![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Valencia, Valencia, Spain;
* Division of Immunology, Shigei Medical Research Institute, Okayama, Japan; and
Centro de Investigación, Hospital "La Fe," Valencia, Spain
2To whom correspondence should be addressed. E-mail: Joaquin.Timoneda{at}uv.es.
 |
ABSTRACT |
|---|
 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
(IV) chains, matrix degrading metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) were quantified by immunocytochemistry and/or Western blotting. Tumor necrosis factor- and interleukin-1ß were measured by ELISA. Semiquantitative RT-PCR was used for determining the steady-state levels for each (IV) chain mRNA. VAD renal BMs showed an irregular thickening, particularly tubular BM. The total collagen IV content was increased, but there was a differential expression of the collagen IV chains. The protein amounts for 1(IV), 4(IV), and 5(IV) were similarly increased, whereas 2(IV) and 3(IV) were decreased. The levels of mRNA for each collagen IV chain changed in parallel with those of the corresponding protein. Both MMP2 and MMP9 were diminished, but no change was detected in TIMP1 or TIMP2. Our data indicate that nutritional VAD leads to alterations in the structure of renal BMs and to quantitative and qualitative variations in its collagen IV composition. These changes may be a factor predisposing to or resulting in kidney malfunction and renal disease.
KEY WORDS: • collagen IV • vitamin A • basement membranes • rat kidney • metalloproteinase
Vitamin A and its derivatives, the retinoids, have a profound influence on organ development, cell proliferation, and cell differentiation (1), and their deficiency originates or predisposes to a range of disabilities. In the case of kidney development, even mild vitamin A deficiency (VAD)3 in pregnant rats results in a reduced number of nephrons in the fetuses, leading to a permanent deficit in adulthood (2). Conversely, retinoids have proved to be an effective treatment in several models of renal damage (3).
The basement membrane (BM) is a specialized structure of the extracellular matrix (ECM), composed of type IV collagens, laminins, entactin, and proteoglycans, which also has a crucial effect on kidney organogenesis and cell differentiation, and mutations affecting its components lead to inherited forms of renal disease. Moreover, alterations in BM structure or composition are associated with a variety of kidney disorders (4). Mammalian BMs contain 6 known collagen IV chains with tissue- and development-specific patterns of expression. The 1 and 2 chains are abundant in most BMs, suggesting their importance in embryonic development but 3–6(IV) chains are selectively expressed in BMs and appear relatively late in development. Thus, the loss or alteration of any chain may have tissue-specific consequences (5). Targeted deletion of the mouse Col4a3 gene results in progressive glomerulonephritis leading to death by renal failure (6). Dramatic changes in the structure of the BM, including ectopic deposition of BM components such as collagen 1(IV), 2(IV), perlecan, and fibronectin, appear before detectable functional defects. Undesirable loss of mesangial and other normal resident cells by unscheduled apoptosis also occurs in glomerular inflammation, progressing to glomerulosclerosis coincident with changes in the amount and composition of ECM. Interestingly, ECM components have a differential capacity to protect rat mesangial cells from induced apoptosis. Collagen IV and laminin, normal constituents of mesangial ECM, suppress cell apoptosis but collagen I and fibronectin, abnormally expressed in the mesangium of diseased glomeruli, do not do so (7). Unfortunately, it is not known whether these differential capacities prevail also for the different subunits of the ECM molecules.
As a common link, retinoids modulate the production of BM and other extracellular matrix proteins by a variety of cells in vivo and in vitro, indicating that alterations in the structure and composition of BMs could mediate in the negative effects of VAD. However, the effects of retinoids on the expression of BM components appear to vary depending on the cell type, the culture conditions, or the presence of a structured ECM (8–10). Moreover, retinoids could also affect BMs in vivo by modifying the oxidative stress or the development of an inflammatory response. It was shown that VAD induces rat colonic inflammation with the deposition of collagen and that feeding a vitamin A-supplemented diet ameliorates the inflammatory process in experimentally induced colitis (11). The discrepancies observed between the effects in vitro or in vivo (12) are a reflection of the pleiotropic actions of retinoids and support the importance of analyzing the effects of VAD in vivo.
