The experiments proposed herein will explore new models for effects of WNK kinases, kelch-like 3, and cullin 3 on the thiazide-sensitive Na-Cl cotransporter (NCC). The NCC of the mammalian kidney is essential to normal blood pressure regulation and to normal potassium balance. Mutations in the transporter cause salt wasting and hypokalemia. Mutations in the WNK kinases, kelch-like 3 or cullin 3 lead to hypertension and hyperkalemia by activating the transporter. Despite intense efforts, mechanisms by which these mutations cause human disease remain unclear. We have recently developed two novel mouse models, permitting us to study how the WNK kinases and cullin 3 signal to the thiazide-sensitive transporter, in vivo. These models compel us to propose novel, paradigm-shifting models for WNK and cullin 3 signaling to NCC. Here, we propose to determine how WNK4 can act both as an inhibitor and a stimulator of ion transport in the distal nephron. We will also test how interactions with other members of the WNK kinase family help to explain the sometimes-contradictory results obtained in the literature. We will also test a new model for cullin 3 regulation in NCC, one in which cullin 3 feeds back to regulate kelch-like 3, giving cullin 3 both stimulatory and inhibitory effects on NCC. To accomplish these goals, we have recruited three prominent research groups from around the world to work together. We will take the models generated using in vivo approaches, and explore the mechanisms involved using well-established in vitro approaches. To this end, we will 1) Determine how the WNK signaling complex formation modulates NCC activity, and 2) Determine how CRL activity modulates WNK kinase signaling.
These aims will be performed using both in vivo and in vitro techniques, insuring that conclusions are physiologically sound and relevant. The long-term goal is to determine how balance and sodium balance can be separated pharmacologically. Mutations in WNK kinases, kelch-like 3 and cullin 3 appear to dissociate the potassium-wasting effects of aldosterone from the sodium- retaining effects. We hope to learn how the kidney normally recognizes whether to excrete potassium or reabsorb salt, so that we can develop dietary better approaches to prevent hypertension, and better pharmaceutical approaches to treat it.
Even though high blood pressure result from mutations in several genes. Rare cases that result from single gene mutations are helpful to identify kidney pathways that control blood pressure. This work is designed to understand how several proteins work together to help humans balance the need to retain or excrete either salt or potassium. This work has broad relevance towards both to prevent and treat hypertension in humans, and how to devise new approaches for hypertension drug development.
| Murillo-de-Ozores, Adrián Rafael; Rodríguez-Gama, Alejandro; Bazúa-Valenti, Silvana et al. (2018) C-terminally truncated, kidney-specific variants of the WNK4 kinase lack several sites that regulate its activity. J Biol Chem 293:12209-12221 |
| Terker, Andrew S; Castañeda-Bueno, Maria; Ferdaus, Mohammed Z et al. (2018) With no lysine kinase 4 modulates sodium potassium 2 chloride cotransporter activity in vivo. Am J Physiol Renal Physiol 315:F781-F790 |
| Cornelius, Ryan J; Zhang, Chong; Erspamer, Kayla J et al. (2018) Dual gain and loss of cullin 3 function mediates familial hyperkalemic hypertension. Am J Physiol Renal Physiol 315:F1006-F1018 |
| Bazúa-Valenti, Silvana; Rojas-Vega, Lorena; Castañeda-Bueno, María et al. (2018) The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway. J Am Soc Nephrol 29:1838-1848 |
| Li, Ai-Jun; Wang, Qing; Ritter, Sue (2018) Selective Pharmacogenetic Activation of Catecholamine Subgroups in the Ventrolateral Medulla Elicits Key Glucoregulatory Responses. Endocrinology 159:341-355 |
| Cornelius, Ryan J; Si, Jinge; Cuevas, Catherina A et al. (2018) Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway. J Am Soc Nephrol 29:2627-2640 |
| Castañeda-Bueno, Maria; Arroyo, Juan Pablo; Zhang, Junhui et al. (2017) Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4. Proc Natl Acad Sci U S A 114:E879-E886 |
| Hoorn, Ewout J; Ellison, David H (2017) Diuretic Resistance. Am J Kidney Dis 69:136-142 |
| McCormick, James A; Ellison, David H (2017) Nephron Remodeling Underlies Hyperkalemia in Familial Hyperkalemic Hypertension. J Am Soc Nephrol 28:2555-2557 |
| Ellison, David H; Felker, G Michael (2017) Diuretic Treatment in Heart Failure. N Engl J Med 377:1964-1975 |
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