1 Department of Pediatrics, The Ohio State University, and Children's Research Institute, Children's Hospital, Columbus, Ohio 43205; and 2 Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa 52242
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ABSTRACT |
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Somatostatin is known to modulate mesangial and tubular cell function and growth, but the somatostatin receptor (sst) subtypes responsible for these effects have not been defined. There are at least five different sst receptor subtypes (sst1-sst5). We used RT-PCR to demonstrate that normal human kidney consistently expresses mRNA for sst1 and sst2 (9 of 9 donors). Some donors expressed sst4 or sst5 mRNA, but none expressed sst3 mRNA. Expression of sst1 and sst2 was further assessed by staining serial sections of normal human kidney with sst1 and sst2 antisera, Arachis hypogaea (AH) lectin (to define distal tubule/collecting duct cells), Phaseolus vulgaris lectin (proximal tubules), and Tamm-Horsfall protein (THP) antiserum (thick ascending limb of the loop of Henle). Specificity of antisera was demonstrated by transfection and absorption studies. Sst2, but not sst1, was expressed in glomeruli. Intense sst1 and sst2 staining localized exclusively to AH+ and THP+ tubules. Thus sst1 and sst2 subtype-selective analogs may be useful to beneficially modulate renal cell function in pathological conditions.
somatotropin release inhibitory factor; renal; mesangium; immunohistochemistry; reverse transcriptase-polymerase chain reaction
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INTRODUCTION |
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SOMATOSTATIN IS WELL RECOGNIZED for its role as a neuropeptide, a hypothalamic inhibitor of growth hormone release, and a paracrine inhibitor of gut peptide secretion (21). Somatostatin also serves to modulate renal cell function and growth. Intravenous infusion of somatostatin decreases glomerular filtration rate, renal plasma flow, urine volume (40), and osmotic and free water clearance (34, 40). Furthermore, somatostatin increases the fractional excretion of sodium and phosphate while decreasing plasma renin activity and urinary excretion of PGE2, dopamine, epinephrine, and other vasoactive factors (34). Whereas some of the effects of systemic infusion of somatostatin are mediated by altering renal blood flow, several studies indicate that somatostatin also directly alters renal function at the cellular level. For example, somatostatin inhibits vasopressin-induced water permeability of microperfused rat papillae (22) and cAMP production in cultured rat renal collecting tubule cells (13). We have demonstrated that somatostatin inhibits epidermal growth factor-induced renal tubular cell proliferation (36). Somatostatin also inhibits serum-induced proliferation of rat mesangial cells (27) and ANG II-induced contraction of cultured human mesangial cells (3, 7, 8).
The ability of somatostatin to directly modulate renal cell function implies the presence of functional somatostatin receptors (sst) in the kidney. Hatzoglou et al. (10) demonstrated that opossum kidney (OK) tubular cells express somatostatin binding sites for octreotide by radioligand binding assays. High-affinity somatostatin binding sites were also detected in rabbit kidney extracts (26). There are at least five different somatostatin receptor subtypes (sst1-sst5). Mitsuma et al. reported that rat kidney expresses sst2 (16) and sst3 (15), but not sst1 (17) as assessed by immunohistochemistry. However, the kidney data were provided only in tabular form in these reports, so the segmental distribution of sst receptor expression in the rat kidney could not be ascertained.
In human kidney, Yamada et al. (41) detected sst1 and sst2 mRNA by Northern blot analysis. The majority of renal carcinomas express sites for somatostatin, as assessed by radioligand binding assays (24), and mRNA for sst2, as detected by RT-PCR (25, 39). Diez-Marques et al. (3) demonstrated specific binding of octreotide to cultured human mesangial cells corresponding to the ability of somatostatin to stimulate cGMP production and inhibit ANG II-induced mesangial cell contraction (8). Reubi et al. (23) detected specific binding of octreotide to human renal tubules, collecting ducts, and vasa recta by in situ radioligand binding assays.