Much knowledge has been obtained concerning the actions of retinoids on the expression of ECM macromolecules in vitro and the reciprocal influence of these molecules on the response of cells to growth factors. However, little is known about the effect of a deficiency of vitamin A on the composition of BMs in vivo, and no study has examined its effects on the subunit composition of BM macromolecules. In the present study, we analyzed by electron microscopy, immunocytochemistry, Western blotting, and RT-PCR the structure and collagen composition of renal BM in rats fed a VAD diet during their postnatal growth. We also determined in renal tissue 2 proinflammatory cytokines, tumor necrosis factor (TNF)- and interleukin (IL)-1ß.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
Mouse monoclonal antibodies (H11, H22, H31, H44, H52, H65) against each of the 6 human (IV) chains were prepared as described (13). Rabbit polyclonal antibodies anti-bovine collagen IV and anti-bovine 7S(IV) were a kind gift of Dr. B. G. Hudson (Vanderbilt University Medical Center, Nashville, TN). Commercial primary antibodies were as follows: rabbit polyclonal anti-human metalloproteinase (MMP)9 (M-5302, Sigma), rabbit polyclonal anti-human tissue inhibitor of metalloproteinase (TIMP)1 (T-8187, Sigma) or anti-human TIMP2 (T-7937, Sigma), and mouse monoclonal anti-human MMP2 (clone 42-5D11, Calbiochem). Secondary antibodies conjugated with alkaline phosphatase, peroxidase, or colloidal gold (5 or 10 nm) were from Promega, Bio-Rad, or Sigma, respectively. Oligonucleotides used as primers for RT-PCR were synthesized by Roche Diagnostics. Chemicals for electron microscopy were from Electron Microscopy Science. Other reagents were of analytical grade.
Animal treatment
VAD rats were prepared as previously described (14). Briefly, pregnant Wistar female rats (Charles River) were randomly assigned either to a control or to a VAD group and housed in individual cages in a room maintained at 22–25°C with a 12-h light:dark cycle. The day after delivery, the dams of the control group with their pups were fed a complete solid diet (AIN-93, ICN). The dams of the VAD group with their pups were fed the same diet but devoid of vitamin A. After 21 d of lactation, male pups of each group were weaned onto their corresponding dam diet until they were 50 d old. Control rats were pair-fed the mean intake of the VAD group.
Tissue sample preparation
Blood and kidney samples for biochemical studies were processed as previously described (15) and stored frozen until they were used. For ultrastructural and immunocytochemical studies, whole anesthetized rats were perfused with 0.5% glutaraldehyde and 4% formaldehyde in 0.1 mol/L cacodylate buffer, pH 7.4.
Samples for ultrastructural studies. Small fragments of kidney were postfixed, dehydrated, and embedded in Epon 812 as described (16). Ultrathin sections were examined in a Philips CM 100 Transmission Electron Microscope.
Samples for immunocytochemistry. Small fragments of kidney were postfixed, dehydrated, and embedded in Lowicryl K4M after the progressive lowering temperature procedure as described (17).
Retinol determination
Plasma retinol concentration was determined by the isocratic HPLC method of Arnaud et al. (18). A Nova-pak C-18 column (3.9 x 150 mm, Waters) and a mixture of acetonitrile:dichloromethane:methanol (70:20:10), as eluent, were used.
Kidney retinoids were extracted as described (19), dissolved in methanol:ethanol (1:1), and measured by reversed-phase gradient HPLC following a published method (20) but using a Nova-pak C-18 column (3.9 x 150 mm, Waters).
Determination of TGF- and IL-1ß in kidney
Pieces of frozen kidney (0.1 g) were homogenized in 1 mL of 50 mmol/L Tris-HCl pH 7.5 containing 0.1% Triton X-100 and 5 µL of protease inhibitor cocktail for mammalian tissue extracts (Sigma), sonicated twice for 30 s with cooling, and centrifuged at 450000 x g for 10 min. The supernatants were analyzed for TGF- and IL-1ß contents by a commercial ELISA kit (Cytokine ELISA assay) as recommended by the manufacturer.
Solubilization of MMPs, TIMPs, and noncollagenous domains (NC1) of collagen IV
Kidney (0.1 g) was homogenized in 2 mL of Tris-HCl 50 mmol/L pH 7.5 containing 0.25% (v:v) Triton X-100, 4% SDS, and the following protease inhibitors: N-ethylmaleimide (4 mmol/L), benzamidine (5 mmol/L), 6-aminohexanoic acid (25 mmol/L) and phenylmethylsulfonyl fluoride (2 mmol/L). The suspension was centrifuged and the supernatant stored at –20°C for MMP and TIMP determination by Western blotting.
