ROMK (Kir 1.1, the product of the KCNJ1 gene) channels in the distal nephron are exquisitely regulated to adjust renal potassium excretion and maintain potassium balance, but the underlying molecular mechanisms remain poorly defined. Our recent discoveries point to the involvement of a new mechanism. We found ROMK is largely regulated in the late distal convoluted tubule and connecting tubule (DCT/CNT) by a plasma potassium sensing kinase arcade, composed of Kidney Specific (KS)-WNK1, WNK4, and ERK. To carry these breakthrough observations toward a completely new understanding of potassium balance, new mouse models of ROMK and the signaling pathway will be developed, and initial phenotyping will be performed. In aim 1, a DCT/CNT-specific inducible cell-specific ROMK knockout will be developed by crossing Emx1-Cre-ERT2 with ROMKfl/fl, and pilot renal function studies will be performed to test if inducible DCT/CNT-specific ROMK knockout mice have altered potassium balance. In aim 2, KS-WNK1fl/fl will be crossed with AQP2-Cre-ERT2 (Welling Lab), and the ability of AQP2-Cre-ERT2 to induce principal cell-specific KS-WNK1 will be tested and compared to DCT specific knockout of KS-WNK1, and pilot renal function studies will be performed to test if principal cell-specific KS-WNK1deletion upregulates ROMK. The studies should provide new mouse models to explore the molecular basis of renal K+ handling and K+ homeostasis in health and disease, and developing and testing new drugs for treatment of common hyperkalemic disorders.