The expression pattern of somatostatin receptor subtypes in different segments of the human kidney has not previously been described. This information is critical for developing strategies to utilize somatostatin subtype-selective analogs to beneficially modify renal transport functions or to treat renal diseases such as mesangial proliferative forms of glomerulonephritis. Herein, we report on somatostatin receptor subtype mRNA expression in normal human kidney for all five somatostatin receptor subtypes. We also demonstrate the segmental expression pattern of sst1 and sst2 by immunohistochemistry.
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METHODS |
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Tissue procurement. Kidney tissue was provided by The Ohio State University and Children's Hospital Cooperative Human Tissue Network with approval from Children's Research Institute Human Subjects Internal Review Committee. Specimens were obtained from normal kidney adjacent to a renal tumor or from cadaveric kidneys unsuitable for renal transplanation.
RT-PCR. RT-PCR was performed with previously described (2) oligonucleotide primers for all five sst receptor subtypes and c-abl, a tyrosine kinase protooncogene constitutively expressed in glomeruli and other cell types (2, 18, 30). Total RNA was isolated by using the TRIzol (GIBCO-BRL, Grand Island, NY) or RNAzol (CINNA/BIOTEX, Friendwood, TX) methods as described by the manufacturers. Total RNA (200 ng) was reverse transcribed with random hexamer primers followed by amplification of cDNA by PCR (GeneAmp kit; PerkinElmer Cetus, Norwalk, CT). For sst1-sst3, reaction mixtures were subjected to 33 cycles of 94°C for 1 min, 60°C for 2 min, and 72°C for 2 min For sst4, mixtures were subjected to 35 cycles of 94°C for 40 s, 62°C for 45 s, and 72°C for 1 min For sst5, PCR conditions included 1.5 mM MgCl2 and 1.5% deionized formamide; mixtures were subjected to 30 cycles of 94°C for 30 s, 64°C for 10 s, and 72°C for 1 min. After completion of PCR cycles, reactions were subjected to 72°C for 9 min. RT-PCR products were resolved by electrophoresis at 100 V through 1% agarose in 1× TAE (0.04 M Tris-acetate, 0.001 M EDTA, pH 8.0) and visualized with ethidium bromide.
Southern hybridization of sst receptor RT-PCR products. Southern analysis was used to confirm that sst1, sst2, and sst5 RT-PCR products contained the expected sst receptor subtype-specific sequences. As previously described (2), the Southern blot probes were complementary to regions of receptor cDNA nested between the binding sites for RT-PCR primers. The RT-PCR products were transferred to a nylon membrane and hybridized with the appropriate oligonucleotide probes that were 32P labeled with T4 polynucleotide kinase. Hybridization was performed in 50% formamide at 42°C overnight. The membranes were washed sequentially with 2× standard sodium citrate (SSC; 0.3 M sodium chloride, 0.03 M sodium citrate, pH 7.0) at room temperature, 2× SSC with 1% sodium dodecyl sulfate at 65°C, and then 0.1× SSC at room temperature. Bound 32P-labeled probe was detected by autoradiography. To control for nonspecific hybridization, c-abl RT-PCR products were also included on all blots.
Antisera preparation for immunohistochemistry of sst1
and sst2.
Antisera against sst1 and sst2 were generated
as previously described (2). Briefly, for generation of
sst1 antiserum, an oligonucleotide coding for the
NH2 terminal, 57 amino acids comprising the first
extracellular domain of sst1 were cloned into pET-32a(+) vector (Novagen, Madison, WI) as a COOH-terminal fusion to thioredoxin by using T4 DNA ligase (TA cloning kit, Invitrogen, Carlsbad CA). Similarly, an oligonucleotide corresponding to the NH2
terminal, 45 amino acids of sst2 were cloned into
pET-32a(+). After the truncated sst1 and sst2
peptides were expressed by AD494 bacteria (Novagen), peptides were
purified by using the Pharmacia HisTrap column system (Amersham
Pharmacia Biotech, Uppsala, Sweden). Rabbits were immunized with 500 µg of truncated sst1 or sst2 peptide in 0.5 ml 0.9% NaCl mixed with an equal volume of Freund's adjuvant. After
four boosts (100 µg peptide each) at 3-wk intervals, antisera were
collected and stored at 70°C.
