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Inhibition of heme oxygenase decreases sodium and fluid absorption in the loop of Henle

¹Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520; and ²Department of Pharmacology, New York Medical College, Valhalla, New York 10595

Submitted 3 April 2003 ; accepted in final form 19 May 2003

	ABSTRACT

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We previously demonstrated that carbon monoxide (CO) stimulates the apical 70-pS K⁺ channel in the thick ascending limb (TAL) of the rat kidney (Liu HJ, Mount DB, Nasjletti A, and Wang WH. J Clin Invest 103: 963-970, 1999). Because the apical K⁺ channel plays a key role in K⁺ recycling, we tested the hypothesis that heme oxygenase (HO)-dependent metabolites of heme may affect Na⁺ transport in the TAL. We used in vivo microperfusion to study the effect of chromium mesoporphyrin (CrMP), an inhibitor of HO, on fluid absorption (J_v) and Na⁺ absorption (J_Na) in the loop of Henle and renal clearance methods to examine the effect of CrMP on renal sodium excretion. Microperfusion experiments demonstrated that addition of CrMP to the loop of Henle decreased J_v by 13% and J_Na by 20% in animals on normal rat chow and caused a decrease in J_v (39%) and J_Na (40%) in rats on a high-K⁺ (HK) diet. The effect of CrMP is the result of inhibition of HO because addition of MgPP, an analog of CrMP that does not inhibit HO, had no effect on J_v. Western blot analysis showed that HO-2 is expressed in the kidney and that the level of HO-2 was significantly elevated in animals on a HK diet. Renal clearance studies demonstrated that the infusion of CrMP increased the excretion of urinary Na⁺ (E_Na) and volume (UV) without changes in glomerular filtration rate. The effect of CrMP on E_Na and UV was larger in HK rats than those kept on normal chow. We conclude that HK intake increases HO-2 expression in the kidney and that HO-dependent metabolites of heme, presumably CO, play a significant role in the regulation of Na⁺ transport in the loop of Henle.

carbon monoxide; sodium and potassium transport; microperfusion

We previously demonstrated that inhibition of HO by chromonium mesoporphyrin (CrMP) decreases the activity of the 70-pS K⁺ channel in the thick ascending limb (TAL) of the rat kidney (16). Because the inhibitory effect can be reversed by CO, this suggests that CO is an HO-dependent metabolite of heme responsible for stimulating the apical 70-pS K⁺ channel (16). Because these K⁺ channels play a key role in K⁺ recycling across the apical membrane (1, 2, 5), their inhibition by blocking HO with CrMP is expected to decrease K⁺ recycling and suppress the activity of the Na-K-2Cl cotransporter. This hypothesis was tested by examining the effect of inhibition of HO on transepithelial Na⁺ transport in the loop of Henle. We demonstrate that luminal perfusion of CrMP significantly decreases Na⁺ absorption and increases Na⁺ excretion in the loop of Henle. Those effects are enhanced by increasing dietary K⁺ intake.

	METHODS

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Animal preparation. Male Sprague-Dawley rats (from Harlan, Indianapolis, IN) weighing 200-250 g were used for the renal clearance and tubule microperfusion experiments. Animals were kept on normal rat chow, a high-K⁺ (HK), or a K⁺-deficient (KD) diet (Harlan Teklad) and tap water until the experiment. The animals were anesthetized by intravenous injection of Inactin (100 mg/kg) and placed on a thermostatically controlled surgical table to maintain body temperature at 37°C. The left jugular vein and the carotid artery were cannulated for the infusion of saline and for collection of arterial blood samples, respectively. These methods have been described previously (29, 30).

Renal clearance studies. Renal clearance techniques were used as previously described (26, 27) to investigate the effects of the HO inhibitor (CrMP) on glomerular filtration rate (GFR) and on absolute (E_Na, E_K) and fractional excretion rates of Na⁺ and K⁺ (FE_Na, FE_K). Surgical fluid losses were replaced with isotonic saline and a priming dose of 25 µCi of [methoxy-³H]inulin (New England Nuclear, Boston, MA) was given in 0.5 ml isotonic saline, followed by a maintenance infusion of 0.9% NaCl containing 25 µCi/h at a rate of 4.6 ml/h. Blood and urine samples were collected after a 60-min equilibration period. Urine collections lasted 30 min, and blood samples were taken at the beginning and end of each collection period. After two control periods, either CrMP (3 mg/kg) or vehicle solution (control) was given intravenously as a bolus injection. Urine and plasma Na⁺ and K⁺ concentrations were measured by flame photometry (type 480 Flame Photometer, Corning Medical and Scientific, Corning, NY) and absolute and fractional renal excretions were calculated by standard methods (29, 30).

