ARTICLE |
Correspondence to: Bryan D. Myers, Div. of Nephrology S201, Stanford Univ. Medical Center, Stanford, CA 94305-5114..
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Summary |
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Cytoskeletal proteins associate with specific cell adhesion complexes and membrane proteins and influence the structural and functional organization of polarized epithelial cells in the kidney. Among such proteins that have been studied in cultured cell lines and in animals are the tight junction complex (ZO-1 and occludin), the adherens cellcell adhesion complex (-, ß-catenin and plakoglobin), and Na+,K+-ATPase, with its associated membrane skeleton proteins ankyrin and fodrin. Although abnormal distribution of these proteins has been implicated in the pathogenesis of various renal diseases, the relevance of these findings to corresponding disease of the human kidney remains to be established. As a first step towards elucidating a role for such proteins in human kidney disease, we undertook a histochemical analysis of the distribution of these proteins in biopsy specimens of human kidney taken from healthy kidney transplant donors. We found each protein to have a characteristic subcellular localization and an intensity of staining that varied among different segments of the nephron in a manner that is consistent with discrete, segmental nephron function. (J Histochem Cytochem 46:14231434, 1998)
Key Words: aquaporins, immunohistochemistry, membrane skeleton, tight junction adhesion proteins, Na+,K+-ATPase, human kidney
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Introduction |
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Each nephron in the kidney is composed of a variety of cell types that are organized in a distinctive order so as to sequentially reabsorb ions and solutes from the glomerular ultrafiltrate and to concentrate the urine. Little is known about mechanisms that lead to the development of discrete cell types or the ordering of cells into specialized segments along the nephron (
For proper function of renal epithelial cells, ion channels, exchangers, and transporters must be localized to functionally and structurally distinct plasma membrane domains, termed apical and basolateral, that face the nephron lumen and interstitial space, respectively (
The tight junction complex is composed of several cytoplasmic and membrane proteins, including zonula occludens-1 (ZO-1) and occludin, and is localized to the boundary of the apical and basolateral plasma membrane domains of polarized transporting epithelial cells (
The E-cadherin/catenin adherens junction complex plays an important role in cellcell adhesion, signal transduction, and the initiation and maintenance of structural and functional organization of cells (
Na+,K+-ATPase and its associated cytoskeletal proteins ankyrin and fodrin play a vital role in ion and solute reabsorption and the maintenance of electrolyte homeostasis (
The distribution of the aforementioned cell membrane-associated proteins has been described fully only in the mouse kidney (
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Materials and Methods |
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Subjects
The subjects of our study were nine healthy donors of a kidney for transplantation into a close relative with end-stage renal failure. Each donor and recipient of the kidney transplant gave informed consent for the performance of a renal biopsy during donor nephrectomy. The procedure was approved previously by the Committee for Research in Human Subjects at Stanford University. The donors ranged in age from 23 to 54 years. They had been diagnosed as having healthy kidneys by virtue of normal levels of creatinine clearance (109 ± 7 ml/min/1.73 m2) and protein excretion (66 ± 12 mg/24 hr). The predonation workup also included a medical history, physical examination, routine urinalysis, blood chemistry, and renal angiogram, all of which failed to reveal evidence of renal disease, diabetes, or hypertension. All recipients of these kidneys subsequently demonstrated prompt functional recovery of the allograft as judged by a rapid and progressive decline of serum creatinine to less than 1.4 mg/dl by the end of the first post-transplant week. To ensure the presence of medullary as well as cortical tissue, the biopsy was performed with a needle biopsy rather than by surgical removal of a wedge of tissue. The biopsy, using an 18-gauge biopsy needle, was performed immediately before application of the vascular clamp to the renal artery of the donor at the time of donor nephrectomy.
Immunohistochemistry
Antibodies.
An affinity-purified rabbit antibody against human ZO-1 was raised against a 69-kD fusion protein corresponding to amino acids 4631109 of ZO-1. An affinity-purified rabbit polyclonal antibody against human occludin was raised against a fusion protein consisting of the 150 amino acid C-terminal of occludin. Both antibodies were obtained from Zymed Laboratories (So. San Francisco, CA) and were used at dilutions of 1~10,000 and 1~200, respectively (see -catenin was raised against the 15 amino acid C-terminal of
-catenin and was kindly provided by Dr. Inke Näthke (Stanford University). It was used at a dilution of 1~200 (see
-subunit of Na+,K+-ATPase, ankyrin-3, and the
-subunit of fodrin have been described previously (
Tissue Preparation for Immunohistochemistry.