The pellet was digested extensively with bacterial collagenase (high-purity collagenase, type VII, Sigma) at 37°C for 48 h in digestion buffer consisting of 50 mmol/L HEPES, pH 7.5, 10 mmol/L CaCl2, 0.05% NaN3, and the protease inhibitor cocktail mentioned above. The digestion was repeated to confirm that no more collagen fragments were solubilized. The suspensions were centrifuged (8000 x g, 15 min) and the solubilized material was stored at –80°C until used for determination of the noncollagenous segments of the collagen IV chains.
Protein quantification by Western blotting
SDS-PAGE was carried out in 10% acrylamide gels (MMPs and TIMPs) or 10–20% acrylamide gradient gels (collagen IV chains) using the buffer system of Laemmli (21). The proteins were transferred electrophoretically to nitrocellulose paper at 150 mA constant current for 18 h at 4°C. Membranes were incubated successively with 5% skimmed milk, the corresponding primary antibodies, and the secondary conjugated antibody in 10 mmol/L Tris-HCl pH 8, 150 mmol/L NaCl and 0.05% Tween 20. Blots were scanned with a SNAP Scan 1236 (AGFA), and protein bands were quantified using the Scion Image program. Linearity ranges were established by blotting different amounts of each sample.
Semiquantitative analysis of mRNA by RT-PCR
Total RNA was isolated from kidney samples using the Quick Prep total RNA extraction kit as described by the manufacturer (Pharmacia Biotech). All samples were normalized to total RNA, and RT-PCR was performed using the "Enhanced avian RT-PCR kit" as recommended by the supplier (Sigma). S26 ribosomal protein mRNA was amplified as an internal control to normalize the amount of total RNA for each sample. The primers for determining expression of the collagen IV chains were complementary to published nucleotide sequences of the globular domains (NC1) of the mouse (1, 2, 4 and 5) (22), rat (3) (23) or human (6) (24) chains. These were: 1(IV) sense: 5'-ATCTCTGGGGACAACATCCGGC-3' antisense: 5'-CATCTCGCTTCTCTCTATGGTGGC-3'; 2(IV) sense: 5'-TGGCTGAGGAGGAAATCAAGCC-3', antisense: 5'-GCTCTGGAAGTTCTGCTCTGG-3'; 3(IV) sense: 5'-TACTGGCAGAGCCCTTGAGCC-3', antisense: 5'-CATTCTTTCTGGATTTAGTGAAGC-3'; 4(IV) sense: 5'-AGTGCGGCTCCTCTTCCTATG-3', antisense: 5'-GCGCTGGGCCTGAACTTCTTT-3'; 5(IV) sense: 5'-TGAAGGGACAGAGCAGCATCC-3', antisense: 5'-GTCTGACATATCAACAGTGGC-3'; 6(IV) sense: 5'-GTCAGCCAGACCCAGATTCCCAG-3', antisense: 5'-CTCCCCAAACTGCTGCCTCTC-3'.
To amplify the S26 ribosomal protein RNA, the following primers were used: 5'-CAGCAGGTCTGAATCGTGGT-3' and 5'-AATTCGCTGCACGAACTGCG-3'. Reverse transcription was performed at 50°C for 30 min and finished at 94°C for 2 min. Then, the appropriate number of cycles for taking each cDNA PCR products into the exponential phase of amplification was run. The resulting PCR products were electrophoresed on 1.5% agarose gel in TBE electrophoresis buffer and stained with ethidium bromide. The intensity of the bands was analyzed following scanner densitometry using analysis software (Gelblot program, UVP Image Store 5000).
Ultrastructural immunolocalization of collagen IV chains
Collagen IV as well as their -chains were located in BM from the proximal tubule epithelium with the immunogold procedure (25) but with an initial incubation of the ultrathin sections in 3% H2O2 for 10 min. After blocking and incubating with primary antibodies and gold-conjugated second antibody, the ultrathin sections were counterstained with uranyl acetate and examined in a Philips CM 100 Transmission Electron Microscope.
Ultrastructural quantitative analysis
Morphometric analysis. The thickness of the BM was determined in randomly selected micrographs at X29400 taken from the glomerulus and proximal tubule epithelium. In each micrograph, the thickness of the BM was measured at intervals of 1 cm with a minimum of 10 measurements per micrograph. The minimum sample size was determined by the progressive mean technique (confidence limit, ±5%) (16).
Quantitative immunocytochemistry. Evaluation of gold particles was carried out by overlaying each electron micrograph with a bidimensional lattice, and then estimating morphometrically the mean area (µm2) [area of the compartment (Ac)] occupied by the BM. Then the labeling density of gold particles was calculated by counting all gold particles falling on each estimated area and dividing this value by Ac (25). The background was determined in a similar manner.
