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
Wen, Donghai; Cornelius, Ryan J; Sansom, Steven C (2014) Interacting influence of diuretics and diet on BK channel-regulated K homeostasis. Curr Opin Pharmacol 15:28-32
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
Wen, Donghai; Cornelius, Ryan J; Yuan, Yang et al. (2013) Regulation of BK-* expression in the distal nephron by aldosterone and urine pH. Am J Physiol Renal Physiol 305:F463-76
Grimm, P Richard; Sansom, Steven C (2010) BK channels and a new form of hypertension. Kidney Int 78:956-62
Holtzclaw, J David; Liu, Liping; Grimm, P Richard et al. (2010) Shear stress-induced volume decrease in C11-MDCK cells by BK-alpha/beta4. Am J Physiol Renal Physiol 299:F507-16
Grimm, P Richard; Sansom, Steven C (2007) BK channels in the kidney. Curr Opin Nephrol Hypertens 16:430-6
Grimm, P Richard; Foutz, Ruth M; Brenner, Robert et al. (2007) Identification and localization of BK-beta subunits in the distal nephron of the mouse kidney. Am J Physiol Renal Physiol 293:F350-9
Wang, Xiaoxia; Pluznick, Jennifer L; Settles, Deann C et al. (2007) Association of VASP with TRPC4 in PKG-mediated inhibition of the store-operated calcium response in mesangial cells. Am J Physiol Renal Physiol 293:F1768-76