Microperfusion of the loop of Henle. The methods of in vivo microperfusion of superficial loops of Henle were similar to those described previously (29, 30). First, a loop of Henle was selected by microperfusing a proximal tubule to locate its last loop on the kidney surface. Then, the loop of Henle was perfused from the last loop of the proximal tubule with a microperfusion pump at a rate of 20 nl/min. Tubule fluid was collected from the first segment of the early distal tubule with an oil block placed distally from the collection site. The rate of fluid Na⁺ and K⁺ absorption in the loop of Henle was expressed as absorption rate per loop, because the length of individual loops of Henle in the rat has been found to vary little. Na⁺ and K⁺ concentrations in the perfusing fluid and the collected tubule fluid were measured with a ultramicroatomic absorption spectrophotometer as previously described (29, 30).

The composition of the perfusion fluids was as follows (in mM): 115 NaCl, 25 NaHCO₃, 4 KCl, 1 CaCl₂, 5 Na-acetate, 5 glucose, 5 L-alanine, 2.5 Na₂HPO₄, and 0.5 NaH₂PO₄ (pH was adjusted to 7.4 and the osmolality was at 295 mosmol/kgH₂O).

Western blot analysis. Rats were kept on different K⁺ diets: KD (<0.01%), HK (10% wt/wt), and normal K⁺ diet (NK; Harlan Teklad) for 1 wk before use. Renal cortex and outer medulla were dissected and homogenized as described previously (16). Protein samples extracted from the renal tissue were separated by electrophoresis on 8% SDS-polyacrylamide gels and transferred to nitrocellulose membranes. The membranes were blocked with 10% nonfat dry milk in Tris-buffered saline (TBS), rinsed, and washed with 1% milk in Tween-TBS. The HO-1 and HO-2 antibodies were purchased from Transduction Laboratories (Lexington, KY) and were diluted at 1:1,000. The protein concentration used for immunoblot was 100 µg.

Materials and statistics. [methoxy-³H]inulin was obtained from New Research Products (Boston, MA), CrMP and magnesium protoporphyrin (MgPP) from Porphyrin Products (Logan, UT). Data are presented as means ± SE. Control and experimental values were compared using the unpaired Student's t-test. Dunnett's test was used for comparison of several treatment groups with a single control group. Differences between groups are reported as significant at P < 0.05.

	RESULTS

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We confirmed our previous findings that HO-2 is expressed in the renal cortex and outer medulla (16) and extended those studies to animals kept on different K⁺ diets. Western blot analysis revealed that the expression of HO-2 is 150 ± 10% (n = 4) higher in the kidney from rats on a HK diet than those kept on a NK or KD diet (Fig. 1A). HO-2 expression is significantly diminished in the kidney from rats on a KD diet compared with that observed in rats on a NK diet. In contrast, HK intake did not significantly affect the expression of HO-1 in the kidney (Fig. 1B).

View larger version (22K): [in this window] [in a new window]   Fig. 1. Western blotting shows the presence of heme oxygenase (HO) type II (A) and type I (B) in the renal cortex and outer medulla from rats on normal-K+ (NK), high-K+ (HK), and low-K+ (LK) diets. PC, positive control.

After it was established that HO-2 expression is affected by dietary K⁺ intake, the role of HO in the regulation of transport in the loop of Henle was investigated. Microperfusion techniques were used to examine the effect of CrMP on Na⁺ and K⁺ transport in the loop of Henle in rats on a NK and a HK diet.

