Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney

Tianxin Yang1, Daniel E. Michele2, John Park1, Ann M. Smart1, Zhiwu Lin1, Frank C. Brosius III1, Jurgen B. Schnermann2, and Josephine P. Briggs1,2,3

Departments of 2 Physiology and 1 Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109; and 3 National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892


    ABSTRACT
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The discovery that 15-deoxy-Delta 12,14-prostaglandin J2 (15d-PGJ2) is a ligand for the gamma -isoform of peroxisome proliferator-activated receptor (PPAR) suggests nuclear signaling by prostaglandins. Studies were undertaken to determine the nephron localization of PPAR isoforms and their heterodimer partners, retinoid X receptors (RXR), and to evaluate the function of this system in the kidney. PPARalpha mRNA, determined by RT-PCR, was found predominately in cortex and further localized to proximal convoluted tubule (PCT); PPARgamma was abundant in renal inner medulla, localized to inner medullary collecting duct (IMCD) and renal medullary interstitial cells (RMIC); PPARbeta , the ubiquitous form of PPAR, was abundant in all nephron segments examined. RXRalpha was localized to PCT and IMCD, whereas RXRbeta was expressed in almost all nephron segments examined. mRNA expression of acyl-CoA synthase (ACS), a known PPAR target gene, was stimulated in renal cortex of rats fed with fenofibrate, but the expression was not significantly altered in either cortex or inner medulla of rats fed with troglitazone. In cultured RMIC cells, both troglitazone and 15d-PGJ2 significantly inhibited cell proliferation and dramatically altered cell shape by induction of cell process formation. We conclude that PPAR and RXR isoforms are expressed in a nephron segment-specific manner, suggesting distinct functions, with PPARalpha being involved in energy metabolism through regulating ACS in PCT and with PPARgamma being involved in modulating RMIC growth and differentiation.

15-deoxy-Delta 12,14-prostaglandin J2; reverse transcription-polymerase chain reaction; acyl-coenzyme A synthase; microdissected nephron segments


    INTRODUCTION
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ABSTRACT
INTRODUCTION
METHODS
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REFERENCES

PROSTAGLANDINS (PGs) are known to be important signaling molecules, formed in response to various extracellular stimuli by oxygenation and peroxidation of arachidonic acid. After secretion from cells, PGs act close to the site of formation. A large body of evidence has established that one mode of action of PGs is initiated by activation of cell surface receptors of the G protein receptor superfamily and subsequent changes in the level of the intracellular messenger molecules cAMP and/or Ca2+. This classic pathway probably mediates many of the known biological effects of PGs. Nevertheless, the complexity of PG signaling has been apparent from the unique properties of a group of cyclopentenone PGs that contain an alpha ,beta -unsaturated carbonyl group in the cyclopentenone ring. Members of this group have been shown to possess potent cytotoxic activities, the cellular mechanism of which does not seem to be explained by the classic pathway (9). It is known that the A and J series of PGs can be transported into the nucleus and can associate with nuclear proteins (24, 25). Recent studies by two separate groups demonstrate that the terminal metabolite of the J series of PGs, 15-deoxy-Delta 12,14-PGJ2 (15d-PGJ2), is a ligand for a nuclear receptor, the gamma -isoform of peroxisome proliferator-activated receptor, PPARgamma (8, 16). These findings suggest a role for PGs in PPARgamma -mediated nuclear signaling as an alternative to the classic signaling through PG surface receptors.

PPARs are a group of zinc-finger-containing transcription factors, a subfamily of the nuclear hormone receptor gene family. To date, three subtypes of PPARs have been described from several species: PPARalpha , PPARbeta (also called PPARdelta or NUC-1), and PPARgamma (15, 20, 27). Two PPARgamma isoforms, gamma 1 and gamma 2, differing only in a 30 NH2-terminal amino acid segment, have recently been characterized (23, 34). PPARs heterodimerize with retinoid X receptor (RXR) and regulate gene transcription after binding to peroxisome proliferator-responsive elements (PPREs) in the promoter region of target genes (21). Most of the known target genes of PPARs are involved in lipid metabolism (27).

