cells (EPCs) assessed by aldehyde dehydrogenase activity (ALDHbr) and cell surface marker expression (CD34+CD133+). We also assessed endothelial function by ultrasonographic measurement of brachial artery flow-mediated vasodilation (FMD) normalized for shear stress. Parametric and nonparametric t tests were used to compare EPCs, FMD, and BP. Results: Baseline characteristics and comorbidities were similar between groups. Compared with controls, 2-week average predialysis systolic BP was lower among subjects with intradialytic hypertension (144.0 versus 155.5 mmHg), but postdialysis systolic BP was significantly higher (159.0 versus 128.1 mmHg). Endothelial cell function was impaired among subjects with intradialytic hypertension as measured by decreased median ALDHbr cells and decreased CD34+CD133+ cells (ALDHbr, 0.034% versus 0.053%; CD34+CD133+, 0.033% versus 0.059%). FMD was lower among subjects with intradialytic hypertension (1.03% versus 1.67%). Conclusions: Intradialytic hypertension is associated with endothelial cell dysfunction. We propose that endothelial cell dysfunction may partially explain the higher event rates observed in these patients. Probing the Mechanisms of Intradialytic Hypertension: a Pilot Study Targeting Endothelial Cell Dysfunction Background: Intradialytic hypertension may be caused by an impaired endothelial cell response to hemodialysis. Carvedilol has been shown to improve endothelial cell function in vivo and in vitro to block endothelin-1 release. Among patients with intradialytic hypertension, we hypothesized that carvedilol would improve endothelial cell function and reduce the occurrence of intradialytic hypertension. Design, settings, participants & measurements: We performed a prospective 12-week pilot study of carvedilol titrated to 50 mg twice daily among 25 hemodialysis participants with intradialytic hypertension. Each patient served as their own control. Changes in endothelial cell function (assessed by flow-mediated vasodilation, endothelial progenitor cells (EPCs by aldehyde dehydrogenase activity and CD34+CD133+), asymmetric dimethylarginine (ADMA) and endothelin-1) and blood pressure (BP) from baseline to study-end were analyzed by paired tests. Results: Flow-mediated vasodilation was significantly improved with carvedilol (from 1.03% to 1.40%, p=0.02). There was no significant change in EPCs, endothelin-1 or ADMA. At baseline, participants exhibited a significant increase in endothelin-1 pre to postdialysis that resolved by study-end. While pre-hemodialysis systolic BP was unchanged (144 to 146 mmHg, p=0.5), post-hemodialysis systolic BP, 44-hour ambulatory systolic BP, and the frequency of intradialytic hypertension decreased with carvedilol (159 to 142 mmHg, p<0.0001; 155 to 148 mmHg, p=0.05; 77% (4.6/6) to 28% (1.7/6), p<0.0001, respectively). Conclusions: Among hemodialysis participants with intradialytic hypertension, targeting endothelial cell dysfunction with carvedilol was associated with modest improvements in endothelial cell function, improved intra and interdialytic BP, and reduced frequency of intradialytic hypertension. Randomized controlled trials are required to confirm these findings. The Role of Dialysate Exposure in Intradialytic Hypertension Background: Intradialytic hypertension is associated with endothelial dysfunction, but the cause of vascular impairment is unknown. Exposure to high concentration sodium has been shown in vitro to promote endothelial stiffness and imbalances in markers of vascular function. We hypothesized that, among patients with intradialytic hypertension, exposure to dialysate sodium would lead to increases in endothelin-1, decreases in nitric oxide, and an intradialytic increase in systolic blood pressure. Design, settings, participants & measurements: We performed a 6-week crossover study of 10 hemodialysis patients with intradialytic hypertension. Changes in blood pressure, endothelin-1, and nitric oxide levels were measured during three different, midweek dialysis treatments consisting of: 1) regular hemodialysis with standard dialysate sodium (140 mEq/L); 2) ultrafiltration only without dialysate exposure; and 3) hemodialysis (Na 140 mEq/L) without ultrafiltration. These changes were analyzed using mixed model analyses. Results: Serum sodium levels rose with dialysate exposure during regular HD and HD without UF sessions (+1.6 and +3 mEq/L, respectively), and fell during UF only session (-0.9 mEq/L). Endothelin-1 level also rose with dialysate exposure during regular HD and HD without UF (+0.15 and +0.25pg/mL, respectively), but fell during UF only session (-0.02 pg/mL). Plasma nitrite levels fell with all treatment types, most significantly with regular HD (-123.25 nM), then HD without UF (-52.77 nM), with lowest decrease seen during UF only session without dialysate exposure (-48.48 nM). Systolic BP rose during all treatments, most significantly with HD without UF (13.3%), followed by regular dialysis (6.9%), and UF only (5.7%). Conclusions: Among hemodialysis patients prone to intradialytic hypertension, there was an association between dialysate exposure and increases in endothelin-1, decreases in nitric oxide, and increases in systolic blood pressure during dialysis. We propose that high dialysate to plasma sodium gradient may contribute to intradialytic hypertension. [Keywords: hemodialysis; intradialytic hypertension; Carvedilol; endothelial cell