Figure 2 and Table 1 summarize results showing the effects of 50 µM CrMP on the rate of Na⁺ (J_Na), fluid (J_V), and K⁺ absorption (J_K). It is apparent that perfusion of the loop with CrMP (50 µM) inhibits Na⁺ and K⁺ absorption in tubules from rats on NK and HK diets. It should be noted that the inhibitory effect of CrMP on J_Na is larger in rats on a HK diet than those on a NK diet. In control rats, J_Na decreased by 20%, from 1.54 ± 0.07 to 1.22 ± 0.05 nmol/min (n = 11). In contrast, CrMP decreased J_Na by 40%, from 1.35 ± 0.07 to 0.79 ± 0.10 nmol/min (n = 10), in rats on a HK diet. The inhibitory effect of CrMP on J_K is also enhanced in animals on a HK diet: inhibition of HO decreased J_K by 64% from 31.7 ± 3.54 to 11.2 ± 5.27 compared with a 28% decrease in the control rats. The reason that the inhibitory effect of CrMP on J_K is larger than that on J_V and J_Na may be due to backleak of K⁺ from the peritubular fluid into the lumen. Huang et al. (7) reported that inhibition of apical K⁺ channels significantly increases the luminal K⁺ concentration and Jamison et al. (9) also observed that net K⁺ secretion takes place at low transepithelial voltage in the TAL. It has been previously shown that CrMP inhibits the apical 70-pS K⁺ channel and this could lead to attenuation of the lumen-positive potential. Moreover, because the concentrations of K⁺ in the medullary interstitial fluid may exceed that in the lumen, these two factors favor passive influx of K⁺ from the peritubular fluid to lumen.

View larger version (14K): [in this window] [in a new window]   Fig. 2. Effects of chromium mesoporphyrin (CrMP) on Na+ absorption (JNa) in the loop of Henle in rats on a NK and HK diet. Data are means ± SE. CrMP was added to the luminal perfusate at a concentration of 50 µM.

Also, J_Na and J_K were slightly lower under control conditions in rats on a HK diet than in rats on a NK diet. A similar observation has been reported previously (25), and this modest decline of J_Na and J_K may be the result of a decrease in the driving force of Na⁺ and K⁺ transport in HK-adapted rats. It is possible that a high plasma K⁺ leads to depolarization of the basolateral membrane, which diminishes the electrochemical gradient of Cl^- exit across the basolateral membrane. Because a decrease in Cl^- diffusion across the basolateral membrane leads to attenuation of the lumen-positive potential that is the driving force for the paracellular Na⁺ and K⁺ absorption, Na⁺ and K⁺ transport is expected to slightly decrease.

The effect of CrMP on J_V was also significantly larger in animals on a HK diet than that observed in rats on a NK diet. Thus infusion of CrMP decreased fluid reabsorption in the loop of Henle. Figure 3 and Table 1 summarize results demonstrating that perfusion of the loop with CrMP decreased J_V by 39% from 9.20 ± 0.48 to 5.65 ± 0.83 nl/min (n = 10) in rats on a HK diet, compared with a decrease of 13% from 9.62 ± 0.42 to 8.35 ± 0.33 nl/min (n = 11) in rats on a NK diet.

View larger version (14K): [in this window] [in a new window]   Fig. 3. Effects of CrMP on fluid absorption (Jv) in the loop of Henle from rats on a NK and HK diet. Data are means ± SE. CrMP was added to the luminal perfusate at a concentration of 50 µM.

To exclude the possibility of unspecific inhibitory action of CrMP, we employed MgPP, an agent that has a similar structure to CrMP but does not inhibit HO, to determine whether MgPP can mimic the effect of CrMP. Figure 4 summarizes the results from five experiments demonstrating that perfusion of the loop of Henle with 50 µM MgPP did not affect J_V. These results indicate that the effect of CrMP on J_Na and J_V results from inhibition of HO.

View larger version (12K): [in this window] [in a new window]   Fig. 4. Effects of CrMP and magnesium protoporphyrin (Mgpp) on Jv in the loop of Henle from rats on a HK diet.

After establishing that inhibition of HO inhibits Na⁺ and fluid absorption in the loop of Henle, we extended our study by examining the effects of CrMP on urinary Na⁺ and K⁺ excretion with renal clearance techniques. After two 30-min baseline periods, a bolus intravenous infusion of CrMP (3 mg/kg) was administered and four additional urinary collections were carried out. Application of CrMP did not significantly affect blood pressure (data not shown). Inspection of Table 2 and Fig. 5 shows that infusion of HO inhibitor also did not significantly alter GFR. However, CrMP significantly enhanced the excretion of Na⁺ (E_Na) from a mean control value of 0.34 ± 0.07 to 1.27 ± 0.22 meq ·min^-1·100 g^-1 in rats on a NK diet (n = 5) and from 0.34 ± 0.12 to 2.42 ± 0.43 meq·min^-1·100 g^-1 in rats on a HK diet (n = 7) (Table 2). It is of interest that infusion of a HO inhibitor did not significantly change urinary K⁺ excretion (E_K) in either rats on a NK or a HK diet (Table 2). Figure 5 also shows the time course of the effect of CrMP on urinary volume (UV) in rats on a NK or HK diet. Inhibition of HO increases UV progressively, from 0.011 (n = 10) to 0.047 ml/min (n = 5) in rats on a NK diet and from 0.015 (n = 7) to 0.042 ml/min (n = 7) in animals on a HK diet.