Statistical analysis
Statistical analyses were performed using GraphPad Prism software. Data are presented as means ± SD, n = 3–5. Significant differences between group means were determined using Student’s t test and a P-value < 0.05.
|
RESULTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
Effect of vitamin A deficiency on renal basement membrane. Electron microscopic examination revealed that BM in VAD kidneys was visibly thickened (Fig. 1) although the thickening was not uniform along the entire BM. On average, glomerular BM (GBM) was 2-fold wider in VAD than in control rats (Fig. 1A and B) whereas tubular BM (TBM) was 6-fold thicker (Fig. 1C and 1D). Moreover, TBM showed an irregular structure with frequent splits (Fig. 1D). It is also particularly noteworthy that in TBM, abundant, disordered collagen fibers appeared emerging from epithelial cells and disrupting the structure of the BM (Fig. 1D). Similarly, the kidney cortex of VAD rats exhibited a disorganized collagen I distribution in the ECM with the frequent presence of irregularly scattered collagen fiber bundles (not shown).
|
1,2(IV) to 3-5(IV) expression (22), we compared the chain composition of collagen IV in VAD and control kidneys. The quantitative immunocytochemistry showed that the VAD diet induced chain-specific changes in collagen IV composition. The amount of 1(IV) chain was 55% greater in VAD-BM, whereas 2(IV) was reduced to 
60% of the control BM. In contrast, the 3(IV) chain in VAD-BM decreased to 45% of the control BM and the 4(IV) chain increased 55%. Both the 5(IV) and 6(IV) chains increased in VAD-BM, 50 and 25%, respectively. These results were confirmed by Western blotting analyses (Fig. 3).
|
|
chain was evaluated by RT-PCR in VAD and control kidneys. The results obtained (Fig. 4) were qualitatively similar to those of protein content. The VAD diet induced an 70% increase in the amount of 1(IV) mRNA and a reduction to 50% in that of 2(IV) mRNA. On the contrary, 3(IV) mRNA in VAD kidneys decreased to 60% of the control level and 4(IV) mRNA increased 25%. Finally, 5(IV) mRNA was incremented 30% in relation to the control. No mRNA for the 6(IV) chain could be detected with the primers used.
|
|
and IL-1ß. IL-1ß content did not differ between control and VAD kidney (5.2 ± 0.4 ng/g wet weight for control vs. 4.3 ± 0.9 ng/g wet weight for VAD kidney, n = 4, P = 0.09). On the contrary, TNF- was increased in VAD kidney (27.3 ± 2.7 ng/g wet weight for control vs. 54.2 ± 5.7 ng/g wet weight for VAD kidney, n = 4, P = 0.001). |
DISCUSSION |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
The profound reduction in the retinoid content of VAD rats induced a notable increase in the thickness of the GBM and TBM and a disruption of the regular structure in the case of TBM. Thickening of the BM is a pathologic and ultrastructural hallmark that precedes clinical signs in a variety of renal progressive diseases such as diabetes or Alport syndrome and is the result of an increased deposition of BM components (26,27). In renal VAD-BM, type IV collagen content was greater than in control BM. However, laminin, another major component of BM, which has been shown to increase in both diseases, did not change (data not shown). Therefore, the increase in collagen IV content appears to be the main contributor to renal VAD-BM thickening.
Interestingly, VAD did not induce a uniform change in the different collagen IV chains. The amounts of 1, 4, 5 and 6(IV) chains were increased, whereas those of 2 and 3(IV) were decreased. Differential contents of collagen IV chains were also observed in several renal pathologies. In experimental chronic serum sickness in rats, a model for immune complex-mediated nephritis, the staining intensities, as determined by immunofluorescence microscopy, for the 1(IV) chain in the mesangial matrix, and for 3 and 4(IV) chains in GBM were increased 10 wk after the induction of disease. However, no change was detected either in the glomerular distribution or in the staining intensity of the 2(IV) chain (28). These 4 chains accumulated also in TBM during the course of the disease, with 1 and 4(IV) having the highest levels (29). In patients with diabetic nephropathy, increments of 3 and 4(IV) in the thickened GBM, but not in the mesangial matrix, and of 1 and 2(IV) in the expanded mesangium were also described (30).
