Identification and characterization of alternative STK39 transcripts within human and mouse kidneys reveals species-specific regulation of blood pressure

Carlo J. Mercado, Xiaochun Wang, Paul R. Grimm, Paul A. Welling, Yen Pei C. Chang

Research output: Contribution to journalArticlepeer-review

Abstract

STK39 encodes a serine threonine kinase, SPAK, which is part of a multi-kinase network that determines renal Na+ reabsorption and blood pressure (BP) through regulation of sodium-chloride co-transporters in the kidney. Variants within STK39 are associated with susceptibility to essential hypertension, and constitutively active SPAK mice are hypertensive and hyperkalemic, similar to familial hyperkalemic hyperkalemia in humans. SPAK null mice are hypotensive and mimic Gitelman syndrome, a rare monogenic salt wasting human disorder. Mice exhibit nephron segment-specific expression of full length SPAK and N-terminally truncated SPAK isoforms (SPAK2 and KS-SPAK) with impaired kinase function. SPAK2 and KS-SPAK function to inhibit phosphorylation of cation co-transporters by full length SPAK. However, the existence of orthologous SPAK2 or KS-SPAK within the human kidney, and the role of such SPAK isoforms in nephron segment-specific regulation of Na+ reabsorption, still have not been determined. In this study, we examined both human and mouse kidney transcriptomes to uncover novel transcriptional regulation of STK39. We established that humans also express STK39 transcript isoforms similar to those found in mice but differ in abundance and are transcribed from human-specific promoters. In summary, STK39 undergoes species-specific transcriptional regulation, resulting in differentially expressed alternative transcripts that have implications for the design and testing of novel SPAK-targeting antihypertensive medications.

Original languageEnglish (US)
Article numbere14379
JournalPhysiological Reports
Volume8
Issue number4
DOIs
StatePublished - Feb 1 2020

Keywords

  • STK39
  • transcriptional regulation

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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