Neural Upregulation of SGLT2-MAP17-PDZK1 Complex in Kidneys of Rats With Heart Failure

Area of Science:

• Nephrology
• Cardiology
• Molecular Biology

Background:

• Congestive heart failure (CHF) involves neurohumoral activation and fluid retention, which renal denervation can alleviate.
• Sodium-glucose cotransporter 2 (SGLT2) inhibitors benefit cardiovascular disease patients.
• Previous studies linked enhanced renal sympathetic nerve activity to SGLT2 in CHF, but mechanisms of SGLT2 expression and translocation were unclear.

Purpose of the Study:

• To investigate the molecular mechanisms of SGLT2 expression and translocation in CHF.
• To examine the role of renal sympathetic nerve activity and the ERK/NF-KB pathway in regulating SGLT2 in CHF.
• To determine the direct effect of norepinephrine on SGLT2-MAP17-PDZK1 complex expression and signaling.

Main Methods:

• Induction of CHF in rats via coronary artery ligation, followed by renal denervation.
• Western blot and immunohistochemistry to assess SGLT2, MAP17, PDZK1, ERK, and NF-KB in rat renal cortex.
• In vitro study using human proximal tubular cells to evaluate norepinephrine's effect on the SGLT2-MAP17-PDZK1 complex and ERK/NF-KB pathway.

Main Results:

• Rats with CHF showed increased renal SGLT2, MAP17, PDZK1 expression, and ERK/NF-KB activation.
• Renal denervation in CHF rats reduced SGLT2-MAP17-PDZK1 expression and ERK/NF-KB activation.
• Norepinephrine stimulated SGLT2-MAP17-PDZK1 expression via ERK/NF-KB activation in human proximal tubular cells.

Conclusions:

• Enhanced renal sympathetic nerve activity in CHF activates the ERK/NF-KB pathway.
• This pathway facilitates SGLT2-MAP17-PDZK1 complex expression and luminal translocation.
• This process augments sodium reabsorption in the kidneys during CHF.