The changes observed in the collagen chain content of VAD kidneys were likely due to modified synthesis because the steady-state mRNA levels correlated with the amounts of each protein (r = 0.87, P = 0.01). Accordingly, the 1(IV) and 4(IV) mRNAs were increased, whereas the 2(IV) and 3(IV) mRNAs were decreased. These results indicate that the 2 collagen chains of each pair (1-2 or 3-4) may not be coexpressed under VAD despite sharing bidirectional promoters. A similar finding was also reported in the renal tubulointerstitium during chronic serum sickness (29) in which increases at the mRNA and protein levels in 1(IV) and 4(IV) chains uncoordinated with those of 2(IV) and 3(IV) were found. The inverse change in the chains of both pairs is indicative of an abnormal collagen molecule formation. Homotrimers of 1(IV) and 4(IV) and/or unusual heterotrimers between them could be formed with the spare chains, affecting not only the structure and function of the BM but also the function of the neighboring cells. Alternatively, the surplus chains could be secreted as monomers and as such interfere with the assembly and functions of a regular BM.
The mechanism by which VAD results in changes in BM composition and particularly in collagen IV chain composition is not understood. Three main possibilities that may act simultaneously can be considered from what it is known. First, VAD could directly affect the expression of BM molecules through the nuclear retinoic acid receptors (RAR) or indirectly by modifying the expression of other transcription or growth factors. As far as we know, no study on the regulation of collagen IV gene expression by RARs has been done. However, several retinoic acid response elements were found in the promoter of 2(I) collagen gene. Binding of RARs to these sites inhibits the expression of the 2(I) gene but has no effect on the 1(I) gene (31). Collagen IV genes are organized in pairs and oriented head-to-head with a short promoter separating the divergent transcription units. At least 3 nuclear factors, Sp1, a CAAT-binding protein, and a CTC-binding factor, are capable of interacting specifically with the Col4a1-Col4a2 promoter as well as with elements located downstream (32). Interestingly, it was found that RARs can interact physically with Sp1, modulate Sp1 binding to its DNA motifs and thus regulate gene transcription (33). Therefore, a direct effect of VAD on collagen IV expression may exist. On the other hand, by deactivating RARs, VAD can also upregulate the expression of other fibrogenic growth factors such as transforming growth factor-ß1 (TGF-ß1), which is capable of increasing the expression of at least 1(IV) collagen and other ECM proteins (34). TGF-ß1 can be expected to be raised in VAD based on the fact that retinoic acid has the ability to inhibit its expression as was described in experimental glomerulonephritis (35).
Second, the effect of VAD on BM could result from an increment in oxidative stress. VAD induces oxidative stress (14); reactive oxygen species such as oxygen peroxide or the superoxide anion activate signaling pathways, resulting in increased TGF-ß1 and collagen IV expression (36). Consistently, experimental treatments aimed to reduce oxidative stress have lowered collagen IV accumulation and attenuated renal injury (37).
Third, the effect of VAD could be the consequence of an inflammatory process. It was demonstrated that VAD exacerbates experimentally induced inflammation and that it even generates a mild inflammatory response with deposition of collagen and infiltration of inflammatory cells in the rat colon after 7 wk (11). In our model of VAD, we analyzed 2 proinflammatory cytokines, IL-1ß and TNF-, in kidney as markers of local inflammation. The fact that only TNF- but not IL-1ß was increased suggests that no acute inflammatory process is acting on kidney. In agreement with this suggestion, myeloperoxidase activity did not differ between control and VAD kidneys (not shown). Increased expression of TNF- by renal tubular cells without inflammatory cell infiltration was described in obstructive uropathy (38). Because ligand-activated RARs are capable of suppressing TNF- production (39), it is possible that VAD raises its expression by renal resident cells. Although a chronic inflammatory process cannot be completely excluded from our results, it seems more likely that the effects of VAD on renal BMs result from a decrease in retinoid activated receptors and an increase in oxidative stress. However, more work has to be done to clarify this subject especially on the differential expression of the collagen IV chains.
We also analyzed the MMPs and their endogenous inhibitors due to their role in degradation and remodeling of BMs. MMP2 and MMP9 were the focus of our study because they have activity against type IV collagen, are synthesized by different renal cell types in response to extracellular signals, and are implicated in the alterations of BMs occurring in several renal pathologies (27,40). Both MMP2 and MMP9 were decreased in kidneys of VAD rats. However, their natural inhibitors, TIMP1 and TIMP2, did not change significantly. This effect on renal MMPs is in agreement with previous published data describing a decrease of both gelatinases in corneas of VAD rats (41). Data on the effects of retinoids on the expression of TIMPs in vivo are scarce. Some information available from patients with emphysema, however, indirectly supports our results because administration of all-trans retinoic acid to these patients had no substantial effect on their plasma TIMP1 levels (42). The fall in the collagenase activities without any change in the amount of the endogenous inhibitors can be an additional factor contributing to the increase in the collagen IV content of renal BMs in VAD.