Transient transfection. Expression vectors for sst1, sst2, and sst5 were generated as previously described (2). OK cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA) and cultured as directed. Cells were periodically tested for mycoplasma contamination by using an RT-PCR mycoplasma detection kit (ATCC). OK cells (5,000 cells per well) were plated in 8-well chamber slides (Fisher Scientific, Pittsburgh, PA) and transfected by using Effectene transfection reagent as directed by the manufacturer (Qiagen, Valencia, CA). Briefly, 0.4 µg of plasmid DNA were mixed with Effectene reagent in a 1:20 ratio of DNA to Effectene. Cells were incubated with the transfection mixture overnight at 37°C. After incubation in regular growth medium at 37°C for an additional 24 h, the cells were washed once with PBS and then fixed with ice-cold 100% methanol for 10 min.
Immunofluorescence of transfected cells. For immunofluorescent staining, cells were rinsed with PBS, then blocked with "Power Block" (Biogenix, San Ramon, CA) for 30 min at room temperature. Cells were then incubated with 300 µl of antisera or preimmune serum. Anti-sst1 serum was diluted in Diluent buffer (Biomedia, Foster City, CA) 1:1,000 while anti-sst2 serum was diluted 1:2,000. For blocking studies, antisera were preincubated for 2 h at room temperature with 50 µg/ml of immunizing peptide. The mixtures were then subjected to centrifugation at 17,000 g at 4°C for 10 min, and the supernatant was used for staining. After incubation with antisera or preimmune serum at 37°C for 1 h, cells were washed three times with OptiMax wash buffer (Biogenix, San Ramon, CA). Cy3-conjugated affinity-purified anti-rabbit IgG antiserum (Jackson Laboratories, West Grove, PA) diluted 1:500 was then applied. After incubation for 1 h at 37°C in the dark, cells were washed three times with wash buffer. After being coverslipped with Vectashield mounting medium (Vector Laboratories, Burlingame, CA), cells were photographed with an Optronics Magnafire digital camera mounted on a Leica DMLB microscope.
Immunohistochemical staining of normal human kidney. For immunohistochemical analysis of sst1 and sst2 expression, 4-µm sections of paraffin-embedded normal human kidney were placed on charged slides and deparaffinized. To block endogenous peroxidase activity, slides were incubated with PeroxiDaze 1 (Biocare Medical, Walnut Creek, CA) for 15 min at room temperature. Endogenous biotin was blocked by incubating sections in avidin-blocking solution for 15 min followed by biotin-blocking solution for 15 min (Vector Laboratories). Sections were then incubated in Power Block for 10 min. Antisera were diluted and absorbed with immunizing peptide as described above. Slides were incubated with preimmune serum or antisera at 4°C overnight. Sections were then processed with the "super sensitive multilink" staining system as described by the manufacturer (Biogenix). Briefly, after slides were washed three times, biotinylated secondary antibody was applied for 20 min at room temperature. Slides were then washed three times in wash buffer for 20 min each wash, followed by incubation in peroxidase-conjugated streptavidin for 20 min. After washing of slides three times for 20 min each, 3-amino-9-ethyl-carbazole chromogen was applied for 3 to 10 min depending on development of slides. Staining was stopped by immersion in distilled water. Slides were counterstained with hematoxylin for 10 s, rinsed in water, immersed in ammonia water for 15 s, and then cemented with Crystal Mount (Biomedia), placed on a 60°C surface for 15 min, coverslipped with Permamount (Biogenix), and photographed as described above.
