Aldosterone is one of the most important cardiovascular toxins.
Drugs aim ed at blocking it prolong life in patients with heart failure, and reduce proteinuria in patients. Yet aldosterone is also an essential endogenous hormone, which has several important homeostatic functions. Drugs that block aldosterone actions, while useful, are also limited by side effects. These side effects are largely, although not exclusively, related to their actions on kidney tubules. Recently effects of aldosterone on kidney tubules have been suggested to be more widespread than previously believed, and involve the distal convoluted tubule, as well as the connecting tubule and collecting duct. Here, we will test for direct effects of aldosterone in mediating cardiac and renal damage by deleting mineralocorticoid receptors (MR) selectively from heart and kidney. Further, we will investigate the mechanisms by which aldosterone modulates the activity of the thiazide-sensitive Na-Cl cotransporter, along the distal convoluted tubule. Here, we will test the hypothesis that aldosterone effects along the distal convoluted tubule are essential for its renal actions, and that aldsosterone-induced renal damage depends on enhanced salt transport. We will also test how aldosterone signals to the thiazide-sensitive Na-Cl cotransporter through SGK1.
In Aim #2, we will examine role of cardiac MR in mediating cardiac damage in the face of hyperaldosteronism. We will use animals in which MR is flanked by LoxP sites. When these animals are bred with animals expressing CRE recombinase, under the control of a tissue specific promoter, it permits MR to be deleted. We have obtained animals in which CRE recombinase is under the control of inducible promoters specific for cardiac myocytes and kidney tubules and have bred inducible knockout animals. For the cardiac experiments, animals will undergo uninephrectomy followed by deletion of cardiac MR. They will then consume fludrocortisone and the effects of cardiac myocyte MR deletion on cardiac toxicity will be determined. For the renal MR deletion experiments, the tubule MR will be deleted first along the entire nephron and then in the distal convoluted tubule specifically. The animal phenotypes will then be determined during normal conditions and after the generation of kidney damage. For the experiments testing mechanisms of MR action on distal salt transport, effects of the aldosterone-induced protein SGK1 on the WNK/SPAK signaling pathway will be examined in cells and in vitro. This project is clinically relevant, as aldosterone contributes importantly to cardiovascular death. Blocking it is important therapeutically, but is hazardous, owing to renal toxicity. If we can demonstrate that cardiac MR is essential for destructive effects of aldosterone, treatment can be directed at blockade in the heart, while avoiding blockade in the kidney. In the kidney, if we can demonstrate that aldosterone effects independent of blood pressure are essential for renal protection, then glomerulus specific MR modulators can be developed. Furthermore, cardiovascular disease is the number one killer of veterans. Blocking MR is considered essential for its prevention. Better and safer methods to achieve this will enhance the health of veterans.
Aldosterone is a hormone that helps individuals to maintain normal blood pressure and electrolyte balance. Unfortunately, when it is secreted in abnormal circumstances, it contributes importantly to damaging the cardiovascular system and the kidneys. Here we plan to unravel the mechanisms of aldosterone action on the heart and the kidney. The goal is to find new methods to protect vulnerable organs from aldosterone effects without producing substantial side effects, thereby improving the lives of veterans at risk for cardiovascular disease.
|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|
Showing the most recent 10 out of 18 publications