SBA-Positive Fibers between the CD Ampulla, Mesenchyme, and Renal Capsule
Karl Schumacher*,
Raimund Strehl*,
Uwe de Vries*,
Hermann Josef Groene and
Will W. Minuth*
*Department of Anatomy, University of Regensburg, Regensburg, Germany; Department of Cellular and Molecular Pathology, DKFZ, Heidelberg, Germany.
Correspondence to Dr. Karl Schumacher, University of Regensburg, Department of Anatomy, Universitätsstrasse 31, D-93053 Regensburg, Germany. Phone: 49-941-943-2875; Fax: 49-941-943-2868;
ABSTRACT. During kidney development, the CD shows two peculiarities.First, the tip of the CD ampulla is always found at a specificdistance from the organ capsule. Second, the CD growth occursas a perfectly straight elongation. It is unknown whether theCD-specific growth is dependent on hormonal action or on structuralelements. Histochemical experiments on neonatal rabbit kidneyyielded new insight into the interface of the CD ampulla andthe surrounding nephrogenic mesenchyme. Incubation of tissuesections with soybean lectin (SBA) showed the existence of fibersextending in a radial course from the ampullar tip through themesenchyme toward the organ capsule. SBA labeling did not colocalizewith collagen type I, III, IV, V, and VI, laminin, fibronectin,and tenascin. It is assumed that while the kidney increasesin volume the structural fixation of the ampullar tip by theSBA-positive fibers causes CD ampullae to maintain a constantdistance from the organ capsule. The connection would explainthe linear extension of the CD in relation to the organ capsule.In addition, the presented data suggest that the SBA-positivefibers between ampullar tip and organ capsule create a structuralmicrocompartmentation of the nephrogenic zone. E-mail: karl.schumacher@vkl.uni-regensburg.de
Ingrowth of the ureteric bud into surrounding nephrogenic mesenchymemarks the onset of metanephros development (1). The first dichotomousbranching determines the kidney poles. Subsequent branchingsform the three-dimensional structure of the later renal pelvis.In contrast to these early structural branchings, later branchingsof the uretric bud give rise to nephrons. The initial CDs withtheir blindly ending ampullae develop from the uretric bud,and the process of nephrogenesis sets in. The CD ampullae inducecompetent cells within the surrounding mesenchyme, which condensateto form comma-shaped and later S-shaped bodies (1,2). By furtherdichotomous branching and successive elongation of the CD, theampullae are pushed further into the uninduced mesenchyme towardthe capsule, where the next generation of nephrons is generated.Cellular interactions during CD arborization (branching morphogenesis)and nephrogenesis have been studied extensively by morphologic(3–6), cell biologic (7–11), and molecular biologic(12–13) methods.
Throughout metanephros development the elongation and branchingof the CD determines the layout for the three-dimensional histoarchitectureof the kidney. In a corticomedullary section of the neonatalrabbit kidney, the directional growth of the CD straight towardthe capsule contrasts with the surrounding highly convolutedtubules (Figure 1a). Impaired CD development leads to a reducednumber of CD ampullae (14), which in turn leads to a decreasein nephron formation (8), segmental atrophy (Ask-Upmark-syndrome)(15), and eventually to the formation of cysts (16). It couldbe demonstrated in renal tissue cultures that transforming growthfactor– (TGF-) leads to an increased branching rate ofthe CD (17), whereas TGF- leads to a decrease (18). HGF representsanother inhibiting signal via its receptor cMET. These signalsare transduced by protein kinase C, a cAMP-dependent proteinkinase and phosphoinositol-3-kinase (19,20).
Figure 1. Hematoxylin-eosin–stained section of the cortex of neonatal rabbit kidney. (a) The maturing collecting duct (CD) ends in an ampulla (black arrowhead) underneath the organ capsule. Laterally a developing nephron (arrow) can be observed. (b) Schematic drawing illustrating how individual ampullae as well as dichotomous branchings maintain a constant distance from the organ capsule.