To determine which tubular segments express sst1 and sst2, serial sections were also stained with Arachis hypogaea (AH) lectin (to define distal tubule/collecting duct cells), Phaseolus vulgaris (PHA-E) lectin (to define proximal tubules), and Tamm-Horsfall protein (THP) antiserum (to define the thick ascending limb of the loop of Henle) (19). Lectins were obtained from Sigma (St. Louis, MO). For THP staining, a goat anti-THP (anti-human uromucoid) antiserum (Cappel/ICN, Costa Mesa, CA) was used at a 1:100 dilution. THP staining was performed as for anti-sst receptor staining except that a 1:100 dilution of biotinylated anti-sheep IgG (Vector) was used instead of the BioGenix multilink secondary antibody. For lectin staining, sections were prepared and blocked as for immunostaining. Sections were then incubated with biotinylated AH lectin or PHA-E lectin. Biotinylated AH and PHA-E were diluted to 0.01 mg/ml and 0.002 mg/ml, respectively. After incubation at room temperature for 1 h, slides were washed three times in wash buffer for 20 min each wash, followed by incubation in peroxidase-conjugated streptavidin for 20 min. Slides were then processed as for immunohistochemistry. To determine the fraction of tubules coexpressing somatostatin receptor and THP, AH lectin, or PHA-E lectin, the same region of serial sections was photographed for each stain. Four separate regions were photographed, magnified, and then compared. All stained tubules in one serial section that could be clearly identified in a corresponding serial section by local landmarks were evaluated. ![]() |
RESULTS |
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Human kidneys express mRNA for several somatostatin receptor
subtypes.
For RT-PCR analysis, kidney tissue from nine different donors was
tested. These donors ranged in age from childhood to 69 yr of age and
were evenly distributed between male and female donors (Table
1). Unfortunately, racial information on
the donors was not provided with the procurement information.
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Immunohistochemical assessment of sst1 and
sst2 expression in normal human kidney.
We next tested for expression of sst1 and sst2
by immunohistochemical staining. To document that the
anti-sst1 and anti-sst2 antisera bind
specifically to the appropriate sst receptor subtype in kidney cells,
opossum kidney (OK) cells were transfected with sst1,
sst2, or sst5 expression vectors and then
assessed for binding by anti-sst1 or anti-sst2
antisera by using immunofluorescence (Fig.
3). The antisera reacted only with cells
transfected with the corresponding sst receptor expression vector. This
result indicates that the antisera do not cross-react with other
somatostatin subtypes. In addition, the specificity of the antisera was
demonstrated by the ability of the immunizing peptide to block binding
of the corresponding antisera to transfected cells (Fig. 3).
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DISCUSSION |
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In this study, we discovered that somatostatin receptor subtypes 1 and 2 are expressed widely throughout the distal nephron and collecting duct in normal human kidney. The physiological source of somatostatin that might bind to these receptors is not known. We previously reported that freshly isolated human renal cortex and cultured human mesangial and tubular epithelial cells express somatostatin mRNA and that mesangial and tubular cells secrete somatostatin peptide (35, 37). The finding that renal cells produce somatostatin and express somatostatin receptors implies that somatostatin may modulate renal function in an autocrine/paracrine manner. In addition, circulating somatostatin may modulate renal function. Fasting plasma somatostatin concentrations are less than 0.02 nM in normal plasma samples (20), which is below the 0.5 nM equilibrium dissociation constant (Kd) calculated for somatostatin receptors in intact human kidney (23). However, somatostatin filtered from the circulation or secreted into the urinary space could modulate downstream tubular cell function.
The finding that sst1 and sst2 are expressed predominately in the distal nephron and collecting duct implies that these receptors play an important role in renal function, perhaps for tubular transport or regulation of cell proliferation and differentiation. Somatostatin inhibits contraction of human mesangial cells (7, 8), vasopressin-induced water permeability of microperfused rat papillae (22), cAMP production in cultured rat renal collecting tubule cells (13), and proliferation of OK proximal tubular cells (10), human renal tubular cells (36), and rat mesangial cells (27).
