Regulation of kidney on potassium balance and its clinical significance / 生理学报

Virtually all of the dietary potassium intake is absorbed in the intestine, over 90% of which is excreted by the kidneys regarded as the most important organ of potassium excretion in the body. The renal excretion of potassium results primarily from the secretion of potassium by the principal cells in the aldosterone-sensitive distal nephron (ASDN), which is coupled to the reabsorption of Na+ by the epithelial Na+ channel (ENaC) located at the apical membrane of principal cells. When Na+ is transferred from the lumen into the cell by ENaC, the negativity in the lumen is relatively increased. K+ efflux, H+ efflux, and Cl- influx are the 3 pathways that respond to Na+ influx, that is, all these 3 pathways are coupled to Na+ influx. In general, Na+ influx is equal to the sum of K+ efflux, H+ efflux, and Cl- influx. Therefore, any alteration in Na+ influx, H+ efflux, or Cl- influx can affect K+ efflux, thereby affecting the renal K+ excretion. Firstly, Na+ influx is affected by the expression level of ENaC, which is mainly regulated by the aldosterone-mineralocorticoid receptor (MR) pathway. ENaC gain-of-function mutations (Liddle syndrome, also known as pseudohyperaldosteronism), MR gain-of-function mutations (Geller syndrome), increased aldosterone levels (primary/secondary hyperaldosteronism), and increased cortisol (Cushing syndrome) or deoxycorticosterone (hypercortisolism) which also activate MR, can lead to up-regulation of ENaC expression, and increased Na+ reabsorption, K+ excretion, as well as H+ excretion, clinically manifested as hypertension, hypokalemia and alkalosis. Conversely, ENaC inactivating mutations (pseudohypoaldosteronism type 1b), MR inactivating mutations (pseudohypoaldosteronism type 1a), or decreased aldosterone levels (hypoaldosteronism) can cause decreased reabsorption of Na+ and decreased excretion of both K+ and H+, clinically manifested as hypotension, hyperkalemia, and acidosis. The ENaC inhibitors amiloride and Triamterene can cause manifestations resembling pseudohypoaldosteronism type 1b; MR antagonist spironolactone causes manifestations similar to pseudohypoaldosteronism type 1a. Secondly, Na+ influx is regulated by the distal delivery of water and sodium. Therefore, when loss-of-function mutations in Na+-K+-2Cl- cotransporter (NKCC) expressed in the thick ascending limb of the loop and in Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule (Bartter syndrome and Gitelman syndrome, respectively) occur, the distal delivery of water and sodium increases, followed by an increase in the reabsorption of Na+ by ENaC at the collecting duct, as well as increased excretion of K+ and H+, clinically manifested as hypokalemia and alkalosis. Loop diuretics acting as NKCC inhibitors and thiazide diuretics acting as NCC inhibitors can cause manifestations resembling Bartter syndrome and Gitelman syndrome, respectively. Conversely, when the distal delivery of water and sodium is reduced (e.g., Gordon syndrome, also known as pseudohypoaldosteronism type 2), it is manifested as hypertension, hyperkalemia, and acidosis. Finally, when the distal delivery of non-chloride anions increases (e.g., proximal renal tubular acidosis and congenital chloride-losing diarrhea), the influx of Cl- in the collecting duct decreases; or when the excretion of hydrogen ions by collecting duct intercalated cells is impaired (e.g., distal renal tubular acidosis), the efflux of H+ decreases. Both above conditions can lead to increased K+ secretion and hypokalemia. In this review, we focus on the regulatory mechanisms of renal potassium excretion and the corresponding diseases arising from dysregulation.

Activation of renal outer medullary potassium channel in the renal distal convoluted tubule by high potassium diet / 生理学报

Renal outer medullary potassium (ROMK) channel is an important K+ excretion channel in the body, and K+ secreted by the ROMK channels is most or all source of urinary potassium. Previous studies focused on the ROMK channels of thick ascending limb (TAL) and collecting duct (CD), while there were few studies on the involvement of ROMK channels of the late distal convoluted tubule (DCT2) in K+ excretion. The purpose of the present study was mainly to record the ROMK channels current in renal DCT2 and observe the effect of high potassium diet on the ROMK channels by using single channel and whole-cell patch-clamp techniques. The results showed that a small conductance channel current with a conductance of 39 pS could be recorded in the apical membrane of renal DCT2, and it could be blocked by Tertiapin-Q (TPNQ), a ROMK channel inhibitor. The high potassium diet significantly increased the probability of ROMK channel current occurrence in the apical membrane of renal DCT2, and enhanced the activity of ROMK channel, compared to normal potassium diet (P < 0.01). Western blot results also demonstrated that the high potassium diet significantly up-regulated the protein expression levels of ROMK channels and epithelial sodium channel (ENaC), and down-regulated the protein expression level of Na+-Cl- cotransporter (NCC). Moreover, the high potassium diet significantly increased urinary potassium excretion. These results suggest that the high potassium diet may activate the ROMK channels in the apical membrane of renal DCT2 and increase the urinary potassium excretion by up-regulating the expression of renal ROMK channels.