There must be a specific reason why the CD exhibit directionalgrowth from the medulla out to the cortex corticis while neighboringnephron segments, such as proximal and distal tubule, form convolutes.Directional growth of the CD cannot be explained by action ofmorphogens, growth factors, or extracellular matrix alone, butthere must be a master-system that determines the histoarchitecturallayout in form of a superordinated morphogenic field (21,22).Directional growth as observed in the CD is unique for the kidneyand can be found neither in excretory ducts of salivary glandsnor in bile duct, bronchial branching, or duct system of theexocrine pancreas. All these organs develop by branching morphogenesisalone, whereas the kidney is formed by a combination of branchingmorphogenesis and nephrogenesis.
In recent years knowledge of molecular interactions betweennephron inducer and the surrounding nephrogenic mesenchyme hasincreased (Table 1). However, there is little data on morphologicfeatures of the interface between these tissues (3,5,6). Ithas been assumed in the past that nephrogenic mesenchyme israndomly arranged around the tip of the CD. It has also beenassumed that the ampulla finds its way by itself. Using morphologicand immunohistochemical methods we could demonstrate for thefirst time that a structural connection exists between the ampullartip and the renal capsule. As the kidney increases in size,we assume that this mechanism could help the ampullar tips maintaintheir orientation toward the capsule. This could explain thelinearity of growth that is observed in CD.
Tissue Preparation and Light Microscopy
One-day-old New Zealand rabbits were anesthetized with etherand killed by cervical dislocation. Both kidneys were removedimmediately. The kidneys were then cut precisely along the corticomedullaryaxis. Human renal tissue was obtained from an anencephalic malefetus at week 14 of pregnancy and from a fetus at week 20 ofpregnancy. Neonatal rabbit kidney and human fetal kidney (week20 of pregnancy) were fixed in paraformaldehyde and embeddedin paraffin. Sections were subsequently stained with hematoxylin-eosin.
Lectin Incubation
Corticomedullary oriented cryosectins (8 µm) of neonatalrabbit and human fetal kidney (week 14 of pregnancy) were preparedusing a cryomicrotome (Microm, Heidelberg, Germany). Fixationin ice-cold ethanol was followed by washing steps in phosphate-bufferedsaline (PBS). The sections were then incubated in blocking solution(PBS + 1% bovine serum albumin [BSA] + 10% horse serum) for30 min. The fluorescein-isothiocyanate (FITC)–conjugatedlectin Soybean Agglutinin (SBA; Vector Laboratories, Burlingame,VT) was applied 45 min in blocking solution 1:4000. SBA preferentiallybinds to oligosaccharide structures with terminal - or -linkedN-acetylgalactosamine and to a lesser extent galactose residues.After several washes in PBS, the specimens were embedded withSlow Fade Light Antifade Kit (Molecular Probes, Eugene, OR)and analyzed using an Axiovert 35 microscope (Zeiss, Oberkochen,Germany).
Co-Incubation Experiments
Co-incubation experiments were performed with SBA and mousemonoclonal antibodies, which recognize specifically rabbit typeI and III collagen (Medicorp, Montreal, Canada). To reveal thebasal aspect of the CD ampulla, mab anti-PCDAmp 1 (6) was appliedtogether with FITC-conjugated soybean agglutinin. Corticomedullaryoriented cryosectins (8 µm) of neonatal rabbit kidneyswere fixed in ice-cold ethanol and rinsed three times with PBS.Sections were blocked with 10% horse serum and 1% BSA in PBS.Type I collagen antibody diluted 1:800 or type III collagenantibody diluted 1:4000 were applied for 1 h. After rinsingthree times with PBS containing 1% BSA, the sections were incubatedwith Texas Red conjugated donkey/anti mouse IgG (diluted 1:200;Jackson Immunoresearch, West Grove, PA) as secondary antibodytogether with FITC-conjugated SBA (diluted 1:4000) for 45 min.After washing in PBS, the sections were embedded with a SlowFade Light Antifade Kit (Molecular Probes). The incubated sectionswere examined with an Axiovert 35 microscope (Zeiss, Oberkochen,Germany).
