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From the Third Department of Medicine*
and the
Second Department of Pathology,
Shiga
University of Medical Science, Otsu, and the Kirin Brewery Co.
Ltd.,
Gunma, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß and their localization in kidneys
after ischemia/reperfusion injury. The mRNA expressions of
PDGF-B, PDGFR-, and PDGFR-ß were enhanced after
injury. In the immunohistochemical analysis and/or in
situ hybridization, PDGF-B and PDGFR-, ß
were expressed after reperfusion in the S3 segment of the proximal
tubuli, where they were not expressed normally. The expressions
of proliferating cell nuclear antigen and vimentin were concomitantly
observed with PDGF-B and PDGFRs in the tubular cells of injured S3
segment at 48 hours after injury. Next, the inhibition of the
PDGF-B/PDGFRs axis with either Trapidil or Ki6896, which was
found to inhibit the phosphorylation of PDGFR-ß selectively,
resulted in a rise of serum creatinine, higher mortality
rate, abnormal regenerating process, and suppressed
proliferation of tubular epithelial cells. These findings suggest that
the PDGF-B/PDGFRs axis is involved in the proliferation of injured
tubular cells and plays an important role in the regeneration of
tubular cells from acute ischemic injury.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Various polypeptide growth factors are generally considered to regulate the proliferation, motilization, and differentiation of renal epithelial cells during both the repair from acute tubular injury and the development of a tubular epithelium.3,4 Indeed, the expression of insulin-like growth factor I (IGF-I), heparin-binding epidermal growth factor-like growth factor (HB-EGF), transforming growth factor-ß1 (TGF-ß1), or hepatocyte growth factor (HGF) was found to be enhanced in regenerating rat kidneys after the damage by toxicants or ischemia.5-11 HB-EGF and HGF were shown to be induced as early as 1 hour and 6 hours, respectively,5,9 whereas the expression of IGF-I was found to be delayed, with a peak expression 3 to 7 days after ischemic injury.6,11 Therefore, the timed and sequential expression of these growth factors is considered to be important in the repair process of damaged renal tubular cells as well as in the development process of renal tubular epithelium.4
Recently, the immunoreactivity of platelet-derived growth factor B-chain (PDGF-B) was demonstrated in the immature tubuli of the developing human kidney,12 suggesting that PDGF-B would be involved in the tubulogenesis. This finding raises the possibility that PDGF-B and PDGF receptors (PDGFRs) may be involved in the regeneration of tubuli after acute tubular injury. Although the role of PDGF-B in the development and proliferation of glomerular mesangial cells and fibroblasts in the kidney has been extensively studied,13-18 little is known about the roles of PDGF-B and PDGFRs in the tubuli of both normal and injured kidneys. Thus, to clarify the role of PDGF-B in the acute tubular injury, we examined both the expressions of the PDGF-B/PDGFRs axis and the effect of the inhibition of PDGF-B action in kidneys with acute tubular injury .
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male Sprague-Dawley rats weighing 250 to 300 g were used. Ischemic tubular injury was induced by clamping bilateral renal arteries for exactly 50 minutes. Core body temperature was maintained at 37 ± 1°C by placing the animal on a homeothermic table and monitoring with a temperature-sensing rectal probe. After the clamp was released, the kidneys were reperfused for various time intervals before the following examination.
Preparation of Kidneys
A 22 gauge needle was inserted into aorta caudal to the renal arteries. The kidneys were perfused with 250 ml of Ringer’s solution to remove all blood from the organ. The kidney was excised, quickly frozen in liquid nitrogen, and stored at -80°C for RNA extraction. For morphological study, kidneys were fixed in 4% paraformaldehyde (PFA) solution or methyl-Carnoy’s solution for immunohistochemistry, or in the 10% formalin for in situ hybridization before kidneys were embedded in paraffin. Sections 4 µm thick were cut for immunohistochemical and in situ hybridization studies.
Northern Blot Analysis
After total RNA was isolated by the acid guanidinium
thiocyanate-phenol-chloroform method, poly A+ RNA
was extracted by use of a Micro Poly(A) Pure (Ambion, Austin, TX).