The kidney is an active site for both production and action of PGs (6, 7), and Delta 12-PGJ2 has been found in human urine in significant quantities (13). Furthermore, all three members of the PPAR family are expressed in the kidney (3, 12). It is possible therefore that J series PGs may act through PPARs and regulate gene expression in kidney. Thus the present study was undertaken to determine the nephron localization of PPAR isoforms and their heterodimer partners, RXRs, and to test for biological activities of this system in the kidney.


    METHODS
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Animals and dissection methods. Microdissection of nephron segments was performed in kidneys of male Sprague-Dawley rats (~8 wk of age) as previously described (38). The following specimens were dissected: glomeruli, proximal convoluted tubules (PCT), proximal straight tubules, cortical thick ascending limb, medullary thick ascending limb (MTAL), cortical collecting ducts, outer medullary collecting ducts, and inner medullary collecting ducts (IMCD). In addition, the macula densa-containing segment (MDCS) was dissected by separating the terminal portion of the thick ascending limb, including the macula densa, removing the adherent glomerulus, and freeing the macula densa as much as possible of adjacent thick ascending limb cells. In general, 10 glomeruli, 10 MDCS, or 6-10 mm of other tubule segments were dissected and pooled to constitute one sample.

RNA isolation. RNA from glomerular and tubular samples was isolated as previously described (35). Briefly, glomerular and tubular samples were thawed in an ice slurry and sonicated for 15 s. Twenty micrograms of ribosomal RNA from Escherichia coli (Boehringer Mannheim, Indianapolis, IN) was added as carrier, and the sample in 100 µl of guanadine isothiocyanate buffer was layered onto a gradient of cesium chloride (100 µl of 97% and 20 µl of 40% cesium chloride in 25 mM sodium acetate buffer) in a 250-µl polycarbonate ultracentrifuge tube. Samples were centrifuged for 2 h at 300,000 g in an ultracentrifuge (model TLA 100; Beckman Instruments, Fullerton, CA) with a fixed-angle rotor. The RNA pellet was redissolved in 0.3 M sodium acetate and ethanol precipitated.

Total RNA from rat adult kidney slices and from mouse kidney at various stages of development was isolated using TRI-Reagent (Molecular Research Center). Tissue samples were homogenized in TRI-Reagent solution. After addition of chloroform and centrifugation, the homogenates separate into three phases: aqueous, interphase, and organic. RNA was precipitated from the aqueous phase by addition of isopropanol. Contaminating genomic DNA was removed with RNase-free DNase I (GeneHunter, Brookline, MA). The purified RNA was redissolved in diethyl pyrocarbonate-treated water containing 20 U of RNasin.

RT-PCR. Primer information with related references is shown in Table 1. RT-PCR was performed as previously described (35). Briefly, reverse transcription was performed in the presence of 100 U monkey murine leukemia virus reverse transcriptase (RT) (Superscript; BRL, Gaithersburg, MD), and 0.5 µg oligo(dT)12-18 (Pharmacia, Piscataway, NJ). The nucleotide sequences of primers used in these studies are shown in Table 1. PCR reactions were performed in a total volume of 50 µl in the presence of 5 pmol of each oligonucleotide primer, 200 µM dNTP, 10 mM dithiothreitol, 50 mM KCl, 1.5 mM MgCl2, 10 mM Tris · HCl, 0.001% gelatin, 1.25 U of AmpliTaq DNA polymerase, pH 8.3 (Perkin-Elmer Cetus, Norwalk, CT), and 1.5 µCi [32P]dCTP (Amersham, Arlington Heights, IL). The samples were first denatured at 94°C for 3.5 min followed by 32 PCR cycles as follows: 94°C for 1 min (melt), 58°C for 1 min (anneal), and 72°C for 1 min (extend). The last cycle was followed by additional extension incubation of 8 min at 72°C.

                              
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Table 1.   List and sequence of primers

Analysis of PCR products. After amplification, PCR products were subjected to size separation by polyacrylamide gel electrophoresis. The band intensity was determined by phosphoimaging with the Phosphor Analyst software on a GS-250 Molecular Imager System (Bio-Rad, Hercules, CA). To confirm the identity of the PCR products of the PPAR isoforms, the products were gel purified and directly sequenced using an ABI 373 DNA sequencer.

