Effects of a high-sodium diet on renal tubule Ca2+transporter and claudin expression in Wistar-Kyoto rats
© Yatabe et al.; licensee BioMed Central Ltd. 2012
Received: 13 June 2012
Accepted: 27 November 2012
Published: 2 December 2012
Urinary Ca2+ excretion increases with dietary NaCl. NaCl-induced calciuria may be associated with hypertension, urinary stone formation and osteoporosis, but its mechanism and long-term effects are not fully understood. This study examined alterations in the expressions of renal Ca2+ transporters, channels and claudins upon salt loading to better understand the mechanism of salt-induced urinary Ca2+ loss.
Eight-week old Wistar-Kyoto rats were fed either 0.3% or 8% NaCl diet for 8 weeks. Renal cortical expressions of Na+/Ca2+ exchanger 1 (NCX1), Ca2+ pump (PCMA1b), Ca2+ channel (TRPV5), calbindin-D28k, and claudins (CLDN-2, -7, -8, -16 and −19) were analyzed by quantitative PCR, western blot and/or immunohistochemistry.
Fractional excretion of Ca2+ increased 6.0 fold with high-salt diet. Renal cortical claudin-2 protein decreased by approximately 20% with decreased immunological staining on tissue sections. Claudin-16 and −19 expressions were not altered. Renal cortical TRPV5, calbindin-D28k and NCX1 expressions increased 1.6, 1.5 and 1.2 fold, respectively.
Chronic high-salt diet decreased claudin-2 protein and increased renal TRPV5, calbindin-D28k, and NCX1. Salt loading is known to reduce the proximal tubular reabsorption of both Na+ and Ca2+. The reduction in claudin-2 protein expression may be partly responsible for the reduced Ca2+ reabsorption in this segment. The concerted upregulation of more distal Ca2+-transporting molecules may be a physiological response to curtail the loss of Ca2+, although the magnitude of compensation does not seem adequate to bring the urinary Ca2+ excretion down to that of the normal-diet group.
KeywordsCalcium Sodium chloride Distal tubule Na+/Ca2+ exchanger Ca2+ channel Claudins
Urinary Ca2+ excretion increases with sodium chloride (NaCl) ingestion . This dietary NaCl-induced calciuria may lead to osteoporosis at low calcium intake [2, 3] and also is associated with urinary stone formation  and hypertension . The increase in urinary Ca2+ excretion is postulated to be due to salt-induced volume expansion  and/or competition between sodium and calcium ions in the renal tubule . However, the precise mechanism for the dietary NaCl-induced urinary Ca2+ increase is not fully understood. In addition, it is not clear if long-term salt loading has any effects on Ca2+-transporting molecule expressions in the kidney.
The bulk of Ca2+ in the pro-urine is reabsorbed in the proximal tubule and the thick ascending loop of Henle through a passive, paracellular movement. Transepithelial Ca2+ permeability is high in these segments, and the rate-limiting barrier is the tight junction. Claudins and other tight junction proteins are known to be important in determining the permeability characteristics of various epithelia . For example, renal expression of claudin 2 is restricted to the proximal nephron , and claudin 2 is believed to form high-conductance cation pores . The distributions and functions of these tight junction proteins are becoming known, but information on their regulation, especially in the kidney, is just emerging.
In contrast, regulated transcellular Ca2+ reabsorption occurs primarily in the distal tubule. In the distal nephron, Ca2+ in the pro-urine enters the cytosol of tubule cells through Ca2+ channel, mainly TRPV5 . The transport of intracellular Ca2+ to the basolateral side is facilitated by a Ca2+-binding protein called calbindin-D28k[10, 11], and Ca2+ exits the cell on the basolateral side through Na+/Ca2+ exchanger 1 (NCX1) and Ca2+ pump (PMCA1b) [12, 13]. NCX1 counter-transports 3 Na+ for Ca2+, but the role of NCX1 in NaCl-induced calciuria has not been studied.
Alterations in the expressions of tight junction proteins and transcellular Ca2+ transporters may in part explain the urinary calcium loss upon salt loading or provide clues on long-term effects of dietary NaCl ingestion. Therefore, we examined the expression changes of renal Ca2+ transport molecules in rat with chronic high-NaCl diet.