Northern Blot analysis was performed as we previously
described.19,20
Briefly, aliquots of poly
A+ RNA (4 µg) were subjected to electrophoresis
and transferred to Nytran nylon membrane. The filters were hybridized
with 32P-labeled cDNA probes for rat
PDGF-B,21
human PDGF receptor-ß,22
human
PDGF receptor- (a generous gift of C.-H. Heldin), or 36B4,
respectively. Hybridization for 36B4 was used as reference for relative
mRNA per lane.23
Immunohistochemistry
Methyl-Carnoy’s-fixed tissue was used for PDGF-B
immunohistochemistry with a monoclonal antibody, PGF-007 (Mochida,
Tokyo).21
Tissue fixed in 4% PFA was used for PDGFRs
immunohistochemistry. Two rabbit polyclonal antibodies, Ab-1
(Oncogene, NY) or P-20-R (Santa Cruz Biotechnology, Santa Cruz,
CA), were used for PDGFR-ß staining. These antibodies are raised
against the synthetic peptides that correspond to amino acid 425–446
of murine or 1082–1101 of human PDGFR-ß. For PDGFR- staining,
rabbit anti-human polyclonal antibody, PDGF(R)-A 951 (Santa Cruz
Biotechnology), which corresponds to amino acid 425–446 of human
PDGFR-, was used. The specificities of antibodies for both PDGFR-
and PDGFR-ß have been already demonstrated with rat tissue by Western
blot analysis.22,24
Both Methyl-Carnoy’s-fixed tissue and
4% PFA-fixed tissue were also stained using mouse monoclonal antibody
against rat proliferating cell nuclear antigen (PCNA; Organon
Teknika, USA) or mouse monoclonal antibody against porcine
vimentin as a primary antibody.
Immunohistochemical staining was performed by the streptavidin-biotin immunoperoxidase method. Immunoreactive products were visualized using diaminobenzidine as a chromogen. Control staining was performed using nonimmune serum and the appropriate secondary antibody. To check the specificity of PDGFR-ß, an absorption test was performed; sections were pre-incubated in the serum containing PDGFR-ß antibody and a 10-fold excess amount of immunizing PDGFR-ß peptide and then processed for further immunohistochemical staining as described above.
In Situ Hybridization
In situ hybridization was performed as we previously described.20 The probe preparation was described previously.21 Briefly, sections of the 10% formalin-fixed kidney on polyL-lysine-coated glass slides were treated with proteinase K at 37°C, and then with 0.1 mol/L triethanolamine in 0.25% acetic anhydride. After these sections were incubated with prehybridization solution, they were hybridized overnight at 48°C with digoxigenin-labeled cRNA probe. After hybridization, sections were washed in 2x SSC for 25 minutes, in 1x SSC for 25 minutes at 55°C, in 0.5x SSC for 25 minutes at 55°C, and finally in 0.5x SSC for 25 minutes at room temperature. Slides were then incubated with alkaline phosphatase-conjugated anti-digoxigenin antibody for 1 hour. Nitro blue tetrazolium development solution was applied for 20 minutes. Slides were air-dried and coverslipped over Entellan.
To evaluate the specificity of the technique, a study with a sense probe that was complementary to the antisense probe and a competitive study using large amounts of unlabeled probes were performed.
Identification of Nephron Segments
As we previously described,19 kidney tissues stained with hematoxylin-eosin (HE) were examined morphologically. To further identify the individual nephron segments, Tamm-Horsfall protein (THP) and peanut agglutinin (PNA) stainings were performed to identify the individual nephron segments.25
Inhibition of PDGF-B/PDGFRs Axis
To clarify the role of PDGF-B/PDGFRs axis in the acute tubular injury further, the effect of the inhibition of PDGF-B action was examined. Two kinds of inhibitors were used: Trapidil, which was shown to inhibit the binding of PDGF-B to PDGFR-ß competitively,26-29 and Ki 6896, which was found to inhibit the phosphorylation of PDGFR-ß selectively.30,31 Trapidil (30, 60, or 90 mg/kg) was given daily by an intraperitoneal injection from 2 days before the ischemic injury. Ki 6896 (100 mg/kg/day) was administrated per os from the day when the ischemic injury was induced. Blood samples were obtained daily from the tail vein for 7 days. The concentrations of serum creatinine were measured by an enzyme method (Boehringer Mannheim, Mannheim, Germany). To investigate the morphological change, HE staining and immunohistochemistry for PCNA were performed in kidney of rats treated with Ki 6896 and vehicle at day 6.
Statistical Analyses
Analysis of variance followed by Scheffé’s test was used to
determine significant difference in multiple comparisons. Comparisons
between two groups were analyzed by Student’s unpaired
t-test. Difference in the mortality rate was analyzed by
2
test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first examined the expression of PDGF-B mRNA in kidneys
subjected to ischemia/reperfusion injury. In postischemic-injured
kidney, the expression of PDGF-B mRNA was significantly enhanced with a
peak expression at 6 hours (P < 0.01, Figure 1
). Similar to PDGF-B, the expression of
both PDGFR- and -ß was also significantly enhanced with a peak at
day 1 (P < 0.05, Figure 1
). The expression of
PDGF-B, PDGFR-, and -ß mRNA remained unchanged after sham
operation (data not shown).