In addition to these effects, somatostatin may have other direct effects on renal cell function and gene expression because somatostatin receptors are linked to a multitude of intracellular signaling pathways. For example, depending on which sst receptor subtype and G proteins are expressed in various cells, somatostatin can lead to inhibition of adenylate cyclase, to stimulation of tyrosine or serine/threonine phosphatase activity, activation of guanylate cyclase, or to modulation of calcium or potassium fluxes (8, 21, 41). Somatostatin also directly inhibits insulin-like growth factor-1 (IGF-1) synthesis (29) and modulates expression of IGF-1 binding protein-1 (6). Furthermore, somatostatin leads to inhibition of c-fos transcription and AP-1 DNA binding (31-33). The widespread expression of somatostatin receptors in the kidney implies that somatostatin plays an important role in regulating renal cell function. Therefore, future studies aimed at understanding how somatostatin modulates kidney function, growth, and development in normal and pathological states are highly warranted.
The availability of somatostatin receptor subtype-selective analogs may allow precise manipulation of the response of renal cells to somatostatin. In recent years somatostatin analogs have been used in the treatment of a wide variety of diseases (21). These analogs have been found to be exceptionally safe and cause relatively few side effects. We propose that somatostatin analogs may be useful to treat several renal disorders. The capacity of somatostatin analogs to inhibit proliferation of tumor cells, which correlates with sst receptor expression, is presently being utilized clinically to treat sst receptor-positive tumors (11). Our observation that somatostatin inhibits renal tubular cell proliferation (36) and the fact that sst receptor binding sites are present on 72% of renal cell carcinomas (24) indicates that somatostatin analogs may be useful for diagnosis and treatment of this malignancy (4). Somatostatin not only inhibits proliferation of cultured rat mesangial cells (27), it also decreases mesangial cell proliferation in vivo after subtotal nephrectomy in rats (38). Because many forms of acute glomerulonephritis, including IgA nephropathy, membranoproliferative glomerulonephritis, and proliferative lupus nephritis, are characterized by excessive mesangial cell proliferation (1), somatostatin analogs may be useful for inhibiting excessive mesangial cell proliferation in such diseases.
Systemic administration of the somatostatin analog octreotide (100 µg twice per day) for 6 mo after induction of diabetes with streptozotocin in rats decreases renal hypertrophy and urinary albumin excretion (5). Similarly, Igarashi et al. (12) reported that octreotide treatment decreased albuminuria in diabetic rats. Furthermore, Gronbaek et al. (9) demonstrated that after three mo of untreated streptozotocin-induced diabetes, the combination of octreotide and captopril (an angiotensin converting enzyme inhibitor) was superior to captopril alone in reducing urinary albumin excretion and renal growth. Although such animal studies of diabetic nephropathy are promising, results in small clinical trials have been variable (14, 28). However, as more knowledge is gained about the renal effects of somatostatin and somatostatin receptor expression, use of somatostatin analogs may be optimized to achieve results in humans that are similar to the results obtained in animal models of diabetic nephropathy.
We speculate that the binding of somatostatin to sst1 compared with sst2 will have distinct effects. The lack of staining for sst1 in the glomerulus suggests that only sst2-selective analogs will influence mesangial cell function. The regulation of sst receptor expression in the kidney is not known. Thus the pattern of sst receptor subtype expression may be altered under pathological conditions. Because somatostatin influences a multitude of signaling pathways, it is clear that as more is elucidated about how somatostatin impacts on renal signaling pathways, and how renal somatostatin receptor expression is regulated, novel methods to use sst receptor subtype-selective somatostatin analogs to modulate renal cell function in pathological conditions will be developed.
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ACKNOWLEDGEMENTS |
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We thank Courtney A. Apple for superb technical help and Carl M. Bates for helpful review of the manuscript.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK-51707 (M. A. Turman) and The Children's Research Institute, Children's Hospital, Columbus, Ohio (M. A. Turman).
Address for reprint requests and other correspondence: M. A. Turman , Section of Nephrology, Children's Hospital, 700 Children's Drive, Columbus, OH 43205 (E-mail: mturman{at}chi.osu.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.
Received 2 August 2000; accepted in final form 1 November 2000.
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