Low Na, High K Diet and the Role of Aldosterone in BK-Mediated K Excretion

Abstract

A low Na, high K diet (LNaHK) is associated with a low rate of cardiovascular (CV) disease in many societies. Part of the benefit of LNaHK relies on its diuretic effects; however, the role of aldosterone (aldo) in the diuresis is not understood. LNaHK mice exhibit an increase in renal K secretion that is dependent on the large, Ca-activated K channel, (BK-α with accessory BK-β4; BK-α/β4). We hypothesized that aldo causes an osmotic diuresis by increasing BK-α/β4-mediated K secretion in LNaHK mice. We found that the plasma aldo concentration (P[aldo]) was elevated by 10-fold in LNaHK mice compared with control diet (Con) mice. We subjected LNaHK mice to either sham surgery (sham), adrenalectomy (ADX) with low aldo replacement (ADX-LA), or ADX with high aldo replacement (ADX-HA). Compared to sham, the urinary flow, K excretion rate, transtubular K gradient (TTKG), and BK-α and BK-β4 expressions, were decreased in ADX-LA, but not different in ADX-HA. BK-β4 knockout (β4KO) and WT mice exhibited similar K clearance and TTKG in the ADX-LA groups; however, in sham and ADX-HA, the K clearance and TTKG of β4KO were less than WT. In response to amiloride treatment, the osmolar clearance was increased in WT Con, decreased in WT LNaHK, and unchanged in β4KO LNaHK. These data show that the high P[aldo] of LNaHK mice is necessary to generate a high rate of BK-α/β4-mediated K secretion, which creates an osmotic diuresis that may contribute to a reduction in CV disease.

Potassium and Its Discontents

“…Thus, the increase in urinary K + excretion in response to a low-salt, high-potassium diet is attenuated in mice lacking BK channels compared with wild-type mice. 25 This provides evidence that K + secretion by BK channels is affected by ENaC activity.…”

Net K + secretion in the thick ascending limb of mice on a low-Na, high-K diet

“…Studies showed that a low Na diet increased NKCC2 phosphorylation and caused a shift from the low-affinity NKCC2A to the high-affinity NKCC2B isoform, partly mediated by the actions of Ang II on AT1 receptors 18,41 . Ang II level is greatly increased in mice on LNaHK, but not on HK 7,8,42 . These findings suggest that elevated Ang II may be responsible for the upregulated NKCC2 activity in mice on LNaHK.…”

“…This study suggests that the ROMK2 isoform in the TAL is regulated by different signaling pathways than the ROMK1 in the ASDN. Mice on LNaHK have highly elevated aldosterone and Ang II compared to CTRL 7,8,42 . Since TAL is absent of 11-β-hydroxysteroid dehydrogenase 2 (HSD11B2) 48 , aldosterone is unlikely to regulate ROMK in TAL.…”

“…Additionally, in mice on LNaHK, elevated aldosterone along with other factors upregulate ENaC, ROMK, and BK expressions and activities to promote K secretion in the ASDN 8,13,14,35 . As shown in Table 2, furosemide still increased urine flow and decreased urine osmolality but did not increase UNaV after 7 days.…”

“…al. showed that in mice on LNaHK, the BK-αβ4-mediated K + secretion in the distal nephron may contribute to the diuretic effect 8 .…”