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In the normal kidney, PDGF-B immunoreactivity was observed in the
parietal epithelial cells, the convoluted proximal tubuli, the thick
ascending limb (TAL), distal tubuli, and to a lesser extent in the
collecting ducts. In the collecting ducts, immunoreactive products were
localized in the basolateral membrane, whereas they were distributed in
the cytoplasm of the epithelial cells in the proximal tubuli, TAL, and
distal tubuli. No immunoreactivity was observed in the S3 segment of
the proximal tubuli in both medullary rays and the outer stripe of the
outer medulla (OSOM; Figure 2A
). In high
power view, glomerular tuft was also positive. These findings are
concordant with those in previous studies.32-34
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and in the inner stripe of the outer
medulla 6 hours after ischemia/reperfusion, but signals became moderate
in this portion at 48 hours. On the other hand, PDGF-B immunoreactivity
appeared at 6 hours in some cells of the S3 segment of the proximal
tubuli. At 48 hours, the injured tubuli at the S3 segment markedly
expressed PDGF-B protein (Figure 2C)
. The immunoreactivity for PDGF-B
observed in other tubular systems in the normal kidney did not alter
significantly after ischemia/reperfusion injury (data not shown).
The localization of PDGF-B mRNA was demonstrated by in situ
hybridization. The pattern of signals for PDGF-B mRNA correlated
closely with the pattern of staining of PDGF-B protein seen in
immunohistochemistry. In the normal kidney, no hybridization signal was
observed in the S3 segment of the proximal tubuli (data not shown).
Strong signals were detected in the injured tubuli of the S3 proximal
tubule (Figure 3A)
. Moderate signals were
also observed in the tubuli adjacent to the injured tubuli (Figure 3A)
.
The PDGF-B sense probe yielded no positive signal (Figure 3B)
.
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Because of the lack of the systematic study on the tubular
localization of PDGFR-ß in the kidney, we first examined the
localization of PDGFR-ß in the normal kidney. We used two different
antibodies against PDGFR-ß to ensure the localization of PDGFR-ß,
and the pattern of the staining with both antibodies was identical. In
the normal rat kidney, immunoreactivity for PDGFR-ß was observed in
the glomerulus, TAL, distal tubule, and collecting duct, and most
strongly in the apical membrane of the distal tubuli and collecting
ducts (Figure 4, A
-D). The specificity of
these results was confirmed by complete disappearance of the staining
after the pre-incubation of primary antibodies with a 10-fold excess of
corresponding immunizing peptides (data not shown). Significant
staining was not recognized in the proximal tubuli (Figure 4, A and B)
.
|
. After 48 hours
postischemia, the S3 segments showed strong immunoreactivity for
PDGFR-ß with a marked positive staining in most of proximal tubular
cells of the S3 segments (Figure 5, C and D)
.
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To investigate the role of PDGF-B/PDGFRs axis in the proliferation
and phenotypic changes of tubular epithelial cells, we examined the
expression of PCNA and vimentin with serial sections by
immunohistochemistry. As previously reported,28,29
the
proliferation, as detected by PCNA expression, was more abundant in the
proximal tubuli of S3 segment, peaking at 48 hours after reperfusion,
than in the S1 or S2 segments, TAL, and collecting ducts. The
expression of PCNA was concomitantly observed with the expression of
both PDGF-B and PDGFR-ß in the tubular cells of the OSOM at 48 hours
(Figure 6, A
-D). Moreover,
immunoreactivity for vimentin was observed in the tubular cells with
intense PDGFR-ß immunoreactivity, whereas it was negative in cells
with subtle immunoreactivity for PDGFR-ß (Figure 6E)
. PDGFR- was
also expressed in the proliferating proximal tubular cells of the S3
segment in the OSOM (Figure 6, F and G)
.
