Sex- and Cell-Specific Changes in BKα Protein Expression in the Aldosterone-Sensitive Distal Nephron (ASDN) in Response to Dietary K+

Background: Within the cortical collecting duct (CCD) of the ASDN, BK channels are essential for renal adaptation to a high K+ diet (HKD) and mediate flow-induced K+ secretion. We have previously reported that dietary K+ loading for 10 d leads to an increase in whole-cell BKα protein expression in female rabbits and channel activity in male mice (Carrisoza-Gaytan et al. 2017, 2020). In whole kidney immunoblots, expression of BKα in females exceeds that in males (Yu et al. 2017). The purpose of this study was to examine the sex- and cell-specific responses to dietary K+ over an 11 d period on BKα protein expression and subcellular distribution in mouse CCD. Methods: 8-wk-old male (M) and female (F) C57BL/6 mice maintained on a control diet (2.4% K+), were randomly switched to a low K+ diet (LKD, 0.0%) or HKD (10%) for up to 11 d, before study at 0, 3, 5, 7, 9, and 11 d (3-4 mice/sex per day). Kidney cryosections were obtained and processed for BKα and AQP2 coimmunostaining to identify CCD AQP2+ principal cells (PCs) and AQP2- intercalated cells (ICs) by confocal microscopy. Whole-cell BKα protein abundance and distribution were quantified in PCs and ICs and normalized to values obtained on day 0. Results: BKα abundance was greater in F vs. M at day 0 in PCs and ICs (2.29±0.46 and 1.57±0.26, respectively, p≤0.005). With HKD, BKα abundance increased by 3 d in PCs and ICs in M (1.41±0.32 and 1.37±0.19, p≤0.001 vs. 0 d) and F (1.17±0.20 and 1.21±0.16, p≤0.05 vs. 0 d), followed by a sustained elevation after 7 d in M only (1.59±0.28 and 1.89±0.20, p≤0.001 vs. 0 d). A LKD led to a reduction in apical and sub-apical expression of BKα in ICs of M (0.53±0.09, p≤0.0001 vs. 0 d), but not F, by 7 d. Basolateral BKα expression increased in M ICs by 7 d (1.87±0.41, p≤0.0001 vs. 0 d), with no changes in F. Conclusion: This study highlights sex- and cell-specific differences in BKα abundance and distribution in the mouse CCD in response to dietary K+. Future efforts will be directed at unraveling the underlying sex-specific regulatory mechanisms. Funding: NIDDK Support, Private Foundation Support