All experimental procedures were approved by the Fukushima Medical University School of Medicine Animal Committee. Eight-week old Wistar-Kyoto rats (Japan SLC Inc. Sendai, Japan) were fed either 0.3% or 8% NaCl chow (Oriental Yeast Co., Tokyo, Japan) for 8 weeks with tap water ad libitum. Unanesthetized systolic blood pressure was measured by the tail-cuff method (Blood Pressure Analyzer model BP-98A; Softron, Tokyo, Japan). Ten measurements were taken and averaged per rat per day. Urine was collected regularly using metabolic cages. At the end of the study, under intraperitoneal pentobarbital anesthesia, blood was drawn from abdominal aorta, and kidneys were collected for assays.
Biochemical analyses were performed by SRL Inc. (Tokyo, Japan) using creatinase-sarcosine-oxidase-POD method for creatinine, electrode method for Na, K and Cl, arsenazo III method for Ca, direct molybdate assay for inorganic phosphate (P) and xylidyl blue method for Mg. Serum concentrations of 1,25-dihydroxyvitamin D3 were measured by radioimmunoassay using the two antibody method.
Quantitative Real-Time RT-PCR
Total RNA was prepared from renal cortex using RNeasy plus mini kit (Qiagen). Subsequently, 0.25 μg of total RNA was reverse-transcribed into cDNA using iScript cDNA Synthesis Kit (Bio Rad) in a 20 μl reaction volume. One μl of reverse-transcription sample was used for real-time quantitative PCR using the iQ5 Real-Time PCR Detection System and iQ SYBR Green Supermix (Bio Rad). The primers used were as follows: NCX1 forward CAGTTGTGTTTGTCGCTCTTGG and reverse GTTGGCCGCATGGTAGATGG, with annealing temperature (Ta) 57°C; GAPDH forward GCAAGTTCAACGGCACAGTCAAG and reverse ACATACTCAGCACCAGCATCACC with Ta 56°C, TRPV5 forward CTTACGGGTTGAACACCACCA and reverse TTGCAGAACCACAGAGCCTCTA with Ta 56°C; PMCA1b forward CGCCATCTTCTGCACAATT and reverse CAGCCATTGTTCTATTGAAAGTTC with Ta 56°C, calbindin-D28k forward GGAGCTGCAGAACTTGATCCand reverse GCAGCAGGAAATTCTCTTCG with Ta 57°C, claudin 2 forward TCTGGATGGAGTGTGCGAC and reverse AGTGGCAAGAGGCTGGGC with Ta 63°C, claudin 7 forward GACTCGGTGCTTGCCCTGCC and reverse GGAGCGGGGTGCACGGTATG with Ta 59°C, claudin 8 forward GTGCTGCGTCCGTCCTGTCC and reverse CCAAGCTCGCGCTTTTGGGC with Ta 59°C. NCX1 and GAPDH primers were designed using Beacon Designer software (PREMIER Biosoft International, Palo Alto, California, USA), claudin 7 and 8 primers were designed using PrimerBlast (NCBI), and TRPV5, PMCA1b and claudin 2, 16 and 19 primers were adopted from elsewhere [14–16]. PCR reactions were performed in triplicate, and mRNA was quantified based on the Ct value, normalized to GAPDH, and expressed as relative amounts.
Immunoblotting of renal cortical proteins was performed similarly as previously reported . The antibodies used were monoclonal anti-rat NCX1 antibody (Abcam), polyclonal anti-claudin 2 antibody (Life Technologies, Carlsbad, CA), and polyclonal anti-TRPV5, anti-NHE3, and anti-GAPDH antibodies (Santa Cruz Biotechnology). The bands were visualized by ECL or ECL plus reagents (Amersham) and quantified by densitometry using ImageJ software.
Sections of rat kidney paraffin blocks were made with 2-μm thickness. Kidney sections of normal- and high-salt diet fed rats were placed on a single slide glass for comparison. After deparaffinization and blocking, the slices were treated with anti-claudin 2 antibody (Life Technologies, Carlsbad, CA), anti-rabbit secondary antibody and DAB using VECTASTAIN-ABC kit (Vector laboratories, Burlingame, CA). The slides were counterstained with haematoxylin and eosin.
All values are expressed as means ± SE. Statistical comparisons were performed by Student's t-test or ANOVA where appropriate. P values <0.05 were considered statistically significant.
