Enhanced renal sympathetic nerves regulate SGLT2-MAP17-PDZK1 complex in the kidneys of rats with congestive heart failure

Congestive heart failure (CHF) is characterized by the activation of neurohumoral drive concomitant with avid fluid retention. Sodium-glucose cotransporter-2 (SGLT2) inhibitors exhibit remarkable reduction of cardiovascular mortality and hospitalization in patients with CHF. Although, we have recently demonstrated a relationship between enhanced renal sympathetic nerve activity and SGLT2 expression during CHF, the precise sequence of critical molecular mechanisms and pathways involved in the expression and membrane trafficking of SGLT2 remains to be examined. The objective of this study was to investigate the role of enhanced sympathetic tone on the expression and membrane trafficking of SGLT2-MAP17(membrane associated protein 17)-PDZK1(PDZ Domain Containing 1) complex via activation of extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-KB) in the renal cortex of CHF rats. CHF was induced by coronary artery ligation. Four weeks after surgery, bilateral renal denervation (RDN) was performed in rats. Rats were randomly divided into four groups (Sham, Sham+RDN, CHF and CHF+RDN). Western blot analysis was performed to evaluate the expression of SGLT2 and a cohost of scaffolding proteins MAP17 and multidomain PDZK1 as well as norepinephrine (NE) initiated intracellular mediators; ERK, pERK, NF-KB, and pNF-KB in the renal cortex. Immunohistochemistry (IHC) was performed to evaluate the precise location of SGLT2 and MAP17 expression within the kindey. In a complementary, in vitro experiment, we determined the direct effect of NE on the expression of SGLT2, MAP17 and PDZK1 as well as the intermediary ERK and NF-KB pathway using human adult proximal tubular cells (HK2 cell line). Rats with CHF exhibited, (1) significantly enhanced expression of SGLT2 (3.5fold), MAP17 (17fold) and PDZK1 (1.3fold) and, (2) significantly increased activation of ERK (2 fold) and NF-KB (5.6 fold) compared to SHAM in the renal cortex. In rats with CHF, bilateral RDN mitigated enhanced expression of renal SGLT2, MAP17, PDKZ1, pERK/ERK and pNF-KB/NF-KB in rats with CHF. Direct action of NE triggered enhanced expression and translocation of SGLT2, MAP17 and PDZK1 to the cell membrane by activation of the ERK/NF-KB pathway, in HK2 cells in vitro. These results demonstrate that enhanced renal sympathetic nerve activity in CHF activates the ERK/NF-KB pathway which in turn facilitates the trafficking and assembling of the transmembrane scaffolding of the SGLT2, MAP17 and PDZK1 complex augmenting sodium reabsorption. The beneficial effects of either SGLT2 inhibition or RDN may be functioning via a mutual intracellular pathway for the reduction of sodium and water retention commonly observed in CHF. This study was funded by NIH R01-DK-129311. This study was funded by NIH R01-DK-129311. This abstract was presented at the American Physiology Summit 2025 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.