View larger version (23K): [in this window] [in a new window]   Fig. 5. Effects of HO inhibitor CrMP on urinary volume and glomerular filtration rate (GFR). Data are means ± SE. CrMP was given by intravenous (iv) bolus injection at a concentration of 3 mg/kg in rats on NK or HK diets. *Significantly different from control values (P < 0.05).

Data summarized in Fig. 6 demonstrate the effects of intravenous injection of CrMP on FE_Na and FE_K. It is apparent that the effect of CrMP on FE_Na is larger in rats on a HK diet than that observed in rats on a NK diet. Thus inhibition of HO increased FE_Na from 0.012 to 2.44% in rats on a HK diet but only from 0.031 to 1.34% in rats on a NK diet. Inspection of Fig. 6 shows that CrMP has no effect on FE_K in rats on a NK or HK diet, although rats on a HK diet had a higher basal level of FE_K.

View larger version (19K): [in this window] [in a new window]   Fig. 6. Effects of CrMP on fractional excretion of Na+ (FENa; top) and K+ (FEK; bottom). CrMP was given by iv bolus at a concentration of 3 mg/kg in rats on NK or HK diets. *Significantly different from control values (P < 0.05).

	DISCUSSION

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Previous studies showed that dietary K⁺ intake affects ion transport in the TAL (15, 17, 18). However, the mechanism by which dietary K⁺ intake alters membrane transport in the TAL is incompletely defined. We previously demonstrated that a high dietary K⁺ intake increases the expression of inducible nitric oxide synthase in the renal cortex and outer medulla and attenuates the inhibitory effect of external Ca²⁺ on the apical 70-pS K⁺ channel in the TAL (3). In the present study, we report that HO-2 expression is also augmented in the kidney from rats on a HK diet. Because HO-2 is also expressed in the TAL (22), the finding that a HK intake increases HO-2 expression suggests that, like nitric oxide, HO-dependent metabolites of heme are also involved in regulating ion transport in the TAL from K⁺-adapted animals. This suggestion is supported by the finding that infusion of CrMP, a known inhibitor of HO, lowers Na⁺ reabsorption along the loop of Henle. Two lines of evidence suggest that the effect of CrMP results from inhibition of HO-dependent metabolism: 1) perfusion of the loop of Henle with MgPP, a CrMP analog and weak inhibitor of HO, did not inhibit Na⁺ absorption in the loop; and 2) the inhibitory effect of CrMP on Na⁺ and fluid absorption was enhanced in rats on a HK diet. This is consistent with our observation that the renal expression of HO-2 was also significantly elevated in these animals.

The mechanism by which inhibition of HO inhibits Na⁺ and fluid absorption in the loop of Henle is not fully understood. The loop of Henle includes the late proximal tubule, the thin descending limb, the TAL, and the early distal convoluted tubule. Immunocytochemical studies show that HO-1 and HO-2 are expressed in the proximal tubule, TAL, and distal tubule (22). Accordingly, the inhibitory effect of CrMP on Na⁺ transport could be the result of inhibition of Na⁺ transport in the late proximal tubule, TAL, or distal convoluted tubule. The observation that CrMP significantly decreases J_v suggests that inhibition of HO decreases the transport in the S3 segment and descending limb, because the TAL has very low water permeability. However, the observation that high dietary K⁺ intake significantly augmented the expression of HO-2 in the renal outer medulla, consisting mainly of the TAL, strongly suggests that this nephron segment is an important site for the regulation of transport by HO-dependent metabolites. One interesting observation in the present study was that the inhibitory effect of CrMP on Na⁺ was greater in HK than control, despite the fact that J_Na and J_K were slightly lower in HK rats. The reduction in J_Na and J_K in HK has been reported previously (25); this modest decline of J_Na and J_K may be the result of a decrease in the driving force of Na⁺ and K⁺ transport from lumen to cell in HK-adapted rats. The increased inhibitory action of CrMP on J_Na may be explained by our recent observation that the ratio of 35- and 70-pS K⁺ channels in the TAL is significantly modulated by HK intake. The 35-pS K⁺ channel was reduced from 57 to 26%, but the 70-pS channel was increased from 2 to 23% by HK. Because the 35-pS K⁺ channel is not regulated by HO-dependent CO production (16), the inhibitory effect of CrMP on Na⁺ absorption would be the result of inhibition of the increased total 70-pS K⁺ channel activity in HK-treated rats.

