Paracrine Communication Links Sodium Chloride Cotransporter Activity in the Distal Convoluted Tubule to Remodeling of the Aldosterone‐Sensitive Distal Nephron

Abstract

We recently discovered that cell‐specific expression of constitutively active SPAK (CA‐SPAK) in the early distal tubule is sufficient to drive a remodeling process of the entire distal nephron that includes structural dystrophy of the aldosterone‐sensitive distal nephron and inhibition of ROMK and ENaC (Grimm et al, JASN ’17). Here, we tested the hypothesis that SPAK‐activation of NCC stimulates the release of paracrine or autocrine factors that cause the dystrophic response in the CNT.We found increased levels of PGE2 in kidney cortical homogenates of CA‐SPAK mice compared to control mice. Comparable elevation of PGE2 was also observed when NCC was physiologically activated by feeding wild‐type mice (WT) a low potassium diet (LKD). Administration of the NCC‐blocking diuretic, hydrochlorothiazide, to either CA‐SPAK or WT mice on LKD, restored PGE2 to control levels, but had no effect on PGE2 of WT or SPAK KO mice. Thus, PGE2 is elevated in response to super activation of NCC.PGE2 synthesis is mediated by prostaglandin E synthase isoforms. As revealed in western blot analysis, the microsomal prostaglandin E synthase‐1(mPGES1) was elevated in the kidney cortex of CA‐SPAK mice and WT mice on LKD compared to control mice. Quantitative microscopy of mPGES1 surprisingly revealed the augmentation of mPGES1 was confined to the CNT and CCD of CA‐SPAK and LKD treated mice. No changes in mPGES1 were observed in the DCT1.In conclusion, these studies identify PGE2 as a potential remodeling autocrine that is released from the CNT and CCD in response to activation of NCC. We speculate that decreased sodium delivery to the CNT and CCD when NCC is activated drives the response, similar to the mechanism by which PGE2 synthesis is stimulated in the macula densa with changes in sodium reabsorption in upstream tubule segments. The autocrine pathway provides a novel means to communicate potassium sensing in the DCT to potassium secretion in the ASDN.Support or Funding InformationSupported by the NIDDK and Fondation LeducqThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.