A fraction of the tissue obtained from the renal allografts was immediately dropped into 10 ml of paraformaldehydelysineperiodate fixative on ice for 30 min (
Immunofluorescence Staining.
Frozen tissue blocks were sectioned at -35 to -40C using a cryostat (2800 Frigocut N; Reichert-Jung, Nussloch, Germany). Six-µm-thick sections were transferred onto subbed glass slides coated with 0.1% gelatin and 0.01% chromium potassium sulfate. Frozen sections were allowed to warm to room temperature (RT) and were then extracted for 10 min at RT with cytoskeleton buffer [50 mM NaCl, 300 mM sucrose, 10 mM piperazine-N,N'-bis 2-ethane-sulfonic acid (pH 6.8), 3 mM MgCl, 0.5% Triton X-100, and 1 mM phenylmethylsulfonyl fluoride (PMSF)]. We have found that this brief incubation in Triton X-100 buffer increases the accessibility of antibodies into the tissue section (see
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Results |
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The needle biopsy cores contained cortex and outer medulla. Representative photomicrographs of the staining for each protein are organized in each figure (AD) from the superficial cortex to inner stripe of outer medulla. The kidney tissue from each subject showed a similar and invariable pattern of protein distributions for each segment of the nephron.
Identification of Nephron Segments
We used antibodies to specific protein markers of different segments of nephrons, including CHIP-28 (AQP-1) (
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Distribution of Tight Junction Proteins
Occludin staining (Figure 1 and Figure 2) is detected in parietal epithelium of Bowman's space, and cells of all tubule segments except for the ascending thin limb of Henle. Cells of proximal convoluted and straight tubules, distal straight tubule, and distal convoluted tubule show distinctly basolateral membrane distribution of the staining for occludin. In cells of the proximal straight tubule, lateral membrane staining is more pronounced: Note that distinctive punctate staining at the luminal surface, compared to that of ZO-1 (see Figure 2), is not detected. Staining in cells of the descending thin limb is apparent at intercellular junctions and basal membranes and is less intense compared with that in other tubule cells. Basolateral membrane and intercellular staining for occludin at the apical junctional complex is apparent in cells of distal straight and convoluted tubule, and intercellular staining is pronounced in cells of collecting ducts. Basolateral membrane staining in collecting duct does not exceed the level of background staining. Blood vessels are stained for occludin at intercellular junctions between endothelial cells but less intensely than that for ZO-1 (see Figure 2). Glomeruli and peritubular capillaries do not stain for occludin. ZO-1 is localized to the apical intercellular junctional complex in all renal tubular epithelial cells, although some diffuse cytoplasmic staining is also detected (Figure 2). Proximal tubule cells show a fine punctate staining along the luminal surface. Within the same section, the intensity of staining is weak in cells of the descending thin limb of Henle, stronger in distal straight tubules, and strongest in distal convoluted tubules and collecting ducts. Distal straight tubule, distal convoluted tubule, and collecting duct show strong, widely spaced punctate staining along the luminal surface, consistent with the flattened morphology of the cells. Staining in the loop of Henle is sparse. Glomeruli demonstrate strong curvilinear staining consistent with a localization of ZO-1 to the junction of podocyte foot processes and slit diaphragms.
Distribution of Cytoplasmic Proteins (Catenins) of Adherens Junctions
Cadherin cellcell adhesion proteins are linked to the actin cytoskeleton through two cytoplasmic proteins termed ß-catenin, which binds to cadherin cytoplasmic domain and -catenin, which binds to ß-catenin and the actin cytoskeleton (for review see
-catenin (Figure 3) and ß-catenin (Figure 4) is detected in all tubule cells, endothelial cells of glomeruli, blood vessels, and peritubular capillaries. Staining for both proteins is localized to the basolateral membrane of cells of all tubule segments except for the ascending thin limb of Henle. The pattern of staining in proximal tubule cells frequently appears as a stringy or serpiginous pattern which corresponds to a tangential view of lateral membrane interdigitations. Lateral membrane staining is accentuated towards the luminal side at the apical junctional complex. In proximal straight tubules, descending thin limb of Henle, and distal straight tubules, staining is distributed more strongly to lateral membranes than to basal membranes, although lateral membrane staining in proximal straight tubules is more widely spaced than that in distal tubules. Cells of distal convoluted tubules and collecting ducts demonstrate strong basolateral membrane staining. Occasionally, two parallel lines of staining are observed in distal convoluted tubules and collecting ducts that correspond to lateral membranes of adjacent cells. Parallel staining of tubules for plakoglobin (
-catenin) revealed cell type and subcellular distributions similar to those of
- and ß-catenin (data not shown).
