Introduction: Potassium (K+) secretion in the cortical collecting duct (CCD) is mediated by ROMK channels in principal cells (PCs) and large-conductance Ca 2 + -activated K + (BK) channels in intercalated cells (ICs), the latter responsible for flow-induced K+ secretion (FIKS). Previous studies have demonstrated that diabetes and altered insulin signaling impair renal K + handling, partly through dysregulation of ENaC and ROMK activity. However, the direct role of insulin receptor (IR) signaling in modulating BK channel-mediated FIKS in the CCD remains unclear. We hypothesize that loss of the IR in the CCD decreases FIKS, contributing to impaired renal K + homeostasis. Methods: To evaluate the contribution of the IR to renal K + secretion, we microperfused single CCDs isolated from control and IR-knockout (IR-KO) mice to measure: i) Na + absorption (JNa) and K + secretion (JK) under low (1 nL/min.mm) and high (5 nL/min.mm) luminal flow conditions, ii) flow-induced intracellular Ca 2 + (Ca 2+ i) responses, assessed by Fura-2 imaging in PCs and ICs, and iii) BKα expression by immunofluorescence using cell-specific markers (AQP2, H + -ATPase, pendrin). Results: CCDs from control and IR-KO mice, perfused at low and high luminal flow rates, exhibited: i) equivalent increases in JNa from 4.9 ± 4.8 to 54.1 ± 20.0 and from 5.6 ± 21.5 to 52.2 ± 14.0 pmol/min.mm, respectively, ii) an increase in JK from –1.3 ± 1.0 to –6.6 ± 1.6 and from –0.4 ± 0.7 to –2.3 ± 0.5 pmol/min.mm, respectively, with the IR-KO exhibiting significantly blunted FIKS (p < 0.01). Flow-induced Ca 2 + i transients were similar between genotypes, suggesting intact Ca 2 + signaling. BKα protein abundance was markedly reduced in IR-KO mice by 30% in PCs, 31% in type-A ICs, and 55% in type-B ICs (p ≤ 0.001 for all cell types). Conclusions: The reduction of BKα, rather than altered Ca 2 + signaling, accounts for attenuated FIKS in IR-KO mice, suggesting that IR signaling is essential for maintaining BK channel expression and FIKS in the CCD. These findings identify IR activity as a key regulator of distal tubular K + handling and suggest a mediator for impaired K + homeostasis observed in insulin-resistant and diabetic states. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Carrisoza-Gaytan et al. (Fri,) studied this question.