Serum electrolytes were similar between the normal- and high-salt fed rats
Blood pressure and biochemistry data at the end of the study
Systolic Blood Pressure (mmHg)
Serum creatinine (mg/dL)
Serum Na (mmol/L)
Serum K (mmol/L)
Serum Cl (mmol/L)
Serum Ca (mmol/L)
Serum Mg (mmol/L)
Serum P (mmol/L)
Urinary calcium excretion was markedly increased in the high-salt rats
Renal claudin-2 protein decreased, but claudin-7, -8, -16 or -19 mRNA was not altered with chronic salt loading
Claudin-7 and −8 are found from distal convoluted tubule to the inner medullary collecting duct . Claudin-8 is believed to act as a paracellular cation barrier , inhibiting the backflow of Ca2+ that has been reabsorbed through transcellular mechanisms. Claudin-7 is generally assumed to be an anion barrier. No significant change was observed in the mRNA expression of claudin-7 or claudin-8 (Figure 5C and 5D).
High-salt diet increased distal, transcellular Ca2+ transporting molecules, TRPV5, calbindin-D 28 , and NCX1.
Modeling of NCX1 function
Chronic salt loading decreased serum 1,25-dihydroxyvitamin D3concentration
To investigate the mechanism of upregulation of TRPV5, calbindin-D28k and NCX1 with salt loading, serum concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D] were measured. 1,25(OH)2D is known to upregulate renal TRPV5, calbindin-D28k and NCX1 . However, rats fed 8% NaCl diet for 8 weeks showed significantly reduced serum concentration of 1,25(OH)2D (176±19 vs 129±7 pg/ml, P <0.05, n=9-11), suggesting the presence of mechanisms other than 1,25(OH)2D for the salt-induced upregulation of these molecules.
This study, for the first time, examined the effects of long-term dietary sodium chloride on renal Ca2+-transporting molecule and claudin expressions. Chronic salt loading decreased the protein expression of claudin 2, a component of proximal, paracellular Ca2+ transport pathway. Concomitantly, dietary NaCl increased the expression of more distal, transcellular Ca2+ reabsorption machinery, TRPV5, calbindin-D28k and NCX1.
Salt loading acutely increases urinary excretion of Ca2+ along with Na+[3, 6]. In this study, the fractional Ca2+ excretion of salt-loaded rats increased approximately 6.0 fold. Generally, the cause for this phenomenon is attributed to an extracellular fluid volume expansion and/or to the reduced reabsorption of both Na+ and Ca2+ in the proximal tubule . Although renal blood flow is reported to be unchanged or sometimes even reduced when salt loading is chronic such as over 8 weeks , from this study, the contribution of volume expansion and/or hyperfiltration cannot be ruled out as creatinine clearance tended to increase in the salt-loaded rats, although not significant. As creatinine determination in rodents can vary depending on the method used , the use of inulin clearance may be favorable. Pressure natriuresis is another possible factor of salt-induced calciuria, as blood pressure of salt-loaded rats tended to increase, although the difference was not statistically significant. Renal artery servo-control experiments would be useful to delineate these in the future.
Approximately 65% of calcium in the pro-urine is reabsorbed in the proximal tubule. In the proximal tubule, claudin-2 is postulated to form tight junction cation pores . Muto et al. have reported that fractional excretion of Ca2+ in claudin-2 knockout mice is 3 times that of wild-type mice, further supporting a role of claudin-2 in proximal tubular paracellular Ca2+ reabsorption . In this study, we found that chronic salt loading decreased renal cortical claudin-2 protein expression. Although there is not enough functional studies of rat claudin-2, sequence similarity to mouse claudin-2 suggests a similar role in Na+ and Ca2+ transport. Therefore, the decreased expression of claudin-2 with high-salt diet may, to some degree, account for the decrease in Ca2+ reabsorption, while limiting Na+ and water reabsorption, as Na+ and water  in addition to Ca2+ may pass through the pores formed by claudin-2. It has been reported that hyperosmolarity stress decreased claudin-2 expression in Madin-Darby canine kidney cells , and hyperosmolarity due to NaCl load may be a possible mechanism of claudin-2 downregulation in this study. As claudin-2 facilitates Ca2+ movement from the luminal to interstitial fluid in the proximal tubule, reduction in claudin-2 may underlie the increased urinary Ca2+ excretion observed under high-salt diet.