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To characterize the role of PDGF-B in acute tubular injury, the
effect of the inhibition of PDGF/PDGFRs axis was examined in rats with
ischemia/reperfusion injury by measuring the concentrations of serum
creatinine. The levels of serum creatinine at day 1 of
ischemia/reperfusion injury increased in a dose-dependent manner with
Trapidil, a competitive inhibitor of PDGF-B binding to
PDGFR-ß,26-29
with a significant increase in rats
treated with 90 mg/kg Trapidil (Figure 7A)
. A significant elevation of the
levels of serum creatinine was also observed in rats treated with Ki
6896, a selective inhibitor of the autophosphorylation of PDGFR-ß
(Figure 7B)
. The values of serum creatinine remained unchanged when
control rats were treated with Trapidil (Figure 7A)
or Ki 6896 (data
not shown). We also evaluated the mortality rate of rats with
ischemia/reperfusion injury. The mortality rate was significantly
higher in rats treated with Trapidil in a dose-dependent manner than in
rats treated with vehicle (Table 1)
. The
mortality rate of rats with ischemia/reperfusion injury treated with Ki
6896 was also slightly elevated. Morphologically, it was frequently
observed that hypertrophic tubular epithelial cells are clustered and
obliterate tubular lumina in rats treated with Ki 6896 (Figure 8, A and B)
, although it was rarely seen
and tubular lamina were preserved in vehicle group. Papillary
regenerating epithelial cells and cellular debris were included in the
tubular limina in vehicle group (Figure 8, C and D)
.
PCNA-positive cells were scattered within single-layered tubule-lining
epithelial cells at low frequency, mainly in the S3 segment of Ki 6896
group (Figure 8E)
. Tubular epithelial cells, which are clustered and
obliterate tubular lumina, did not proliferate (Figure 8E)
. In
contrast, numerous PCNA-positive cells were distributed within the
surface-lining epithelial cells frequently, not only in S3 but also in
the cortical area in vehicle group. Further, PCNA-positive cells were
often clustered in multilayered concentric form in the regenerating
tubules of vehicle group (Figure 8F)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and
PDGFR-ß mRNA was enhanced in kidneys with ischemic tubular injury.
In situ hybridization and/or immunohistochemistry revealed
that both PDGF-B and PDGFRs were induced in the tubular epithelial
cells of the S3 segment of the proximal tubule after acute renal
injury, whereas this segment was negative for them in the normal
kidney. In contrast, changes in glomeruli were relatively subtle
compared with those observed in tubuli. Moreover, the cellular
proliferation, as demonstrated by the staining for PCNA, and the
phenotypic change, as demonstrated by vimentin, were well correlated
with the expression of PDGF-B and PDGFRs in the injured tubular cells
after acute injury. Finally, the inhibition of PDGF-B/PDGFRs axis in
rats with acute tubular injury resulted in resulted in a rise of serum
creatinine, higher mortality rate, abnormal regenerating process, and
suppressed proliferation of tubular epithelial cells. The importance of PDGF-B/PDGFRs axis in the repair of renal tubular epithelial cells from acute injury was suggested by an increase in mRNA levels in the injured kidneys. Although the expression of mRNA of various growth factors was found to be induced by ischemic injured kidneys, the time course of the induction was different among them. HB-EGF was found to be induced by 1 hour,9 HGF as early as 6 hours,5 and TGF-ß1 at 12 hours,10 whereas the induction of IGF-I was shown to be delayed, with maximal induction from 3 to 7 days after injury.6,11 These data suggest that the timed and sequential expression of various growth factors including PDGF-B shown in the present study would be important for the repair process from acute tubular injury.
The localization of PDGF-B immunoreactivity in the normal kidney in the present study was similar to that in previous studies.32-34,36 Although the distribution of PDGFR-ß in this study was different from that in most previous studies, which could not detect the immunoreactivity for PDGFR-ß in the tubuli,16,37,38 our results are partly in agreement with the recent report of Kliem et al, who showed that PDGFR-ß was expressed in the distal tubuli and collecting ducts in normal rat kidney.32 The difference might be due to the difference in the antibodies. Thus, we used two different antibodies and obtained identical findings. We also confirmed our results by the neutralization of immunoreactivity with immunizing peptides. Moreover, we previously demonstrated the specific binding of Ab-1 antibody to rat tissue by Western blotting.22
Colocalization of PDGF-B and PDGFRs was observed in the distal tubuli, TAL, and collecting ducts, whereas only PDGF-B was recognized in the proximal tubuli of the S1 and S2 segments in the normal kidney. Considering those localizations, PDGF-B/PDGFRs axis would be expected to play some roles to maintain the normal tubular function in an autocrine and paracrine manner. The physiological role of PDGF-B in the tubuli has not been clarified yet. PDGF-B/PDGFRs axis may be involved either in the renewal of normal tubular cells as a mitogen or in the ion transporter as a nonmitogen under the normal condition. The latter hypothesis might be supported by the findings that another growth factor, such as EGF, could be involved in the nonmitogenic tubular function.39,40
In the acutely injured kidney, strong immunoreactivity for PDGF-B was
observed in injured epithelial cells of S3 segment, where PDGF-B was
not usually expressed, and in TAL segment both adjacent to the
injured S3 segment and in the inner stripe after ischemia/reperfusion
injury. The expression of PDGF-B mRNA in the same segments was
confirmed by in situ hybridization. Like PDGF-B, PDGFR-ß
was dramatically induced in the S3 segment of the proximal tubuli,
where PDGFR-ß was not usually expressed. Moreover, the
expression of PDGFR- was induced in the tubular epithelial cells of
the same segment. These observations indicate that PDGF-B/PDGFRs axis
may play an important role in the repair of the injured tubular cells
in an autocrine and paracrine manner.
