Mice lacking the 1-subunit (gene, Kcnmb1; protein, BK-1) of the large Ca-activated K channel (BK) are hypertensive. This phenotype is thought to result from diminished BK currents in vascular smooth muscle where BK-1 is an ancillary subunit. However, the 1-subunit is also expressed in the renal connecting tubule (CNT), a segment of the aldosterone-sensitive distal nephron, where it associates with BK and facilitates K secretion. Because of the correlation between certain forms of hypertension and renal defects, particularly in the distal nephron, it was determined whether the hypertension of Kcnmb1 ؊/؊ has a renal origin. We found that Kcnmb1 ؊/؊ are hypertensive, volume expanded, and have reduced urinary K and Na clearances. These conditions are exacerbated when the animals are fed a high K diet (5% K; HK). Supplementing HK-fed Kcnmb1 ؊/؊ with eplerenone (mineralocorticoid receptor antagonist) corrected the fluid imbalance and more than 70% of the hypertension. Finally, plasma [aldo] was elevated in Kcnmb1 ؊/؊ under basal conditions (control diet, 0.6% K) and increased significantly more than wild type when fed the HK diet. We conclude that the majority of the hypertension of Kcnmb1 ؊/؊ is due to aldosteronism, resulting from renal potassium retention and hyperkalemia.adrenal medulla ͉ BK ͉ eplerenone ͉ mineralcorticoid ͉ volume expansion
The large-conductance, calcium-activated potassium (BK) channels help eliminate potassium in mammals consuming potassium-rich diets. In the distal nephron, principal cells contain BK-␣/1 channels and intercalated cells contain BK-␣/4 channels. We studied whether BK-4 -deficient mice (Kcnmb4 Ϫ/Ϫ ) have altered renal sodium and potassium clearances compared with wild-type mice when fed a regular or potassium-rich diet for ten days. We did not detect differences in urinary flow or fractional excretions of potassium (FE K ) or sodium (FE Na ) between Kcnmb4-deficient and wild-type mice fed a regular diet. However, a potassium-rich diet led to Ͼ4-fold increases in urinary flows for both groups of mice, although Kcnmb4-deficient mice exhibited less urinary flow, higher plasma potassium concentration, more fluid retention, and significantly lower FE K and FE Na than wild-type mice despite similar plasma aldosterone levels. Immunohistochemical analysis revealed increased basolateral Na-KATPase in principal cells of all potassium-adapted mice, but expression of Na-K-ATPase in intercalated cells was Ͼ10-fold lower. The size of intercalated cells reduced and luminal volume increased among potassium-adapted wild-type but not Kcnmb4-deficient mice. Paradoxically, this led to increased urinary fluid velocity in potassium-adapted Kcnmb4-deficient mice compared with wild-type mice. Taken together, these data suggest that BK-␣/4 channels in intercalated cells reduce cell size, increasing luminal volume to accommodate higher distal flow rates during potassium adaptation. These changes streamline flow across the principal cells, producing gradients more favorable for potassium secretion and less favorable for sodium reabsorption. A high-K diet is a natural diuretic, 1 causing decreased Na and Cl reabsorption in the thick ascending limb (TAL) because of medullary recycling and high interstitial K levels. 2 The decreased Na transport in the medullary TAL disrupts the concentrating mechanism, thereby increasing flow to the distal nephron. 2 The high deliveries of Na to the connecting tubules (CNT) and cortical collecting ducts (CCD) is exchanged for K, and the increased flow stimulates K secretion to maximize the amount of K secreted to Na absorbed. The renal outer medullary kidney K channel (ROMK) and the large conductance, calcium-activated K channels (BK) in the CNT and CCD serve to eliminate K during K adaptation. [3][4][5][6] In the distal nephron, the CNT and CCD consist of two epithelial cell types: principal cells (PCs) and intercalated cells (ICs). The PCs mediate Na and water reabsorption and K secretion, and the ICs mediate acid/base transport. Under normal conditions, K secretion by the PCs is mediated primarily by the ROMK channel. 7 However, flow-induced K secretion in the distal nephron is mediated by BK. 4,8,9 BK are a complex of pore-forming ␣ and accessory  subunits (BK-␣/). The PCs of the CNT
Some suggest that sickle cell disease (SCD) is associated with a "proinflammatory state" that predisposes patients to acute chest syndrome in the setting of triggering factors. Conflicting data emerged when inflammation markers in SCD were compared with healthy individuals. Therefore, we examined transgenic sickle and control mice at baseline and with endotoxin (LPS) intraperitoneal injection to determine whether a proinflammatory state truly exists. At baseline, sickle mice had elevated levels of circulating leukocytes and soluble vascular cell adhesion molecule 1 (sVCAM-1). No other differences were observed at baseline or in response to saline. However, LPS challenge was associated with significant increases in mortality (p<0.05), airway tone (p<0.03), serum and bronchoalveolar lavage levels of cytokines tumor necrosis factor-alpha (p<0.03), interleukin-1beta (p<0.02), and sVCAM-1 (p<0.01) in sickle mice compared with control subjects. Furthermore, 4 hours after LPS, microarray analysis identified 413 genes differentially expressed in the sickle mice (n=5) compared with only 7 in the control subjects (n=5). No difference in lung parenchyma was observed by light microscopy. This enhanced response to LPS suggests that the sickle red blood cell confers a subclinical "proinflammatory state." This enhanced response to inflammatory insult, particularly by adhesion molecules such as sVCAM-1, could play a role in the increased susceptibility to pulmonary dysfunction that has been observed clinically in SCD.
Purpose of review To summarize recent studies of hypertension associated with a defect in renal K excretion due to genetic deletions of various components of the large, Ca-activated K channel (BK), and review new evidence and theories regarding K secretory roles of BK in intercalated cells. Recent Findings Isolated perfused tubule methods have revealed the importance of BK in flow-induced K secretion. Subsequently, mice with genetically deleted BK subunits revealed the complexities of BK-mediated K secretion. Deletion of the BKα results in extreme aldosteronism, hypertension and an absence of flow-induced K secretion. Deletion of the BKβ1 ancillary subunit results in decreased handling of a K load, increased plasma K, mild aldosteronism and hypertension that is exacerbated by a high K diet. Deletion of the BKβ4 (β4KO) leads to insufficient K handling, high plasma K, fluid retention, but with milder hypertension. Fluid retention in β4KO may be the result of insufficient flow-induced secretion of ATP, which normally inhibits epithelial Na channels (ENaC). Summary Classical physiological analysis of electrolyte handling in knock-out mice has enlightened our understanding of the mechanism of handling K loads by renal K channels. Studies have focused on the different roles of the BK-α/β1 and BK-α/β4 in the kidney. BKβ1 hypertension may be a “three-hit” hypertension, involving a K secretory defect, elevated production of aldosterone, and increased vascular tone. The disorders observed in BK knock-out mice have shed new insights on the importance of proper renal K handling for maintaining volume balance and blood pressure.
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