prostaglandin receptors Our recent study comparing clinical

Our recent study comparing clinical parameters and K+ transport in red prostaglandin receptors from HbSS and HbSC patients indicated significant differences between the two genotypes (Rees et al., 2015). In particular, KCC activity was higher in HbSC patients with more severe forms of SCD (Rees et al., 2015), whilst the same was not true for KCC activity in red cells from HbSS patients. These findings, along with differences in clinical pathology, support the hypothesis that HbSC disease is a distinct clinical entity. Since changes in red cell membrane permeability represent an early event in SCD pathogenesis, with a direct association with HbS polymerisation, further work on membrane transport in red cells from HbSC patients is an imperative. In this report, we characterise more fully the behaviour of the main K+ transport systems in red cells from HbSC patients and highlight important differences in comparison with red cells from patients with SCA.
Materials and Methods
Results
Discussion The present findings show significant differences in cation homeostasis comparing red cells from HbSC and HbSS patients. The sickling shape change occurred at higher levels of O2 tension in red cells from HbSS than HbSC patients, together with activation of the main conductive cation channels, Psickle and the Gardos channel. Both transport pathways showed a similar correlation with sickling. The level of activity of the two channels was significantly lower in HbSC cells compared to HbSS ones, and also required more profound hypoxia to become activated, consistent with a reduced participation of these systems in mediating solute loss and dehydration. By contrast, KCC activity was significantly higher in oxygenated red cells from HbSC patients than those from HbSS individuals. KCC activity varied considerably between HbSC individuals. It also showed a different relationship to O2 tension to that observed in red cells from HbSS patients, being inactivated at low O2 tension (as seen in normal HbAA red cells). There was a higher level of activity of KCC in denser HbSC red cells compared to that observed in lighter ones. Taken together, these findings are consistent with a greater role for KCC in dehydration of red cells from HbSC patients. They also present a characteristic of red cell membrane transport in HbSC patients which may be important in pathogenesis, and further substantiate the hypothesis that HbSC disease is a different entity to that of homozygous HbSS SCD. Polymerisation of HbS initiates the clinical complications of SCD (Bunn and Forget, 1986). The resulting sequelae are multiple and diverse, and their individual impact on pathogenesis is difficult to elucidate. Early changes include altered red cell membrane permeability (Gibson and Ellory, 2002; Lew and Bookchin, 2005; Tosteson, 1955; Joiner, 1993). That red cells from SCD patients have elevated cation permeability, which can contribute to disease by mediating solute loss, dehydration and raised HbS concentration, has been established for some time (Tosteson, 1955). The reduced lag time to polymerisation upon deoxygenation observed in shrunken red cells with elevated [HbS] is considered central to disease progression (Eaton and Hofrichter, 1987). Previous reports of cation transport in red cells from HbSC patients have been published but studies were limited to a very small number of individuals (Canessa et al., 1986; Olivieri et al., 1992; Gibson et al., 2001). The present work investigates the behaviour of red cell samples from over a hundred HbSC patients. Of the three transporters involved in dehydration (Lew and Bookchin, 2005), the present findings are consistent with a lesser role for Psickle and Gardos in HbSC disease, whilst supporting a greater involvement of KCC activity (Table 1). The observation that KCC activity in red cells from HbSC patients correlates with frequency of hospitalisation (Rees et al., 2015), a marker of disease severity, emphasises the importance of understanding in detail how this transporter is regulated.