The goal of this work is to determine how aldosterone causes cardiovascular disease, including hypertension and heart failure. Mice in which the mineralocorticoid receptor can be deleted in the kidney only will be used to examine aldosterone's role in signaling. These mice exhibit diminished sodium flux through both the thiazide-sensitive NaCl cotransporter and the epithelial sodium channel. Yet transport via the former is fully normalized when the mice are placed on low potassium diet, indicating that sodium channel stimulation is the major direct effect of aldosterone. The proposed experiments will test whether mineralocorticoid receptors along the second part of the distal convoluted tubule, known as the DCT2, modulate sodium chloride transport, but do so by occupancy with glucocorticoids, rather than by aldosterone. This will be done by comparing effects of deleting the aldosterone synthase gene, which leads to deficient aldosterone production, with the effects of deleting the mineralocorticoid receptor. The activity of the sodium channel will be measured using patch clamp and whole cell recording and the activity of the thiazide-sensitive NaCl cotransporter will be assessed using thiazide testing and phosphor-protein analysis. If channel transport activity is low in the receptor knockout, but not the synthase knockout, this will support the hypothesis. In a second aim, novel mediators of aldosterone signaling will be sought. We will dissect collecting ducts from mice with and without mineralocorticoid receptors, and consuming diets of varied electrolyte content. These collecting ducts will be subjected to RNAseq, to determine transcriptional differences that may underlie aldosterone effects. We will compare the transcripts differentially expressed in high aldosterone states versus those absent in mice with low aldosterone or lacking mineralocorticoid receptors. We will then select candidate genes to be tested using cultured epithelial cells, and ultimately in vivo. We will seek proteins that are essential for stimulating sodium channels under high aldosterone conditions.
This work is designed to discover how the steroid hormone aldosterone regulates salt and water transport by the kidney. Aldosterone is an important contributor to cardiovascular disease in veterans, including both heart failure and hypertension, two of the most common and morbid diseases in this population. Although we have drugs to block aldosterone effects, these are beset by side effects, which limit their full effectiveness. We have already made paradigm shifting discoveries about aldosterone regulation of salt transporters, which are being translated to help fight these important disease processes. The proposed work will provide additional information suggesting novel approaches to alter the deleterious actions of this steroid hormone.
| 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; 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 |
| Ellison, David H (2017) Treatment of Disorders of Sodium Balance in Chronic Kidney Disease. Adv Chronic Kidney Dis 24:332-341 |
| Cuevas, Catherina A; Su, Xiao-Tong; Wang, Ming-Xiao et al. (2017) Potassium Sensing by Renal Distal Tubules Requires Kir4.1. J Am Soc Nephrol 28:1814-1825 |
| Hoorn, Ewout J; Ellison, David H (2017) Diuretic Resistance. Am J Kidney Dis 69:136-142 |
| Ellison, David H; Felker, G Michael (2017) Diuretic Treatment in Heart Failure. N Engl J Med 377:1964-1975 |
| Hadchouel, Juliette; Ellison, David H; Gamba, Gerardo (2016) Regulation of Renal Electrolyte Transport by WNK and SPAK-OSR1 Kinases. Annu Rev Physiol 78:367-89 |
| Terker, Andrew S; Yarbrough, Bethzaida; Ferdaus, Mohammed Z et al. (2016) Direct and Indirect Mineralocorticoid Effects Determine Distal Salt Transport. J Am Soc Nephrol 27:2436-45 |
| Zhang, Chong; Meermeier, Nicholas P; Terker, Andrew S et al. (2016) Degradation by Cullin 3 and effect on WNK kinases suggest a role of KLHL2 in the pathogenesis of Familial Hyperkalemic Hypertension. Biochem Biophys Res Commun 469:44-48 |
| Terker, Andrew S; Zhang, Chong; Erspamer, Kayla J et al. (2016) Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis. Kidney Int 89:127-34 |
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