In the proximal tubule, NHE3 is shown to be important as a part of driving force for Ca2+ reabsorption, mediating apical Na+ entry and consequently water reabsorption to produce osmotic gradient . In our study, renal NHE3 protein significantly increased with salt loading. However, this finding is not in accordance with some previous studies, such as that of Frindt and Palmer who found no change in luminal NHE3 with 5% NaCl diet for 1 week in rats using in situ biotinylation . As regulation of NHE3 occurs on multiple levels, including trafficking, interacting proteins and oligomerization , protein level may not be directly related to apical NHE3 activity. If NHE3 activity is indeed increased in the high salt-fed rats, this may increase the pressure for Ca2+ reabsorption in the proximal tubule. However, competition between Na+ and Ca2+ for paracellular transport binding site may occur in the proximal tubule. It has been reported that Ca2+ inhibits paracellular Na+ conductance by competitive binding on claudin-2 . If Na+ and Ca2+ share a binding site, inversely, high Na+ may inhibit claudin-2 Ca2+ conductance. This competition between Na+ and Ca2+ may play a large role in the dietary NaCl-induced hypercalciuria.
Thick ascending limb of the loop of Henle is responsible for approximately 20% of Ca2+ reabsorption. Claudin-16 and −19 are shown to be important for paracellular Mg2+ and Ca2+ in this segment. In our study, there was an increase in the fractional excretion of Mg, albeit smaller than that of Ca. However, there was no significant difference in renal claudin-16 or −19 mRNA in rats on high-salt diet. Extracellular volume expansion decreases transepithelial voltage and Mg2+ reabsorption in the TAL . Although not directly detectable in our experimental setting, there may have been some volume expansion in the high-salt fed rats which may have contributed to the increase in Mg2+ fractional excretion.
Distal nephron is the final and most-regulated site of urinary Ca2+ reabsorption [46, 47]. A concerted increase in the expression levels of TRPV5, calbindin-D28k, and NCX1, was observed with salt loading in this study. Claudin-8, the distal tubular paracellular cation barrier, was not altered by salt loading. It may be that with salt loading, the proximal, paracellular Ca2+ reabsorption is reduced, and more distal, transcellular Ca2+ transport molecules are upregulated to facilitate Ca2+ reabsorption as a compensatory mechanism. However, salt loading may reduce the Ca2+ reabsorption via NCX1, as illustrated in Figure 7. Therefore, the upregulation of distal Ca2+ transport machinery with chronic salt-loading may partially compensate for the urinary Ca2+ loss, although with a limited effect.
As for the mechanism of TRPV5, calbindin-D28k, and NCX1 upregulations by dietary NaCl, one possibility is the endocrine factors that regulate Ca2+-related molecules, such as parathyroid hormone  and vitamin D . For example, 1,25(OH)2D has been shown to increase the expressions of TRPV5, calbindinD28k, and NCX1 . However, in this study, serum concentration of 1,25(OH)2D was significantly lower in the high-salt group than the control group. Unless there is a significant difference between serum and intrarenal 1,25(OH)2D levels, it is likely that salt-induced transcellular Ca2+-transporter upregulation is mediated by pathway(s) other than 1,25(OH)2D.
The weakness of the study includes a lack of regional expression data, as excised renal cortex was used in the study. Higher-resolution immunohistological staining experiments and qRT-PCR/Western blotting from micro-dissected tissue specimens are necessary in the future. However, this study aimed to lay the foundation for a more detailed mechanistic examination of the effects of chronically high dietary sodium on the expression of renal Ca transporters and on urinary calcium excretion.
Our findings suggest that the decrease in renal claudin-2 protein by salt loading may increase the Ca2+ in tubular fluid reaching the distal tubule, while the concerted upregulation of more distal Ca2+-handling molecules may curtail some of the Ca2+ loss in the urine. Findings of our study may have implications on further research on the pathophysiology of osteoporosis, urinary stone formation and hypertension associated with excessive salt intake.
Na+/Ca2+ exchanger 1
25(OH)2D: 1,25-dihydroxyvitamin D3.
We thank Hiroko Ohashi, Atsuko Hashimoto and Kaori Aso for their technical assistance. Junichi Taniguchi at Jichi Medical University provided us with insightful comments on the manuscript. We are also grateful for the support of Tomoyuki Ono and Sanae Sato in completing this study. MSY was supported by KAKENHI 23790950 Grant-in-Aid for Young Scientists (B), NISHINOMIYA Basic Research Fund (Japan), and a program project grant from Fukushima Medical University.
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