The mechanism of blood pressure regulation by high potassium diet in the kidney / 生理学报

Hypertension is one of the strongest risk factors for cardiovascular diseases, cerebral stroke, and kidney failure. Lifestyle and nutrition are important factors that modulate blood pressure. Hypertension can be controlled by increasing physical activity, decreasing alcohol and sodium intake, and stopping tobacco smoking. Chronic kidney disease patients often have increased blood pressure, which indicates that kidney is one of the major organs responsible for blood pressure homeostasis. The decrease of renal sodium reabsorption and increase of diuresis induced by high potassium intake is critical for the blood pressure reduction. The beneficial effect of a high potassium diet on hypertension could be explained by decreased salt reabsorption by sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT). In DCT cells, NCC activity is controlled by with-no-lysine kinases (WNKs) and its down-stream target kinases, Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive 1 (OSR1). The kinase activity of WNKs is inhibited by intracellular chloride ([Cl-]i) and WNK4 is known to be the major WNK positively regulating NCC. Based on our previous studies, high potassium intake reduces the basolateral potassium conductance, decreases the negativity of DCT basolateral membrane (depolarization), and increases [Cl-]i. High [Cl-]i inhibits WNK4-SPAK/OSR1 pathway, and thereby decreases NCC phosphorylation. In this review, we discuss the role of DCT in the blood pressure regulation by dietary potassium intake, which is the mechanism that has been best dissected so far.

Noncrystalline uric acid inhibits proteoglycan and glycosaminoglycan synthesis in distal tubular epithelial cells (MDCK)

Hyperuricemia is associated with renal stones, not only consisting of uric acid (UrAc) but also of calcium oxalate (CaOx). Glycosaminoglycans (GAGs) are well-known inhibitors of growth and aggregation of CaOx crystals. We analyzed the effect of noncrystalline UrAc on GAG synthesis in tubular distal cells. MDCK (Madin-Darby canine kidney) cells were exposed to noncrystalline UrAc (80 µg/mL) for 24 h. GAGs were labeled metabolically and characterized by agarose gel electrophoresis. The expression of proteoglycans and cyclooxygenase 2 (COX-2) was assessed by real-time PCR. Necrosis, apoptosis and prostaglandin E2 (PGE2) were determined by acridine orange, HOESCHT 33346, and ELISA, respectively. CaOx crystal endocytosis was evaluated by flow cytometry. Noncrystalline UrAc significantly decreased the synthesis and secretion of heparan sulfate into the culture medium (UrAc: 2127 ± 377; control: 4447 ± 730 cpm) and decreased the expression of perlecan core protein (UrAc: 0.61 ± 0.13; control: 1.07 ± 0.16 arbitrary units), but not versican. Noncrystalline UrAc did not induce necrosis or apoptosis, but significantly increased COX-2 and PGE2 production. The effects of noncrystalline UrAc on GAG synthesis could not be attributed to inflammatory actions because lipopolysaccharide, as the positive control, did not have the same effect. CaOx was significantly endocytosed by MDCK cells, but this endocytosis was inhibited by exposure to noncrystalline UrAc (control: 674.6 ± 4.6, CaOx: 724.2 ± 4.2, and UrAc + CaOx: 688.6 ± 5.4 geometric mean), perhaps allowing interaction with CaOx crystals. Our results indicate that UrAc decreases GAG synthesis in MDCK cells and this effect could be related to the formation of UrAc and CaOx stones.