Culture Experiments
Cortical explants from kidneys of newborn New Zealand rabbits(up to 1-d-old) were isolated according to methods describedearlier (25). The explants consisted of a piece of capsule fibrosawith adherent CD ampullae, S-shaped bodies, and nephrogenicblastema, which were mounted in tissue carriers. The tissuewas placed in a 24-well plate containing Iscove’s modifiedDulbecco’s medium (IMDM; Life Technologies-BRL Life Technologies,Eggenstein, Germany) including 10% FBS (Boehringer, Mannheim,Germany) for 24 h in an incubator (5% CO2/95% air). The tissuecarriers were subsequently transferred into a perfusion culturecontainer (Minucells and Minutissue, Bad Abbach, Germany). IMDM(order #21980-032; Life Technologies BRL-Life Technologies)containing aldosterone (1 x 10-7 M; Sigma-Aldrich-Chemie, Deisenhofen,Germany) and 1% antibiotic-antimycotic solution (Life TechnologiesBRL-Life Technologies) was continuously perfused for 14 d ata rate of 1 ml/h with an IPC N8 peristaltic pump (Ismatec, Wertheim,Germany). The waste medium was collected separately in bottles.
Microdissection Procedure
CD ampullae with S-shaped bodies from cortical explants of newbornNew Zealand rabbit kidneys were microdissected under opticalcontrol of a KL 1500 stereomicroscope (Leica, Solms, Germany).The microdissected material was transferred to a microscopeslide and fixed in ice-cold ethanol. After incubation with FITC-conjugatedSBA (diluted 1:4000 in blocking solution), the specimens werecovered by a cover glass and examined with an Axiovert 35 microscope(Zeiss, Oberkochen, Germany).
Light microscopical analysis of the embryonic cortex of neonatalrabbit kidney shows that CD exhibit linear growth from the medullato the subcapsular region (Figure 1a). CD run evenly spacedand in parallel. The ampullar tips are found at an average distanceof 20 µm beneath the capsule (Figure 1b). This distanceis maintained whether ampullae are in the process of branchingor not.
Light microscopical analysis shows a wide cleft around the CDampullae spatially separating the nephron inducer and the competentmesenchyme (Figure 2, a and d). This cleft is not species-specificbut can be observed in neonatal rabbit kidney (Figure 2a) andin embryonic human kidney, week 20 of pregnancy (Figure 2d),mouse and rat as well (1,10,16). There is no close contact betweenthe two tissues. It is obvious that contacts between mesenchymalcell processes and epithelial cells are not frequent. Earlierinvestigations by Lehtonen et al. (48) and by our group (6)have demonstrated the existence of a characteristic extracellularmatrix at this site. The basal aspect of the CD ampulla differsfrom the matrix surrounding other tubules. Measurements yieldedthat the matrix layer around the ampullar tip averages 1.6 µm(0.2 to 3.1 µm) in thickness.
Figure 2. Microscopical micrographs of the epithelial-mesenchymal interface. A light-microscopically visible cleft (arrow) between CD ampulla and the surrounding mesenchyme exists both in the neonatal rabbit kidney (a) and in the embryonic human kidney (week 20 of pregnancy) (d). Histochemical incubation with soybean lectin (SBA) revealed that SBA-positive fibers (arrow) extend through this cleft toward the organ capsule in neonatal rabbit kidney (b) as well as in embryonic human kidney (e). Details illustrating SBA-positive fibers (arrow) at the epithelial-mesenchymal interface in neonatal rabbit kidney (c) and in human embryonic kidney (f). A, CD ampulla; CF, fibrous organ capsule.
The CD ampulla plays an important role during the histoarchitecturallayout of the organ during kidney development. As the kidneyincreases in size, the necessary elongation of the CD is drivenby cell divisions in the ampullar neck zone. The CD ampullamaintains a constant distance to the renal capsule and doesnot deviate from linear elongation (Figure 1). Obviously, thisis possibly due to a structural connection between the CD ampullaand the renal capsule. Present immunohistochemical incubationswith soybean agglutinin (SBA) show the existence of fibers runningfrom the ampullar tip to the capsule. These fibers can be demonstratedin neonatal rabbit (Figure 2, b and c) as well as in human embryonickidney, week 14 of pregnancy (Figure 2, e and f).
Analyzing the cortex of neonatal rabbit kidney after SBA incubationreveals that the fiber network is exclusively found betweenthe CD ampulla, the surrounding mesenchyme, and the coveringorgan capsule (Figure 3a). Downward to the ampullar neck andshaft, no SBA-positive fibers are visible. Around the cortical(Figure 3a) and medullary CD (Figure 3b), no SBA-positive fiberscan be detected. The interstitium of matured kidney is completelyfree of SBA-positive fiber material. Only in the renal pelvis,some SBA positive fibers can be seen beyond the epithelium (Figure 3c).