Distribution of Na+,K+-ATPase and Associated Membrane Cytoskeletal Proteins
Previous studies have demonstrated that Na+,K+-ATPase is tightly bound to a membranecytoskeletal complex composed of ankyrin and the actin binding protein fodrin (spectrin). Na+,K+-ATPase (Figure 5), ankyrin (Figure 6), and fodrin (Figure 7) staining is detected in proximal convoluted, proximal straight, distal straight and distal convoluted tubules, collecting ducts, and glomeruli. The intensity of staining is variable, with the highest intensity in distal straight tubules, followed by distal convoluted tubules, then proximal convoluted tubules, proximal straight tubules, and finally collecting ducts. The intensity of the staining is weakest in cells of proximal straight tubule and collecting duct, although it becomes stronger on the basolateral membrane of collecting duct cells in inner stripes of the outer medulla. Staining is localized to the basolateral membrane with more abundance in the basal membrane in cells of the proximal convoluted and distal straight tubules. Little or no staining above background is detected in the thin loop of Henle. Staining is occasionally present in endothelial cells of glomeruli. We note that cell type and subcellular distributions of Na+,K+-ATPase, ankyrin, and fodrin were similar.
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Discussion |
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Differential distribution of Na+,K+-ATPase, ankyrin, fodrin, E-cadherin, ZO-1, - and ß-catenin, plakoglobin, desmoplakin, laminin A, and
6-integrin along the kidney nephron has been previously described in the mouse (
Tight Junction Complex Proteins
On the basis of previous physiological measurements of tight junction function, tight junction proteins would be expected to be more strongly expressed in distal nephron, where paracellular permeability is low, compared to proximal tubule segments, where permeability is high (
Recently, occludin has been identified as an integral membrane protein of the tight junctions (
CellCell Adhesion Proteins
Immunohistochemical staining of mouse kidney showed that - and ß-catenin are distributed to the basal membrane and apical junctional complex in proximal tubule cells, and to the basolateral membrane with additional cytoplasmic staining in cells of the distal nephron (
- and ß-catenin in human kidney were similar to those in mouse (see Figure 8). However, cells of the human nephron exhibited more distinct lateral staining for
- and ß-catenin throughout the nephron. A stringy or serpiginous pattern of staining, corresponding to convoluted lateral membrane interdigitation of proximal tubule cells, was frequently noted in human kidney.
Na+,K+-ATPase, Ankyrin, and Fodrin
The cellular distribution and staining intensity of Na+,K+-ATPase in mouse kidney correlated well with the description of Na+,K+-ATPase enzymatic activity along the nephron (1-subunit of the Na+,K+-ATPase, and the fixation/staining protocol used to detect the distribution of Na+,K+-ATPase in human kidney were the same as those used in the mouse kidney (
Previous studies have demonstrated that Na+,K+-ATPase, ankyrin, and fodrin bind with high affinity to form a complex, and it has been proposed that the interaction between Na+,K+-ATPase and the membrane-associated cytoskeleton is important for restricting the distribution of Na+,K+-ATPase to a specific domain of polarized epithelial cells (
There are several examples of studies indicating abnormal distribution of proteins in human renal diseases (eg. 6-integrin interaction for epithelial polarization in developing tubules and a contributory role of redistribution of
3- and ß1-integrin to the apical membrane in the pathophysiology of ischemic injury to the kidney has been proposed (
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Acknowledgments |
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Supported by grants R01 DK50712 and M01-RR00070 from the National Institutes of Health. Dr Kwon's postdoctoral fellowship was supported by the Satellite Dialysis Centers Fund in Nephrology.
Received for publication April 15, 1998; accepted August 10, 1998.
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