Cell culture. Characteristics and in vitro maintenance of renal medullary interstitial cells (RMICs) have been described previously (18). The present study has demonstrated the presence of lipid droplets in these cells by oil red O staining method (data not shown). Troglitazone and 15d-PGJ2 were dissolved in DMSO with a final concentration of 0.1% DMSO in culture medium. Control medium contained 0.1% DMSO. Cells were plated at a density of 4.3 × 104 cells/ml and were grown in RPMI medium supplemented with 5% FBS in the presence of 10 µM troglitazone, 1 µM 15d-PGJ2, or 0.1% DMSO. After incubation, the cells were trypsinized, and the cell number was counted at the times indicated. To examine the cell morphology, the cells were directly stained with fluorescein diacetate.


    RESULTS
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mRNA expression of PPARgamma isoforms in fat tissues and kidney. PPARgamma is known to have two isoforms, PPARgamma 1 and PPARgamma 2, which are alternatively spliced products of the same gene. PPARgamma 2 differs from PPARgamma 1 by a sequence of 30 additional NH2-terminal amino acids. Using a primer pair specific to PPARgamma 2 (Fig. 1A), the 100-bp PCR product specific for PPARgamma 2 was detected in fat tissue, but not in kidney, whereas the nonspecific 793-bp product was detected in both tissues (Fig. 1B), indicating that the isoform expressed in kidney is PPARgamma 1 and that PPARgamma 2 is absent.


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Fig. 1.   A: primer design for amplification of two peroxisome proliferator-activated receptor (PPAR) gamma -isoforms. B: RT-PCR from fat and kidney with two sets of primers: sense primer 1 and antisense primer 1 (S1 and AS1) are specific for PPARgamma 2, and sense primer 2 and antisense primer 2 (S2 and AS2) are common to both PPARgamma 1 and -gamma 2 isoforms.

Distribution of PPAR subtype mRNA in kidney regions. To amplify PPARalpha , -beta , and -gamma , primers were selected in divergent regions of the published cDNA sequences (Table 1). As shown in Fig. 2, products of expected size were obtained for the PPAR isoforms (523 bp for PPARalpha , 496 bp for PPARbeta , and 793 bp for PPARgamma ). PPARalpha mRNA was present in cortex, PPARgamma mRNA was present in inner medulla, and PPARbeta mRNA was present in both cortex and inner medulla. Product identity was confirmed by direct sequencing. When PCR for PPAR isoforms was performed in the absence of reverse transcription, there was no recognizable band, indicating the origination of the products from mRNA, not from genomic DNA (data not shown).


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Fig. 2.   Distribution of mRNAs of three PPAR subtypes (alpha , beta , and gamma ) in the kidney regions by RT-PCR. PCR products were separated on 5% polyacrylamide gel and analyzed by phosphoimage.

Nephron localization of mRNA of PPAR subtypes. RT-PCR for each PPAR isoform was performed on cDNA derived from microdissected nephron segments from 10-wk-old Sprague-Dawley rats. All three isoforms were tested in each sample, with four sets of determinations performed to localize isoform expression. Figure 3 shows a representative gel. Each isoform exhibited a unique and consistent distribution pattern. PPARalpha mRNA was detected in PCT, PPARgamma mRNA was found in IMCD, and PPARbeta mRNA was found in all nephron segments examined. RT-PCR of beta -actin was run to verify homogeneity of mRNA amounts in each sample. A single 351-bp band for beta -actin with similar intensity was detected in all samples.


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Fig. 3.   Localization of mRNA expression of three PPAR subtypes (alpha , beta , and gamma ) in isolated nephron segments of Sprague-Dawley rats. PCR for the three PPAR subtypes and beta -actin was performed on the same cDNA (representative example from 4 separate experiments). IMCD and OMCD, inner and outer medullary collecting ducts, respectively; CCD, cortical collecting duct; MDCS, macula densa-containing segment; CTAL and MTAL, cortical and medullary thick ascending limbs, respectively; PST and PCT, proximal straight and convoluted tubules, respectively; and Glm, glomeruli.