Figure 3. Distribution of SBA labeling in neonatal rabbit kidney. (a) Embryonic zone: the lectin particularly labels fibers (arrow) at the basal aspect of the CD ampulla (A) that head for the organ capsule (CF). SBA-positive fibers are absent in half-matured tissue. (b) Matured zone: the basal aspect of medullary CD (MCD) and thin limbs of loop of Henle (HL) reacts strongly with SBA. (c) Renal pelvis region: SBA binds to epithelial cells of the renal pelvis. Few fibers (arrow) are strongly positive for SBA in the tissue that surrounds the renal pelvis epithelium (RP).
Earlier immunohistochemical assays showed that PCDAmp1 (6) iscolocalized with osteopontin (45) in the extracellular matrixaround the ampulla. Both proteins are strongly expressed atthe ampullar tip while their expression decreases along thematuring CD. Several other proteins and proteoglycans can befound at the basal aspect of the CD ampulla, whereas only tenascinand fibronectin are expressed in the surrounding mesenchyme(Table 1). We consequently investigated whether the SBA-positivefibers contain known proteins at this site. Double-labelingof the tissue shows that the extending fiber material is notpositive for PCDAmp1 (Figure 4a), collagen type I (Figure 4c),and collagen type III (Figure 4e), but it is positive for SBA(Figure 4, b,d, and f). Further colocalization experiments revealedthat SBA-positive fibers do not colocalize with collagen IV,V, and VI, laminin, fibronectin, and tenascin (no figure).
Figure 4. Colocalization experiments of SBA-positive fibers with PCD Amp1, collagen type I and III. (a) PCD Amp1 is expressed at the basal aspect of the CD ampulla (asterisks). (b) No colocalization could be observed with extending SBA-positive fibers. Collagen type I (c) and III (e) antibodies react strongly with fibers located in the region of organ capsule. However, a reaction with SBA-positive fibers present between CD ampulla and the organ capsule could not be observed (d and f).
Microdissection experiments were performed to answer the questionof whether SBA-positive fibers are visible when the ampullaeare microsurgically isolated by forceps (Figure 5, a and b).Whole mount labeling of an isolated dichotomous branched CDampulla shows numerous fibers at the outside of the ampullartip. After preparation, the SBA-positive fibers remain attachedto the surface and are not lost in the surrounding mesenchyme(Figure 5a). Higher magnification of the explants gave the impressionthat the fibers are not randomly distributed but focused toindividual focal points in the basement membrane (Figure 5b).Culture experiments should further reveal how far SBA-positivefibers are maintained or lost during culture. The tissue explantsdemonstrated that the majority of cultured ampullae lost theSBA-positive fibers during a 14-d perfusion culture period (Figure 5c).However, only in a few ampullae could SBA-positive fibersbe detected with reduced fluorescence signal compared with freshlyisolated tissue.
Figure 5. SBA incubation of microdissected CD ampulla (A). (a) Both ends of a branching CD are labeled with SBA. The SBA-positive fibers remain fixed at the basal aspect of the CD ampulla. (b) Higher magnifications show fibers that originate from the CD ampulla (asterisks). (c) Culture experiments: after 14 d of culture under serum-free conditions, the CD ampullae (A) and fibers (arrow) are still present in the renal cortical explants. However, the signal for SBA binding to the fibers appears reduced.
Induction of nephrons is triggered between the ampulla tip ofthe CD and the surrounding nephrogenic mesenchyme. Althoughthe initial inductive signal is not yet discovered, subsequentcell biologic interactions between both tissues have been investigatedin great detail (7,9,11,12,13,19,26,39). It is further unknownto date whether nephrogenesis is initiated solely by an exchangeof soluble factors (10,33) or by direct cell-cell contacts,as demonstrated in transfilter experiments (49), or by a combinationof both.
The present morphologic results of embryonic renal tissue showthat mesenchymal cells are not randomly distributed around theampulla tip (Figure 2) and that a distinct space is presentat the interface of the CD ampulla and the surrounding mesenchyme(Figure 2, a and d). SBA-positive fibers are demonstrated toprotrude from the basal aspect of the CD ampulla tip throughthe mesenchyme toward the capsula fibrosa (Figure 2, b, c, e, and f).The fibers originate from the ampulla tip, a regionwhere WNT-11 (7), ret (12,41), osteopontin (45), and PCDAmp1 (6) are exclusively expressed (Figure 6a).
