Abstract
Aberrant activation of with-no-lysine kinase (WNK)-STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) kinase signaling in the distal convoluted tubule (DCT) causes unbridled activation of the thiazide-sensitive sodium chloride cotransporter (NCC), leading to familial hyperkalemic hypertension (FHHt) in humans. Studies in FHHt mice engineered to constitutively activate SPAK specifically in the DCT (CA-SPAK mice) revealed maladaptive remodeling of the aldosterone sensitive distal nephron (ASDN), characterized by decrease in the potassium excretory channel, renal outer medullary potassium (ROMK), and epithelial sodium channel (ENaC), that contributes to the hyperkalemia. The mechanisms by which NCC activation in DCT promotes remodeling of connecting tubule (CNT) are unknown, but paracrine communication and reduced salt delivery to the ASDN have been suspected. Here, we explore the involvement of prostaglandin E2 (PGE2). We found that PGE2 and the terminal PGE2 synthase, mPGES1, are increased in kidney cortex of CA-SPAK mice, compared to control or SPAK KO mice. Hydrochlorothiazide (HCTZ) reduced PGE2 to control levels, indicating increased PGE2 synthesis is dependent on increased NCC activity. Immunolocalization studies revealed mPGES1 is selectively increased in the CNT of CA-SPAK mice, implicating low salt-delivery to ASDN as the trigger. Salt titration studies in an in vitro ASDN cell model, mouse CCD cell (mCCD-CL1), confirmed PGE2 synthesis is activated by low salt, and revealed that response is paralleled by induction of mPGES1 gene expression. Finally, inhibition of the PGE2 receptor, EP1, in CA-SPAK mice partially restored potassium homeostasis as it partially rescued ROMK protein abundance, but not ENaC. Together, these data indicate low sodium delivery to the ASDN activates PGE2 synthesis and this inhibits ROMK through autocrine activation of the EP1 receptor. These findings provide new insights into the mechanism by which activation of sodium transport in the DCT causes remodeling of the ASDN.
Highlights
Potassium homeostasis is dependent on ion transport processes in two adjacent distal tubule segments, the distal convoluted tubule (DCT), and the aldosterone-sensitive distal nephron (ASDN; Hadchouel et al, 2016; Welling, 2016)
Aldosterone sensitive distal nephron remodeling in the DCT-specific CA-SPS1-related proline-alaninerich protein kinase (SPAK) mice is manifested by a decrease in ROMK and ENaC protein abundance, and by a structural atrophy of the connecting tubule (CNT) (Grimm et al, 2017)
We explored the involvement of prostaglandin E2 (PGE2) as a candidate paracrine remodeling factor, using the DCT-specific CA-SPAK mouse model to isolate the direct effects of NCC activation in the DCT from downstream consequences in the aldosterone sensitive distal nephron (ASDN)
Summary
Potassium homeostasis is dependent on ion transport processes in two adjacent distal tubule segments, the distal convoluted tubule (DCT), and the aldosterone-sensitive distal nephron (ASDN; Hadchouel et al, 2016; Welling, 2016). Distal convoluted tubule cells sense small physiological changes in plasma potassium levels and signal the change through a with-no-lysine kinase (WNK)-STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) signaling network, called the “potassium switch” to adjust the activity of the thiazide sensitive sodium chloride co-transporter (NCC) (Hadchouel et al, 2016). In states of dietary potassium deficiency, the kinase cascade phospho-activates NCC to increase sodium reabsorption, decreasing distal sodium delivery to limit potassium secretion in the ASDN (Terker et al, 2015; Wade et al, 2015). Loss-of-function mutations in the Kelch-like 3/Cullin ubiquitin E3 ligase complex, which targets the WNK kinases for proteasomal degradation cause FHHt (Boyden et al, 2012; Louis-Dit-Picard et al, 2012)
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