Nephron localization of mRNA of RXR subtypes. Since RXR is the required heterodimer partner of PPAR, we also examined the nephron localization of two isoforms of RXR, RXRalpha and RXRbeta . As shown in Fig. 4, RXRalpha mRNA was present predominately in PCT and IMCD, whereas RXRbeta was present in all nephron segments examined except MTAL.


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Fig. 4.   Localization of mRNA expression of two retinoid X receptor (RXR) subtypes (alpha  and beta ) in isolated nephron segments of Sprague-Dawley rats.

mRNA expression of PPARgamma in cultured kidney cell lines. RT-PCR for PPARgamma was performed on cDNA derived from cultured kidney cell lines including M-1 (30), mIMCD-K2 (32), and RMIC (18). PPARgamma mRNA was detected in all three cell lines tested, with relatively abundant expression in RMIC (Fig. 5).


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Fig. 5.   mRNA expression of PPARgamma in cultured cells of kidney origin. Representative gel shows PCR product of PPARgamma from RMIC, mIMDC-K2, and M1 cells which were derived from renal medullary interstitial cells, mouse inner medullary collecting duct cells, and mouse cortical collecting duct cells, respectively.

mRNA expression of PPAR during mouse kidney development. RT-PCR for the three PPAR subtypes was performed on cDNA derived from the developing mouse kidney beginning at embryonic day E14.5 to 2 wk after birth. As shown in Fig. 6, PPARbeta mRNA expression was increased in late gestation period and tended to decrease after birth. In contrast, PPARgamma and PPARalpha mRNA expression gradually increased with development, with high levels maintained after birth.


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Fig. 6.   mRNA expression of three PPAR subtypes (alpha , beta , and gamma ) during mouse kidney development. Whole kidney was dissected from different developmental periods, and PCR was performed on 10× and 100× dilutions of cDNA. E, embryonic; PND, postnatal developmental.

Activation of gene expression by PPAR ligands. Acyl-CoA synthase (ACS) is a well-established target gene of PPARs. To evaluate the functional role of PPARs in the kidney, we examined the effect of fenofibrate and troglitazone, activators for PPARalpha and PPARgamma (2), respectively, on renal ACS mRNA expression. ACS mRNA in renal cortex was significantly stimulated in animals fed with fenofibrate (0.5% in food) (28) for 1 wk, but medullary expression was unchanged, consistent with the distribution pattern of PPARalpha in the kidney (Fig. 7, left). As expected, treatment with fenofibrate also significantly induced ACS mRNA expression in liver (Fig. 7, right), another major site of PPARalpha expression. In contrast, administration of troglitazone by gavage (100-400 mg · kg-1 · day-1) for 3 days had no obvious effect on ACS mRNA expression in either cortex or medulla (data not shown).


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Fig. 7.   Regulation of mRNA expression of acyl-CoA synthase (ACS) in kidney and liver in vivo by fenofibrate (F). Sprague-Dawley rats were fed with fenofibrate for 1 wk, and RT-PCR for ACS and beta -actin were performed on 1 µg RNA isolated from kidney regions and liver.

Effect of PPARgamma on RMIC growth and differentiation. PPARgamma has been implicated in modulation of cell growth and differentiation in PPARgamma -expressing cells. Therefore, we examined the effect of PPARgamma ligands on the cell growth in RMIC. Proliferating RMICs were treated with 10 µM troglitazone, 1 µM 15d-PGJ2, or 0.1% DMSO for the times indicated. As shown in Fig. 8, both troglitazone and 15d-PGJ2 significantly inhibited cell growth, and 15d-PGJ2 was more potent than troglitazone in growth inhibitory activity (Fig. 8). PPARgamma ligands also induced dramatic changes in cell morphology in RMIC characterized by extensive process formation (Fig. 9).