Comparative study of two tests of renal diluting ability in Bartter's syndrome

1. Different results concerning distal NaCl reabsorption have been reported for patients with Bartter's syndrome in tests of renal diluting ability. We describe clearance studies performed on 3 patients with Bartter's syndrome using different routes for body fluid content expansion: water was given orally and 0.45 NaCl solution intravenously. The impact of fluid composition was evaluated in one patient who additionally underwent a "reverse test": i.e., intravenous 5 glucose in water and an oral load of 0.45 NaCl solution. 2. Urine flow per ml glomerular filtration rate (GFR) reached higher levels when the iv route was used (20.6 +/- 1.8 vs 11.8 +/- 5.7, P < 0.05). Fractional excretion of Na+, Cl- and osmoles increased during NaCl infusion but not during the oral load. Also, distal delivery of solute increased and was greater than that observed in the oral test (21.9 +/- 5.5 vs 11.4 +/- 2.1, P < 0.05). 3. In contrast, fractional distal chloride reabsorption in the iv test reached subnormal values which were lower than in the oral load test (65.0 +/- 11.2 vs 86.8 +/- 11.0, P < 0.05). A positive correlation was observed between distal delivery and Cl- fractional excretion (r = 0.87; P < 0.005). In one patient, the 5 glucose infusion resulted in greater urine flow and distal delivery when compared to distilled water or 0.45 NaCl taken orally (28.1 vs 13.3 ml/min and 27.3 vs 12.8, respectively). These values were as high as those observed during iv administration of hypotonic saline. 4. The iv route was always associated with lower rates of fractional distal chloride reabsorption (70.7 vs 89.1) regardless of the solute composition and should be recommended when testing the renal diluting ability of patients suspected of Bartter's syndrome.

Transepithelial pH gradients in cortical distal tubules during metabolic alkalosis

1. The cortical distal tubule of the rat kidney participates in the regulation of acid-base balance, showing bicarbonate reabsorption, secretion or absence of transport under different experimental conditions. In the present study, we measured differences in transepithelial pH using double ion-exchange resin/reference microelectrodes in control and alkalotic (chronic plus acute) male Wistar rats and in alkalotic rats receiving a K+ supplement in diet and infusion. 2. pH was measured in the tubule lumen during stationary microperfusion with 25 mM bicarbonate Ringer solution, and in peritubular vessels next to the perfused tubules. 3. Differences in transepithelial pH were 0.70 +/- 0.12 (N = 16) pH units in early distal tubules (ED) and 1.03 +/- 0.050 (N = 15) in late distal tubules LD) of control rats, 0.22 +/- 0.056 (N = 17) in ED and 0.25 +/- 0.050 (N = 20) in LD of alkalotic rats, and -0.02 +/- 0.039 (N = 24) in ED and -0.02 +/- 0.040 (N = 24) in LD of K(+)-supplemented alkalotic rats. 4. In control rats, the transepithelial potential difference (PD) (-8.9 +/- 1.45 mV (N = 16) in ED and -32.7 +/- 2.99 mV (N = 15) in LD) was not large enough to explain transepithelial H+ and HCO3- gradients, suggesting the presence of an active transport mechanism responsible for their maintenance. 5. The present data show that the cortical distal tubule is able to establish transepithelial pH (HCO3-) differences, that these differences are reduced by alkalosis and abolished by alkalosis plus K+ supplementation, and that, although inversion of pH gradients (evidence for bicarbonate secretion) was observed in individual tubules, this inversion was not significant in the groups studied

Latent distal renal tubular acidosis (dRTA) in primary biliary cirrhosis (PBC) and chronic autoinmune hepatitis (CAH)

In an attempt to evaluate the latent distal renal tubular acidosis (dRTA7) in patients with primary biliary cirrhosis (PBC), and chronic autoinmmune hepatitis (CAH), and differences between them in relation to the sodium urinary excretion ([a]u), thirty four patients divided in two groups were studied. Group A: 17 patients who fullfilled criteria for PBC diagnosis (clinical and humoral and liver biopsy). Group B: 17 patients who fullfilled criteria for CAH diagnosis (clinical and humoral evidence, antinuclear and smooth muscle antibody tiles of 1/80 or above and liver biopsy). Patients with ascitis and/or edema were excluded form the study. Ability to acidify urine was evaluated by gradient between pCO2 in urine and blood (U-BpC02) after alkali infusion. Five patients with dRTA in both groups, the mean [Na]u in Group A was 152.2 ñ 33.8, versus 50.8 ñ 8.1 mEq/l, in Group B. (p=0.00016). We concluded that the prevalence of dRTA was similar en patiens with PBC and CAH but the urinary acidifications impairment of the former did not correlate with [Na]u, as it did whit the latter