PGE2 is a Candidate Distal Nephron Remodeling Factor

Abstract

We recently discovered that DCT1 cell‐specific expression of constitutively active SPAK (CA‐SPAK) drives a remodeling process of the entire distal nephron that includes atrophy of the aldosterone‐sensitive distal nephron and parallel inhibition of ROMK and ENaC (Grimm et al, JASN ’17). The mechanism by which genetic activation of NCC drives downstream nephron remodeling remains elusive but observations that PGE2 inhibits ROMK and ENaC ex vivo raises that paracrine signaling may be involved (Jin et al, AJPR 2007; Guan et al, JCI 1998). Here, we tested the hypothesis that activation of NCC causes atrophy of the CNT through increased PGE2 synthesis and release. We found increased levels of PGE2 in kidney cortical homogenates of CA‐SPAK mice compared to control mice on a control diet. Feeding wild‐type mice (WT) a low potassium diet (LKD) to physiologically activate NCC resulted in a comparable elevation of PGE2 and ASDN remodeling response, characterized by a decrease in ROMK/ENaC. Administration of the NCC‐blocking diuretic, hydrochlorothiazide, to CA‐SPAK mice restored PGE2 to control levels but had no effect on PGE2 of control or SPAK KO mice. Thus, PGE2 is elevated in response to super activation of NCC. PGE2 synthesis is controlled by specific prostaglandin E synthase isoforms. As revealed in western blot analysis, the microsomal prostaglandin E synthase‐1 (mPGES1) was selectively elevated in the kidney cortex of CA‐SPAK mice and WT mice on LKD compared to control mice, and this response was blocked by thiazide diuretics. Localization of mPGES1 by quantitative microscopy surprisingly revealed that increased protein abundance of mPGES1 was confined to the CNT and CCD of CA‐SPAK or the DCT2 and CNT of LKD treated mice. No significant changes in mPGES1 were observed in the DCT1. In conclusion, these studies identify PGE2 as a possible remodeling factor that is released from the late DCT and ASDN in response to NCC activation. We speculate that decreased sodium delivery to the CNT and CCD when NCC is activated drives the response; similar to how low NaCl drives PGE2 synthesis in the macula densa. The paracrine/autocrine pathway provides a novel means to communicate potassium sensing in the DCT to potassium secretion in the ASDN by driving tubule remodeling of specific segments of the distal tubule. Support or Funding Information NIH, NIDDK T32 and Fondation LeDucq

Paracrine and endocrine regulation of renal K+ secretion

“…An appealing hypothesis is that NCC activation may play a role. Preliminary findings from Welling's group indicate that transgenic mice expressing a constitutive active SPAK at DCT1 have not only higher levels of phospho-NCC (140) but also a higher abundance of PGE 2 at the renal cortex, at levels similar to those induced by LK diets (141). Such an increase in cortical PGE 2 was abolished by treating transgenic mice with thiazides (141).…”

“…Preliminary findings from Welling's group indicate that transgenic mice expressing a constitutive active SPAK at DCT1 have not only higher levels of phospho-NCC (140) but also a higher abundance of PGE 2 at the renal cortex, at levels similar to those induced by LK diets (141). Such an increase in cortical PGE 2 was abolished by treating transgenic mice with thiazides (141). The authors pointed out that NCC hyperactivation and a consequent low Clluminal environment at downstream segments could induce PGE2 by a mechanism similar to that triggered at macula densa (142).…”