dysfunction; endothelial progenitor cells]Item Spironolactone to treat hypertension in end-stage renal disease : analysis of effectiveness and safety(2013-05) Smith, Amber Lanae; Koeller, JimPurpose: Cardiovascular events and complications are the major causes of death in patients with end-stage renal disease (ESRD)Ā¹ā»Ā³. Antihypertensive agents that block the renin-angiotensin-aldosterone system (RAAS) are considered first-line therapy in patients with ESRD as these patients have a propensity for RAAS overactivationā“ā»ā·. Studies show that aldosterone receptor blockade reduces BP in patients with chronic kidney disease (CKD) and helps prevent negative outcomes from continued renal cellular damageāøā»Ā¹ā°. Spironolactone, an aldosterone antagonist, has the potential to provoke hyperkalemia. Consequently, current guidelines do not recommend spironolactone to manage hypertension in ESRD because of this riskā¶ā»ā·. Our primary objectives were to determine the change in BP and serum potassium levels following spironolactone use. Methods: This study was a retrospective, pre-post cohort study in ESRD patients with difficult-to-control BP receiving HD. Patients prescribed spironolactone (25 mg to 50 mg) between January 2009 and January 2013 were identified using an e-prescribing record from three HD clinics in San Antonio, TX. Patients were included if they were prescribed spironolactone as 'add-on' therapy to control BP for at least 8 weeks. Results: Seventy patients were evaluated and the majority of them were overweight, diabetic, Hispanic females with a mean 65 years of age. Mean SBP and DBP decreased from baseline to week 8 [-20.74 mmHg (p < 0.0001) and -9.7 mmHg (p < 0.0426), respectively]. Mean serum potassium levels increased by an average of 0.18 mEq/L (4.5 mEq/L to 4.68 mEq/L, p = 0.09). Data analysis revealed that only 9 of 70 patients had a serum potassium level > 5.5 mEq/L at week 8. There were no adverse cardiac events reported as a result of these potassium concentrations. A two-fold decrease in SBP was seen in patients with a body mass index (BMI) > 25 kg/mĀ² compared to patients with a BMI of ā¤ 25 kg/mĀ². At the end of the study, 23 patients (33%) achieved the goal BP for healthy adults of < 140/90 mmHg. Conclusion: These findings demonstrated that using spironolactone use in ESRD patients receiving HD can be effective and safe.Item Structural Modeling and Analysis of Structures in Aorta Images(2012-10-19) Xu, HaiMorphology change analysis of aorta images acquired from biological experiments plays a critical role in exploring the relationship between lamina thickness (LT), interlamellar distance (ILD) and fragmentation (furcation points) with respect to pathological conditions. An automated software tool now is available to extract elastic laminae (EL) and measure LT, ILD and fragmentation along their ridge lines in a fine detailed aspect. A statistical randomized complete block design (RCBD) and F-test were used to assess potential (non)-uniformity of LT and ILD along both radial and circumferential directions. Illustrative results for both normotensive and hypertensive thoracic porcine aorta revealed marked heterogeneity along the radial direction in nearly stress-free samples. Quantifying furcation point densities were also found that can offer new information about potential elastin fragmentation, particularly in response to increased loading due to hypertension. Furthermore, when biological scientists analyze the elastic lamina structure, how to automatically generate a macro-level geometric parameter mapping might greatly help them understand the over-all morphology changes of blood vessel cross section. In this dissertation, another automated system is designed to quickly locate more pronounced EL branches to construct layer level abstraction of LT/ILD measurements and transform the sparse pixel level information to dense normalized Virtual Layer Matrix (VLM). The system can automatically compute the EL orientations, identify pronounced ELs, transform the denoised LT measurement points onto a VLM and then provide statistics/segmentation analysis. By applying the k-means segmentation technique to VLMs of LT-ILD, one can easily delineate regions of normal vs. hypertrophic and/or hyperplasia LT-ILD measurements for cross-image references.Item The effect of calcium supplementation on blood pressure(Texas Tech University, 1984-05) Clement, LouiseNot availableItem The effectiveness of biofeedback and relaxation procedures in reducing high blood pressure(Texas Tech University, 1975-05) Fidel, EdwardNot availableItem The role of estrogen receptors in the contribution of constrictor prostanoids to aortic coarctation-induced hypertension(2009-05-15) Sellers, Minga MiownThis study investigated the effects of selective estrogen receptor (ER) agonists on constrictor prostanoid (CP) function and on the development of mean arterial pressure (MAP) in aortic coarctation-induced hypertension (ACIH). Female Sprague-Dawley rats were divided randomly into four groups: intact (INT), ovariectomized (OVX), OVX + ER? selective agonist (4, 4?, 4?