Abstract. WNK1 is a member of a novel serine/threonine kinase family, With-No-K, (lysine). Intronic deletions in the encoding gene cause Gordon syndrome, an autosomal dominant, hypertensive, hyperkalemic disorder particularly responsive to thiazide diuretics, a first-line treatment in essential hypertension. To elucidate the novel WNK1 BP control pathway active in distal nephron, WNK1 expression in mouse was studied. It was found that WNK1 is highly expressed in testis Ͼ heart, lung, kidney, placenta Ͼ skeletal muscle, brain, and widely at low levels. Several WNK1 transcript classes are demonstrated, showing tissue-, developmental-, and nephron-segment-specific expression. Importantly, in kidney, the most prominent transcripts are smaller than elsewhere, having the first four exons replaced by an alternative 5'-exon, deleting the kinase domain, and showing strong distal nephron expression, whereas larger transcripts show low-level widespread distribution. Alternative splicing of exons 11 and 12 is prominent-for example, transcripts containing exon 11 are abundant in neural tissues, testis, and secondary renal transcripts but are predominantly absent in placenta. The transcriptional diversity generated by these events would produce proteins greatly differing in both structure and function. These findings help further define and clarify the role of WNK1 and the thiazideresponsive pathway relevant to essential hypertension in which it participates.

Objective-Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110␣)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110␣) provides protection in a setting of MI is unknown, and PI3K(p110␣) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110␣) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110␣). Methods and Results-Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110␣) activity (caPI3K-Tg and dnPI3K-Tg, respectively) were subjected to MI for 8 weeks. The caPI3K-Tg subjected to MI had better cardiac function than nontransgenic mice, whereas dnPI3K-Tg had worse function. Using microarray analysis, we identified PI3K-regulated miRNA and mRNA that were correlated with cardiac function, including growth factor receptor-bound 14. Growth factor receptor-bound 14 is highly expressed in the heart and positively correlated with PI3K(p110␣) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction. Conclusion-Activation of PI3K(p110␣) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110␣) represent new drug targets for heart failure.