Large conductance, Ca-activated K channels (BK) are comprised of a pore-forming alpha subunit (BK-?) and an ancillary beta subunit (BK-?1-4). BK hypertension, demonstrated by several laboratories for mice with knock-outs of the BK-?1 subunit (?1KO), is mostly the result of fluid retention secondary to defective renal handling of K resulting in hyperkalemic aldosteronism. This competitive renewal proposes to continue studies of the regulation of the renal BK-?/?1. We previously determined with ?1KO and ?4KO that BK-?/?1 and BK-?/?4, which are localized in the connecting tubule principal cells (CNT) and intercalated cells (IC), respectively, of the distal nephron, have distinct roles to maximize the K secreted per Na reabsorbed when animals are placed on a high K diet.
The first Aim determines the relative roles of aldosterone and high plasma [K] to enhance BK-?/?1 mediated K secretion.
The second Aim addresses the role of BK-?/?1 in Na-independent K secretion. When mice are placed on a low Na diet, the transtubular K gradient (TTKG), an indirect measurement of the driving force for K secretion, is significantly reduced for ?1KO, compared with WT. These data indicate that the BK-?/?1 is used for non-ENaC-mediated, Na-independent K secretion. We have preliminary evidence that the large negative transepithelial potential required for Na-independent K secretion is the result of ?-IC cell HCO3 secretion via pendrin in conjunction with apical Cl recycling via CFTR Cl channels.
The third Aim i s based on our previous study showing co-dependent transport of K and ATP from IC cells of the cortical collecting duct.
This Aim will examine the role of the BK-?/?4 in IC to enhance the ratio of K secreted to Na absorbed in the CNT and cortical collecting ducts by the high flow-induced excretion of ATP, which locally inhibits ENaC-mediated Na reabsorption. These results will be important for determining how K is handled by renal BK channels in conditions of iatrogenic increases in plasma [K] or with crush syndrome, which causes fatal increases in plasma [K] levels.

Public Health Relevance

As a consequence of pharmacological treatment for high blood pressure and other medical conditions, plasma K concentrations often become very high or very low in patients. Because abnormal levels of plasma K often lead to cardiac arrhythmias and sudden death, it is important to understand the mechanisms by which chemicals regulate the kidney proteins that eliminate K from the body.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071014-07
Application #
8540410
Study Section
Special Emphasis Panel (ZRG1-DKUS-E (03))
Program Officer
Ketchum, Christian J
Project Start
2005-04-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$311,684
Indirect Cost
$101,796
Name
University of Nebraska Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Baskin, Alison S; Linderman, Joyce D; Brychta, Robert J et al. (2018) Regulation of Human Adipose Tissue Activation, Gallbladder Size, and Bile Acid Metabolism by a ?3-Adrenergic Receptor Agonist. Diabetes 67:2113-2125
Wang, Bangchen; Wang-France, Jun; Li, Huaqing et al. (2018) Furosemide Reduces BK-??4-mediated K+ Secretion in Mice on an Alkaline High K+ Diet. Am J Physiol Renal Physiol :
Wang, Bangchen; Wen, Donghai; Li, Huaqing et al. (2017) Net K+ secretion in the thick ascending limb of mice on a low-Na, high-K diet. Kidney Int 92:864-875
Arnardottir, Nanna Yr; Oskarsdottir, Nina Dora; Brychta, Robert J et al. (2017) Comparison of Summer and Winter Objectively Measured Physical Activity and Sedentary Behavior in Older Adults: Age, Gene/Environment Susceptibility Reykjavik Study. Int J Environ Res Public Health 14:
Arnardottir, Nanna Yr; Koster, Annemarie; Domelen, Dane R Van et al. (2016) Association of change in brain structure to objectively measured physical activity and sedentary behavior in older adults: Age, Gene/Environment Susceptibility-Reykjavik Study. Behav Brain Res 296:118-124
Wen, Donghai; Sansom, Steven C (2015) Physiological role of NBCe2 in the regulation of electrolyte transport in the distal nephron. Am J Physiol Renal Physiol 309:F489-91
Cornelius, Ryan J; Wen, Donghai; Li, Huaqing et al. (2015) Low Na, high K diet and the role of aldosterone in BK-mediated K excretion. PLoS One 10:e0115515
Wen, Donghai; Yuan, Yang; Warner, Paige C et al. (2015) Increased Epithelial Sodium Channel Activity Contributes to Hypertension Caused by Na+-HCO3- Cotransporter Electrogenic 2 Deficiency. Hypertension 66:68-74
Wen, Donghai; Yuan, Yang; Cornelius, Ryan J et al. (2015) Deficient acid handling with distal RTA in the NBCe2 knockout mouse. Am J Physiol Renal Physiol 309:F523-30
Wen, Donghai; Cornelius, Ryan J; Rivero-Hernandez, Dianelys et al. (2014) Relation between BK-?/?4-mediated potassium secretion and ENaC-mediated sodium reabsorption. Kidney Int 86:139-45

Showing the most recent 10 out of 26 publications