Reciprocal Regulation of Na/K-ATPase and Sodium Glucose Co-Transporter 2

Sodium Glucose Co-Transporter 2 (SGLT2) is the major driving force for glucose reabsorption and inhibition of SGLT2 improves renal and cardiac function in patients with chronic kidney disease (CKD). Since SGLT2 uses the sodium gradient established by Na/K-ATPase (NKA) for glucose reabsorption, we hypothesize that there is link between SGLT2 and NKA in regulation of renal and cardiac functions. To demonstrate this hypothesis, we measured the SGLT2 expression level in LLC-PK1 cells (a porcine proximal tubule cell line), PY-17 cells (a cell line derived from LLC-PK1 cells with NKA α1 knockdown), and AAC-19 cells (a cell line that re-introduce a rat NKA α1 into the PY17 cells). The RT-PCR result showed that reduction of NKA in PY17 causes significant increase in SGLT2 expression (about 1.7-fold change compared to that in LLC-PK1 cells), while reintroduction of NAK in AAC-19 cells brought down the SGLT2 expression level that comparable to LLC-PK1 cells. Reciprocally, we found that inhibition of SGLT2 blocked NKA related signaling pathway. Specifically, treatment of LLC-PK1 cells with ouabain at 10 or 100 nM induced Src activation while pretreatment of the cells by 1 μM EMP (a specific SGLT2 inhibitor) for 24h blocked ouabain-induced Src activation. Our previous work has demonstrated that the plasmalemmal NKA/Src complex serves a scaffolding and signaling function beyond its well-known ion pumping role and blocking NKA/Src signaling attenuates cardiac hypertrophy and improves heart function in animal model of CKD. Based on these findings, we demonstrated a functional link between SGLT2 and NKA and postulate that the renal and cardiovascular benefit of SGLT2 inhibition may reside within their capacity for regulation of NKA signaling, which need to be further validated in animal models. Marshall Start up Funding to Jiang Tian, NIH R15HL164682-01 to Jiang Liu and Jiang Tian, NIH R01 DK129937 to Sandrine Pierre and Jiang Liu. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.