To clarify this hypothesis, we first examined the spatial relationship between PDGF-B/PDGFRs and regeneration. In ischemia/reperfusion model, both PDGF-B and PDGFRs were expressed in the proximal tubular cells undergoing proliferation, which was demonstrated by the PCNA staining. Furthermore, vimentin and PDGFR-ß were concomitantly expressed in the same injured tubular cells. Because vimentin is usually expressed in mesenchymal cells and is thought to be a marker of dedifferentiation of the tubular epithelium,35,41 these data suggest that the activation of PDGFRs might be involved in the phenotypic changes of injured tubular cells. Therefore, PDGF-B and PDGFRs expressed in the injured tubular cells might be considered to promote the repair process by inducing the proliferation and phenotypic changes of the injured cells.
To characterize further the potential role of PDGF-B/PDGFRs axis in the recovery from acute tubular injury, we attempted to inhibit PDGF-B/PDGFRs axis using two kinds of inhibitors, Trapidil and Ki 6896. Trapidil was shown to inhibit the action of PDGF-B,26-29 including PDGF-induced mitogenesis,26 by inhibiting the binding of PDGF to PDGFR-ß competitively.27 In the present study, the inhibition of PDGF-B/PDGFRs axis with Trapidil in rats with injured kidney resulted in more severe renal damage on day 1 and a high mortality rate. To confirm these results, we also used a different inhibitor, Ki 6896, which was found to selectively inhibit the autophosphorylation of PDGFR-ß without inhibiting the phosphorylation of receptors for other growth factors such as EGF, insulin, and FGF.30,31 Blockade of PDGF-B/PDGFR axis with Ki 6896 in rats with acute tubular injury resulted in significantly higher levels of serum creatinine than vehicle. Morphologically, tubular obliteration by clustered hypertrophic epithelial cells was observed in the Ki 6896 group at day 6. This finding was considered to be evidence of an abnormal process of regeneration. Further, cell proliferation was severely suppressed in this group. Considering these facts, PDGF-B/PDGFR axis appears to be involved in the functional recovery of the kidney after acute tubular injury. And it was suggested that PDGF stimulates the regenerating process of tubular epithelial cells including cellular proliferation. Because PDGF also exerts hemodynamic effects,42 vasodilatation induced by inhibition of PDGF might partly contribute to the deterioration of renal function.
The bulk of the studies about PDGF-B and/or PDGFR-ß have tended to focus on the biology of mesangial cells in the kidney. Their role in the mesangial cells is well understood by use of knockout mice,17,18 the model animals for studying glomerulonephritis33,43 , and cultured mesangial cells.13 However, little is known about the importance of PDGF-B and PDGFRs in tubular cells. The current study determined the abundant localization of both PDGF-B and PDGFRs in normal rat tubuli and further demonstrated marked induction of them after acute tubular injury, suggesting the importance of PDGF-B/PDGFRs axis in renal tubuli as well as mesangial cells.
In conclusion, the current study provides evidence of the importance of PDGF-B/PDGFRs axis in kidneys in both the normal condition and acute tubular injury. In the repair process from acute renal injury, both PDGF-B and PDGFRs were expressed in the injured tubular cells which were undergoing proliferation, suggesting that the PDGF-B/PDGFRs axis could be involved in the regeneration from acute tubular injury. Moreover, inhibition of PDGF-B/PDGFRs axis resulted in more severe renal damage, suggesting that PDGF-B/PDGFRs axis could contribute to the repair process from acute tubular injury.
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Footnotes |
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Accepted for publication July 12, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-actin expression in human glomerulogenesis. Kidney Int 1992, 42:390-399[Medline]
-receptor in the developing and mature human kidney. Kidney Int 1997, 51:1140-1150[Medline]
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