-(4-Propyl-[1H]-pyrazole-1, 3, 5-triyl)trisphenol; OVX+PPT), or OVX + ER? selective agonist (2,3-bis(4-Hydroxyphenyl)-propionitrile; OVX+DPN). Rats were then subjected to abdominal aortic coarctation (hypertensive, HT) or sham surgery (normotensive, NT). PPT, DPN or vehicle treatments were given daily as a subcutaneous injection. MAP was measured every other day at 2-14 days after coarctation. Mesenteric arterioles were harvested 12-14 days after coarctation for isometric tension studies to examine concentration-responses to VP. Basal and VP-stimulated prostanoid release and mRNA and protein levels of ER? and ER? (using real time RT-PCR and immunoblotting) were measured in separate groups of arterioles. MAP was higher in INT-HT, OVX+PPT-HT and OVX+DPN-HT than in OVX-HT after 12 days. Vascular reactivity to VP was greater in OVX+PPT-NT rats than in other groups. There were no significant differences in vascular reactivity to VP in HT groups. Blockade of thromboxane receptor (TP) with SQ 29,548 (TP receptor antagonist) did not have a significant effect in any groups. Inhibition of intracellular calcium release with simvastatin (blocker of IP3 mediated calcium release) was greater in NT than in HT groups, and greater in OVX- and DPN-treated groups than in INT and PPT-treated groups. VP-stimulated release of thromboxane (TXA2) and prostacyclin (PGI2) were highest in INT-HT and OVX+PPT-HT rats. Neither mRNA nor protein expression of ERs changed significantly in response to selective ER agonist treatment or during hypertension. Selective ER? stimulation with PPT during development of ACIH resulted in similar effects to those seen in INT rats for CP release, VP reactivity of mesenteric arterioles and MAP, while selective stimulation of ER? only increased MAP. While ER? is capable of modulating most of the effects of estrogen on the vasculature, ER? has stimulatory effects on MAP during the development of ACIH that merit further investigation. Further studies of the vascular actions of ER? and ER? may lead to better hormonal therapies that successfully prevent and/or treat cardiovascular disease in post-menopausal women.Item With No Lysine (WNK) Family Proteins and Their Interaction with Downstream Kinases(2011-08-26T17:35:34Z) Wedin, Kyle Edward; Cobb, Melanie H.With no lysine (WNK) kinases are a family of protein kinases characterized by unusual kinase domain architecture. These large proteins, divergent outside of a kinase core and protein-protein interaction motifs, have been associated with pseudohypoaldosteronism 2, a form of Mendelian-inherited hypertension, and numerous downstream effectors that regulate vesicle trafficking, membrane protein localization, and ion handling. This study shows that WNK2 is also a functioning protein kinase with the same unusual kinase domain architecture and regulation by an autoinhibitory region. Like WNK1, WNK2 is able to signal to the extracellular-signal regulated kinase 5 (ERK5) pathway. One effector for WNK1 is oxidative stress responsive 1 (OSR1), a sterile20-like kinase. All four WNKs are able to phosphorylate OSR1 and stimulate its activity toward an ion transporter substrate, to roughly a similar degree. The WNKs have similar kinetic properties, with Km toward OSR1 in the micromolar range and kcatĀ¬ near 1 min-1. No significant differences in activity toward OSR1 were seen for a mutant kinase domain at a site divergent among the WNKs that shows differential binding to substrate. Analysis of the phosphorylation sites of OSR1 reveals multiple sites along the activation loop that can promote increased activation if carrying a negative charge. It is unknown if these sites are phosphorylated in vivo. However, a second site of WNK1 phosphorylation just outside of the OSR1 kinase domain does not seem to affect WNK-OSR interactions. Further studies of interactions of the WNKs with their downstream effectors will reveal unusual functions for this unique family of proteins.Item With No Lysine 1 (WNK1): A Potential Regulator of The Lysosomal Degradation Pathway(2007-05-22) Lenertz, Lisa Yvonne; Cobb, Melanie H.With no Lysine (K) 1 (WNK1) is an atypical serine/threonine protein kinase that has its catalytic lysine positioned in a unique location. This kinase, along with another member of the WNK family, WNK4, has been genetically linked to pseudohypoaldosteronism type II (PHAII), which is characterized by both hypertension and hyperkalemia. Several groups have used reconstitution assays in Xenopus oocytes and mammalian cell lines to show WNKs regulate the surface expression and/or activity of various ion transporters and channels, including the epithelial sodium channel (ENaC) and the sodium chloride co-transporter (NCCT). Although the mechanisms for regulating these cell surface proteins are not well defined, it appears that WNKs may modulate the intracellular trafficking of these channels and transporters. To help define the mechanisms WNK1 utilizes to influence blood pressure and to characterize this kinase biochemically, I performed a WNK1 kinase activation screen and a WNK1 yeast-two-hybrid screen. I have shown that WNK1 kinase activity increases in response to osmotic stress, which may imply its kinase activity is important for regulating ion homeostasis in response to a change in cell volume. I have also shown that a proline-rich region of WNK1 interacts with vacuolar protein sorting 4a (VPS4a), an ATPase that helps sort cargo from the plasma membrane to lysosomes. Cells expressing a VPS4 ATP-hydrolysis mutant trap cargo from the cell surface in an aberrant endosomal structure, slowing protein degradation via the lysosomal pathway. I hypothesize that WNK1 delivers cargo to VPS4a to facilitate the degradation of plasma membrane proteins.