Because of its cardio-protective effects, a low Na, high K diet (LNaHK) is often warranted in conjunction with diuretics to treat hypertensive patients. However, it is necessary to understand the renal handling of such diets in order to choose the best diuretic. Wild type (WT) or Renal Outer Medullary K channel (ROMK) knockout mice (KO) were given a regular (CTRL), LNaHK, or high K diet (HK) for 4–7 days. On LNaHK, mice treated with either IP furosemide for 12 hrs, or given furosemide in drinking water for 7 days, exhibited decreased K clearance. We used free-flow micropuncture to measure the [K+] in the early distal tubule (EDT [K+]) before and after furosemide treatment. Furosemide increased the EDT [K+] in WT on CTRL but decreased that in WT on LNaHK. Furosemide did not affect the EDT [K+] of KO on LNaHK or WT on HK. Furosemide-sensitive Na+ excretion was significantly greater in mice on LNaHK than those on CTRL or HK. Patch clamp analysis of split-open TALs revealed that 70-pS ROMK exhibited a higher open probability (Po) but similar density in mice on LNaHK, compared with CTRL. No difference was found in the density or Po of the 30 pS K channels between two groups. These results indicate mice on LNaHK exhibited furosemide-sensitive net K+ secretion in the TAL that is dependent on increased NKCC2 activity and mediated by ROMK. We conclude that furosemide is a K-sparing diuretic by decreasing the TAL net K+ secretion in subjects on LNaHK.

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.

A low-Na, high-K diet (LNaHK) is considered a healthier alternative to the "Western" high-Na diet. Because the mechanism for K secretion involves Na reabsorptive exchange for secreted K in the distal nephron, it is not understood how K is eliminated with such low Na intake. Animals on a LNaHK diet produce an alkaline load, high urinary flows, and markedly elevated plasma ANG II and aldosterone levels to maintain their K balance. Recent studies have revealed a potential mechanism involving the actions of alkalosis, urinary flow, elevated ANG II, and aldosterone on two types of K channels, renal outer medullary K and large-conductance K channels, located in principal and intercalated cells. Here, we review these recent advances.

The gene SLC4A5 encodes the Na+-HCO3− co-transporter electrogenic 2 (NBCe2), which is located in the distal nephron. Genetically deleting NBCe2 (KO) causes Na+-retention and hypertension, a phenotype that is diminished with alkali loading. We performed experiments with acid-loaded mice and determined whether over-active epithelial Na+ channels (ENaC) or the Na+-Cl− co-transporter (NCC) causes the Na+ retention and hypertension in KO. In untreated mice, the mean arterial pressure (MAP) was higher in KO, compared with wild type (WT); however, treatment with amiloride, a blocker of ENaC, abolished this difference. In contrast, hydrochlorothiazide (HCTZ), an inhibitor of NCC, decreased MAP in WT, but not KO. Western blots showed that quantity of plasmalemmal full-length ENaC-α was significant higher in KO than in WT. Amiloride treatment caused a 2-fold greater increase in Na+ excretion in KO, compared with WT. In KO, but not WT, amiloride treatment decreased plasma [Na+] and urinary K+ excretion, but increased hematocrit and plasma [K+] significantly. Micropuncture with microelectrodes showed that the [K+] was significantly higher and the transepithelial potential (Vte) was significantly lower in the late distal tubule (LDT) of the KO compared with WT. The reduced Vte in KO was amiloride-sensitive and therefore revealed an upregulation of electrogenic ENaC-mediated Na+ reabsorption in this segment. These results show that, in the absence of NBCe2 in the LDT, acid-loaded mice exhibit disinhibition of ENaC-mediated Na+ reabsorption, which results in Na+ retention, K+ wasting, and hypertension.

Background: ADA3, a conserved component of several HAT complexes, regulates mitosis. Results: ADA3 associates with the centromere through CENP-B and regulates chromosome segregation by directing centromeric loading of CENP-B. Conclusion: ADA3 regulates mitosis by its association with the CENP-B/centromere and regulates segregation of chromosomes. Significance: This study provides the mechanism of how ADA3 regulates mitosis to maintain genomic stability.