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

STK39 encodes a serine threonine kinase, 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 mice are hypertensive and hyperkalemic, similar to familial hyperkalemic hyperkalemia in humans. duanyu1842K null mice are hypotensive and mimic Gitelman syndrome, a rare monogenic salt wasting human disorder. Mice exhibit nephron segment-specific expression of full length duanyu1842K and N-terminally truncated duanyu1842K isoforms and with impaired kinase function. and function to inhibit phosphorylation of cation co-transporters by full length However, the existence of orthologous duanyu1842K2 or KS-duanyu1842K within the human kidney, and the role of such duanyu1842K 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 antihypertensive medications. © 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

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