Role of PON3 in regulating renal Na+ and K+ homeostasis

ABSTRACT The mammalian paraoxonase (PON) family consists of three highly conserved members (PON1, PON2 and PON3) with unique anti-oxidative and anti-atherosclerotic properties. PON1 and 2 have been implicated in blood pressure (BP) regulation. While the role of PON3 in regulating BP has not been investigated, it is expressed in the aldosterone-sensitive distal nephron where the fine tuning of Na+ absorption and K+ secretion occurs. PONs share key structural and functional features with MEC-6, an endoplasmic reticulum-resident chaperone of C. elegans. MEC-6 is required for proper folding, assembly, and surface expression of the mechanosensitive degenerin channel in touch receptor neurons. The chaperon function is conserved between mammalian PONs and C. elegans MEC-6. We have previously shown that both PON2 and PON3 regulate functional expression of the epithelial Na+ channel (ENaC), a member of the ENaC/degenerin family of ion channels. ENaC mediates the rate-limiting step of Na+ reabsorption in distal nephron and has a key role in volume and BP control. While the constitutive K+ secretion is conducted by the renal outer medullary K+ (ROMK) channels, ENaC-dependent and flow-induced K+ secretion is mediated by the large conductance K+ (BK) channels. In the preliminary studies, we found that Pon3 KO mice have higher ENaC activity and enhanced amiloride-sensitive natriuresis, suggesting ENaC functional expression is upregulated in the absence of PON3. In addition, we have identified BK channel as a novel target of PON3. When expressed in HEK293 cells, PON3 interacted with BK α subunit to reduce its surface expression and channel activity. Our proposed studies will define mechanisms by which PON3 functions as a chaperone in the regulation of ENaC and BK expression. We will determine the consequences of deleting PON3 in renal Na+ and K+ handling and BP control in mice. Successful completion our proposed studies will enhance our understanding of the mechanisms by which PONs function as chaperones and their physiological roles in kidney function and BP control.