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Fig. 8.   Effect of PPARgamma ligands on cell growth of RMIC. Cells were plated at a density of 4.3 × 104 cells/ml and exposed to 10 µM troglitazone, 1 µM 15-deoxy-Delta 12,14-prostaglandin J2 (15d-PGJ2), or 0.1% DMSO. Cells were trypsinized and counted at the times indicated.



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Fig. 9.   Effect of PPARgamma ligands on morphology of cultured RMIC. RMICs were grown and treated as described in Fig. 8. Cells were stained directly with fluorescein diacetate after treatment for 3 days.


    DISCUSSION
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Over the last decade and a half, a large number of putative hormonal nuclear receptors have been identified, but for many, including those in the PPAR family, the natural ligands have been unknown, and therefore their physiological role has been uncertain (21). Recently, there has been remarkable progress in the identification of natural ligands of this nuclear receptor subclass, with 15d-PGJ2 identified as a ligand of PPARgamma (8, 16) and leukotriene B4 identified as a natural ligand for PPARalpha (4). In the present studies, we examined the renal distribution of expression of PPARalpha , -beta , and -gamma , and their obligate heterodimer RXR partners and show that ligands for the PPAR receptors alter gene expression or cell viability in a pattern consistent with the distribution of their receptors. These studies support the hypothesis that PGs, including 15d-PGJ2, may act through the PPAR receptor class to regulate gene expression and cell growth in the kidney.

The PPAR subfamily consists of three members, PPARalpha , -beta , and -gamma , which share a high degree of similarity in their overall amino acid sequences, particularly in the DNA binding domain (5). The three PPARs bind to the same PPRE in the promoter regions of their target genes and appear to have similar effects on gene transcription of several enzymes involved in fatty acid oxidation in vitro (27). They bind many of the same ligands, although with variable affinities (27). Distinct functions for PPAR family members are suggested from their tissue-specific expression patterns: PPARalpha mRNA is mainly expressed in liver, kidney, and heart; PPARgamma is mainly expressed in fat tissues and spleen; PPARbeta , which is also called PPARdelta or NUC-1, is expressed widely (3, 17).

PPAR activators are known to produce peroxisome proliferation in kidney, but the kidney is a highly heterogeneous organ, with multiple distinct cell types and functions. Study of gene expression of different subtypes of PPARs in defined nephron segments is one approach by which to study their cell type-specific functions in the kidney. Our data demonstrated that three PPARs had distinct localization patterns in kidney regions and in isolated nephron segments. PPARalpha mRNA was expressed predominately in cortex and further localized to PCT, consistent with previous reports (3, 12). PPARgamma was expressed only in renal medulla, but not in cortex, and further localized to IMCD and RMIC. This finding is largely but not completely in agreement with the study by Guan et al. (12) in which PPARgamma message was found to be present in both cortex and medulla and was localized predominantly in IMCD but not in RMIC. The discrepancy may be due to differences in species or in experimental protocols. We found that PPARbeta was detected in both cortex and medulla and was expressed in all nephron segments examined, consistent with the observation by in situ hybridization technique (3) and with the ubiquitous expression noted previously (17).

PPAR requires RXR as a heterodimer partner to regulate PPAR target gene transcription. In vitro studies have shown that all three PPAR subtypes can interact with either RXRalpha , -beta , or -gamma (17, 19). However, we found that RXRalpha mRNA was specifically colocalized with PPARalpha and PPARgamma in PCT and IMCD, respectively, favoring the occurrence of heterodimers of PPARalpha -RXRalpha in PCT and PPARgamma -RXRalpha in IMCD. RXRbeta was expressed in all nephron segments, coinciding with the expression pattern of PPARbeta , suggesting that both receptors may have a constitutive function for all nephron segments. The partnership between PPAR and RXR in vivo will be complex since RXR can also serve as the heterodimer partner for other hormones such as thyroid hormone and vitamin D receptors.