Figure 6. (a) Schematic representation of structural elements between the CD ampulla (A), the nephrogenic mesenchyme (M) and the organ capsule (CF). SBA-positive fibers (F) are present between the basal aspect of the ampulla and the capsule. Along their course, the fibers come in contact with mesenchymal cells. The ampullar tip expresses WNT-11 (o) and ret (x). S, S-shaped-body. (b) Hypothetical illustration of growth in renal CD. (1) The CD elongates by cell divisions in the ampullar neck region. (2) During kidney development, fibers could cause a connection between the ampullar tip and the renal capsule. (3) Cellular processes, such as filopodia and lamellopodia, could use these extracellular fibers as guide structures.
Experiments of Mounier et al. (5) in human fetal kidney revealedthat type I and III collagens are absent in the mesenchyme surroundingthe ampulla tip. These findings are confirmed by our resultsin neonatal rabbit kidney (Figure 4, c and e). In addition,type I and III collagens do not colocalize with SBA-positivefibers (Figure 4, d and f). Further colocalization experimentsrevealed that SBA-positive fibers do not colocalize with collagenIV, V, and VI, laminin, fibronectin, and tenascin (no figure).It is a new finding that fibers labeled by SBA originate radiallyfrom the ampullar tip, through the surrounding mesenchyme, andtoward the capsula fibrosa (Figure 6a). In our opinion, thesefibers lead to a structural microcompartmentation between thenephron inducer and the surrounding mesenchyme (Figure 2, b and e).In addition, the described fibers may help answer questionsconcerning cellular communication and spatial relations duringnephrogenesis. For example, mechanical fixation of the ampullartip at the capsule by the SBA-positive fibers could maintaina constant spatial relation between CD ampulla and mesenchymethroughout organ growth. It is known that longitudinal growthof tubules takes place along a basement membrane that displaysembryonic characteristics and contains 1-laminin, 5-laminin(3,23), and fibronectin (5). However, it is unknown how thedirection of tubular growth is determined. It can be assumedthat the CD ampulla is attracted by secreted factors or hormonalaction from the surrounding mesenchyme to grow toward the organcapsule. Factors like HGF, which promotes CD growth, could actin this fashion (11). In this case, the hormone-secreting cellshave to remain at a constant distance to the ampulla. The maintenanceof this position nearby the ampulla could be attributed to extracellularstructures, which are revealed by the SBA labeling. Straighttubular elongation requires synchronized cell divisions to occurin opposing walls. If more divisions occur in one wall site,a change of growth direction would inevitably result. The growingduct would slant toward the side where fewer divisions takeplace. Therefore modulation of the frequency of cell divisioncould very well be a mechanism to determine directional growthand convoluted growth. Regulation of cell division in combinationwith a structural connection in form of SBA-positive fiberswould lead to the perfect linear growth.
Further, cellular processes such as filopodia and lamellopodiacould use these extracellular fibers as guide structures togrow along (Figure 6b). Microscopic processes originating fromampullar epithelial cells could follow the three-dimensionalmatrix scaffold to reach mesenchymal cells and exchange morphogenicsignals (15). Such cellular processes have not been discoveredin the embryonic kidney so far. However, transfilter tissueculture experiments have demonstrated the formation of processesbetween spinal cord and nephrogenic mesenchyme during induction.If pore size is reduced so that processes cannot establish cell-cellcontacts, no induction of tubules takes place (49).
Our current data show for the first time structural elementsbetween the CD ampulla, the nephrogenic mesenchyme, and theorgan capsule. Ongoing experiments will show when these fibersappear during development, which kind of cell synthesizes them,what their molecular makeup is, and how the fibers are rearrangedduring dichotomous branching of the CD ampulla.
Acknowledgments
The skillful assistance of Mrs. L. Besl is gratefully acknowledged.
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Received for publication May 10, 2002.
Accepted for publication June 21, 2002.
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Abstract
Introduction
(TGF-
leads to a decrease (18). HGF represents another inhibiting signal via its receptor cMET. These signals are transduced by protein kinase C, a cAMP-dependent protein kinase and phosphoinositol-3-kinase (19,20). 
