Gender and Racial Differences in Stress, Coping, and Health-Related Quality of Life in Chronic Kidney Disease.

CONTEXT: Living with chronic kidney disease can be stressful and influence an individual's health-related quality of life. Effective coping strategies may reduce stress and improve quality of life in individuals with chronic medical conditions. OBJECTIVES: Health-related quality of life (HRQOL) is an important outcome for patients living with chronic kidney disease (CKD), and it is necessary to better understand potential gender and racial differences and predictors associated with reduced HRQOL, so that effective interventions can be developed. METHODS: Participants included 182 patients with CKD who were administered a battery of questions that included the Medical Outcomes Study Short-Form 36, Perceived Stress Scale, and the Brief COPE. Demographic and disease-specific information was abstracted from the patients' medical record. RESULTS: No differences by race were observed with regard to stress, quality of life, or coping with the exception that minority patients reported use of religious coping more often (P = 0.001) and had higher levels of energy compared with nonminority patients with CKD (P = 0.27). Women with CKD tended to use self-distraction (P = 0.002), positive reframing (P = 0.035), venting (P = 0.024), and religious coping (P = 0 < 0.001) more often than men. No significant differences in perceived stress or domains of quality of life were observed between men and women with CKD. A link between coping strategies and HRQOL was observed in women (P = 0.001-0.02) but not men. Perceived stress was associated with poorer quality of life for men (P = 0.017 to <0.001) and women (P = 0.001 to <0.001), but more domains of men's quality of life were affected by perceived stress compared with women. CONCLUSIONS: The findings of the study suggest that the wider range of coping strategies used by women may be associated with buffering the link between perceived stress and quality of life. Men with CKD may benefit from interventions that not only reduce stress but also facilitate the use of a broader range of coping strategies to reduce stress and improve quality of life.

Phosphatidylinositol 4-phosphate 5-kinase reduces cell surface expression of the epithelial sodium channel (ENaC) in cultured collecting duct cells.

Ubiquitination of ENaC subunits has been shown to negatively regulate the cell surface expression of ENaC channels. We have previously demonstrated that epsin links ubiquitinated ENaC to clathrin adaptors for clathrin-mediated endocytosis. Epsin is thought to directly modify the curvature of membranes upon binding to phosphatidylinositol 4,5-bisphosphate (PIP2) where it recruits clathrin and stimulates lattice assembly. Murine phosphatidylinositol 4-phosphate 5-kinase alpha (PI5KIalpha) has been shown to enhance endocytosis in a PIP2-dependent manner. We tested the hypothesis that PI5KIalpha-mediated PIP2 production would negatively regulate ENaC current by enhancing epsin-mediated endocytosis of the channel. Expression of PI5KIalpha decreased ENaC currents in Xenopus oocytes by 80%, entirely because of a decrease in cell surface ENaC levels. Catalytically inactive mutants of PI5Kalpha had no effect on ENaC activity. Expression of the PIP2 binding region of epsin increased ENaC current in oocytes, an effect completely reversed by co-expression of PI5KIalpha. Overexpression of epsin reduced amiloride-sensitive current in CCD cells. Overexpression of PI5KIalpha enhanced membrane PIP2 levels and reduced apical surface expression of ENaC in CCD cells, down-regulating amiloride-sensitive current. Knockdown of PI5KIalpha with isoform-specific siRNA resulted in a 4-fold enhancement of ENaC activity. PI5KIalpha localized exclusively to the apical plasma membrane domain when overexpressed in mouse CCD cells, consistent for a role in regulating PIP2 production at the apical plasma membrane. We conclude that membrane turnover events regulating ENaC surface expression and activity in oocytes and CCD cells can be regulated by PI5KIalpha.

Clathrin-mediated endocytosis of the epithelial sodium channel. Role of epsin.

Here we present evidence that the epithelial sodium channel (ENaC), a heteromeric membrane protein whose surface expression is regulated by ubiquitination, is present in clathrin-coated vesicles in epithelial cells that natively express ENaC. The channel subunits are ubiquitinated and co-immunoprecipitate with both epsin and clathrin adaptor proteins, and epsin, as expected, co-immunoprecipitates with clathrin adaptor proteins. The functional significance of these interactions was evaluated in a Xenopus oocyte expression system where co-expression of epsin and ENaC resulted in a down-regulation of ENaC activity; conversely, co-expression of epsin sub-domains acted as dominant-negative effectors and stimulated ENaC activity. These results identify epsin as an accessory protein linking ENaC to the clathrin-based endocytic machinery thereby regulating the activity of this ion channel at the cell surface.