The TAL is responsible for absorption of 25% filtered NaCl load and plays a key role in the urinary concentrating ability (1). The absorption of NaCl involves two steps: 1) NaCl enters the cells across the apical membrane through the Na-K-2Cl cotransporter; and 2) Na⁺ is extruded across the basolateral membrane via Na-K-ATPase and Cl^- leaves the cell by diffusion along a favorable electrochemical gradient. K⁺ recycling is important to maintain the activity of the Na-K-2Cl cotransporter because it provides an adequate K⁺ supply for the cotransporter (1, 2). Therefore, inhibition of either apical K⁺ channels (24) or Na-K-2Cl cotransporters (4) could block transepithelial NaCl absorption. In addition, if CrMP inhibits basolateral Cl^- channels, it can also lead to a decrease in transepithelial NaCl absorption (23). However, it is safe to conclude that the diuretic effect of CrMP results at least partially from inhibition of apical K⁺ recycling by decreasing HO-dependent metabolites such as CO, because it was previously shown that CO can reverse the inhibitory effect of CrMP on the apical 70-pS K⁺ channel (16). It is most likely that the effect of CrMP is caused by decreasing CO generation. A large body of evidence indicates that CO plays an important role in the regulation of several cell functions. CO has been reported to regulate blood pressure (10-12, 14). This effect is possibly mediated by stimulation of Ca²⁺-activated large-conductance K⁺ channels (27, 28). CO has also been suggested to be involved in energy metabolism and synaptic transmission (21). Our present data suggest that CO may be involved in the regulation of NaCl transport in the loop of Henle.

Three observations support the suggestion that the effect of CrMP is mediated by inhibition of HO-2. First, the expression level of HO-1 was significantly lower than that of HO-2 under control conditions (22). Second, the expression of HO-1 was not altered by a high dietary K⁺ intake. Third, HK intake significantly increased the expression of HO-2 and enhanced the inhibitory effect of CrMP on Na⁺ absorption in the loop of Henle. However, the role of HO-1 in the regulation of NaCl transport in the loop could not be completely excluded. The mechanism by which HK intake increases HO-2 expression is not clear. High dietary K⁺ intake has been demonstrated to increase plasma aldosterone levels. However, it is unlikely that a large increase in HO-2 levels results from an increase in plasma aldosterone levels, because low-Na⁺ intake did not increase HO-2 expression in renal cortex and outer medulla (unpublished observation).

Inhibition of Na⁺ absorption in the loop of Henle is expected to increase Na⁺ delivery in the collecting tubule (13), and this should lead to stimulation of Na⁺ absorption and K⁺ secretion in the initial cortical collecting tubule. However, our clearance studies demonstrated that infusion of CrMP did not alter K⁺ excretion, although Na⁺ excretion increased significantly. It is possible that CrMP inhibits apical Na⁺ channels, apical small-conductance secretory K⁺ channels, or the Ca²⁺-dependent large-conductance K⁺ channel. CO has been shown to activate the Ca²⁺-dependent large-conductance K⁺ channel in smooth muscle cells (26-28). If inhibition of HO with CrMP would similarly block the Ca²⁺-dependent large-conductance K⁺ channel in principal cells, CrMP should also attenuate flow-dependent K⁺ secretion that is mediated by Ca²⁺-dependent large-conductance K⁺ channels (31). Alternatively, inhibition of HO may stimulate K absorption in the medullary collecting duct via H-K-ATPase (32). Further experiments are needed to examine these possibilities.

In conclusion, HO-2 expression is regulated by K⁺ intake and HO-dependent metabolites of heme such as CO regulate Na⁺, K⁺, and fluid absorption in the loop of Henle.

	DISCLOSURES

 
This work is supported by National Institutes of Health Grants HL-34300 (to W. H. Wang) and DK-17433 (to G. Giebisch).

	ACKNOWLEDGMENTS

 
The authors thank M. Steinberg for editorial assistance.

	FOOTNOTES

 

Address for reprint requests and other correspondence: T. Wang, Dept. of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar St., P.O. Box 208026, New Haven, CT 06520-8026 (E-mail: tong.wang{at}yale.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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