PPARalpha , the first member of the PPAR subfamily, was cloned as an orphan nuclear receptor activated by agents that induce peroxisome proliferation (14). There is accumulating evidence that PPARalpha is a major mediator for regulation of energy homeostasis. PPARalpha mRNA is predominantly distributed in tissues capable of oxidizing fatty acids, such as liver, kidney, and heart. In extension of the initial observation by Braissant et al. (3), we showed that PPARalpha mRNA was localized in renal cortex and in proximal tubules where high peroxisomal beta -oxidation activity has been described (26). In support of these findings, we showed that ACS, a known PPAR target gene, was stimulated in renal cortex but not medulla of rats fed with fenofibrate, an efficient activator for PPARalpha . Indeed, transport by the proximal tubule is among the highest of all nephron segments, and as a consequence this segment is highly vulnerable to damage caused by energy depletion. Our data suggest that PPARalpha may be involved in energy supply to proximal tubule through regulation of gene transcription of such PPAR target genes as ACS. Although in vitro studies suggest that all PPAR isoforms can regulate transcription of the group of genes involved in fatty acid oxidation, we found that in vivo renal ACS is regulated by fenofibrate but not by troglitazone. This represents another line of evidence for distinct function of PPAR isoforms in vivo. PPARalpha is probably involved in energy metabolism in PCT as discussed above, whereas the abundant expression of PPARgamma in renal medulla and RMICs suggest that in these cells it may serve other functions.

The J series of PGs are known to possess potent antitumor, antiproliferation, and antivirus activity, but the biological significance and the cellular mechanism underlying these effects are poorly understood (9). The discovery that 15d-PGJ2 is a ligand for PPARgamma suggests that this receptor may mediate the cytotoxic effect of the J series of PGs. This hypothesis has been supported by recent evidence. Thiazolidinedones have been shown to inhibit cell growth in cultured human aorta and coronary myocytes (22). More recently, ectopically expressed PPARgamma has been shown to induce cell cycle withdrawal in cultured NIH-3T3 cells, in addition to its effect in inducing adipogenesis (1). The present study shows that both troglitazone and 15d-PGJ2 have a similar effect in inducing growth inhibition and differentiation of RMICs. These findings suggest a possibility that PPARgamma may be the major receptor mediating the wide range of biological activities of the J series of PGs. This issue needs to be more extensively investigated in future studies.

Previous studies, using whole embryo and adult tissues, have shown that the three PPAR subtypes are differentially expressed during development (17). To address this issue in the kidney, we examined expression patterns of the three subtypes during murine kidney development. All three PPARs were expressed in early embryonic kidneys; PPARalpha and PPARgamma mRNA levels increased with development and remained elevated 2 wk after birth, whereas PPARbeta mRNA peaked in late gestation. These data demonstrate that the three subtypes of PPARs are differentially regulated during murine kidney development, providing additional evidence to support the distinct function of PPAR subtypes in renal function.

In summary, different nephron localization patterns of various subtypes of PPAR/RXR suggest their distinct functions in different nephron segments. PPARalpha is localized to renal cortex and further localized to PCT; activation of PPARalpha by fenofibrate stimulates ACS gene expression in cortex, but not renal medulla, consistent with the distribution pattern of PPARalpha and suggesting a role of PPARalpha in energy metabolism in PCT. However, PPARgamma is abundant in inner medulla and localized in IMCD and RMIC. Activation of PPARgamma induces RMIC growth inhibition and cell shape changes, suggesting a potential role of PPARgamma in controlling the proliferation and differentiation of RMIC.


    ACKNOWLEDGEMENTS

We are grateful to Drs. E. Nord, G. Fejes-Toth, and B. Stanton for generously supplying us with renal medullary interstitial cells, M-1 cells, and mIMCD-K2 cells. The gift of troglitazone from Dr. J. W. Johnson (Parke-Davis) is gratefully acknowledged.


    FOOTNOTES

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-37448, DK-39255, and DK-40042. Additional support was in part from the General Clinical Research Center at the University of Michigan, funded by National Center for Research Resources Grant M01-RR-00042.

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. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: J. P. Briggs, NIDDK, NIH, Bldg. 31, Rm. 9A17, 31 Center Drive MSC 2560, Bethesda, MD 20892 (E-mail: BriggsJ{at}hq.niddk.nih.gov).

Received 24 August 1998; accepted in final form 1 July 1999.


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DISCUSSION
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