Our study indicates that chronic VAD during the growing period alters the structure and composition of renal BMs, and modifies the ratio of individual collagen IV chains at both the mRNA and the protein levels. The altered BM could modify the function and the activation state of contacting cells contributing or predisposing to organ damage. In this sense, it was shown that collagen IV and laminin, normal constituents of BM, but not collagen I or fibronectin, protect mesangial cells from apoptosis, a process considered to mediate in the progression of glomerular inflammation to irreversible glomerulosclerosis (7). Although the renal functional implications of BM alterations are not completely elucidated, they are found in most of the renal pathologies analyzed at this level even before proteinuria appears. In fact, an insidious progress to plasma protein leak induced by defects in the collagen IV composition of glomerular BMs was demonstrated (43). Future work will focus on the effects of VAD on other BMs, the mechanisms mediating these effects, and its reversibility.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
3 Abbreviations used: ac, area of the compartment; BM, basement membrane; ECM, extracellular matrix; GBM, glomerular basement membrane; IL, interleukin; MMP, matrix metalloproteinase; NC, noncollagenous; RAR, retinoic acid receptor; TBM, tubular basement membrane; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinases; TNF, tumor necrosis factor; VAD, vitamin A deficient or vitamin A deficiency.
Manuscript received 6 August 2004. Initial review completed 14 September 2004. Revision accepted 2 January 2005.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
1. Sporn, M. B. Roberts, A. B. Goodman, D. S. eds. The Retinoids: Biology, Chemistry, and Medicine 1994 Raven Press New York, NY. .
2. Lelièvre-Pégorier, M., Vilar, J., Ferrier, M. L., Moreau, E., Freund, N., Gilbert, T. & Merlet-Bénichou, C. (1998) Mild vitamin A deficiency leads to inborn nephron deficit in the rat. Kidney Int. 54:1455-1462.[Medline]
3. Wagner, J. (2001) Potential role of retinoids in the therapy of renal disease. Nephrol. Dial. Transplant. 16:441-444.
4. Müller, U. & Brändli, A. W. (1999) Cell adhesion molecules and extracellular-matrix constituents in kidney development and disease. J. Cell Sci. 112:3855-3867.[Abstract]
5. Hudson, B. G., Tryggvason, K., Sundaramoorthy, M. & Neilson, E. G. (2003) Alport’s syndrome, Goodpasture’s syndrome and type IV collagen. N. Engl. J. Med. 348:2543-2556.
6. Miner, J. H. & Sanes, J. R. (1996) Molecular and functional defects in kidneys of mice lacking collagen 3(IV): implications for Alport syndrome. J. Cell Biol. 135:1403-1413.
7. Mooney, A., Jackson, K., Bacon, R., Strenli, C., Edwards, G., Bassuk, J. & Savill, J. (1999) Type IV collagen and laminin regulate glomerular mesangial cell susceptibility to apoptosis via ß1 integrin-mediated survival signals. Am. J. Pathol. 155:599-606.
8. Boylan, J. F., Lohnes, D., Taneja, R., Chambon, P. & Gudas, L. J. (1993) Loss of retinoic acid receptor gamma function in F9 cells by gene disruption results in aberrant Hoxa-1 expression and differentiation upon retinoic acid treatment. Proc. Natl. Acad. Sci. U.S.A. 90:9601-9605.
9. Taub, M. (1991) Retinoic acid inhibits basement membrane protein biosynthesis while stimulating dome formation by Madin Darby canine kidney cells in hormonally defined serum-free medium. J. Cell. Physiol. 148:211-219.[Medline]
10. Traianedes, K., Ng, K. W., Martin, T. J. & Findlay, D. M. (1993) Cell substratum modulates responses of preosteoblasts to retinoic acid. J. Cell. Physiol. 157:243-252.[Medline]
11. Reifen, R., Nur, T., Ghebermeskel, K., Zaiger, G., Urizky, R. & Pines, M. (2002) Vitamin A deficiency exacerbates inflammation in a rat model of colitis through activation of nuclear factor-
B and collagen formation. J. Nutr. 132:2743-2747.
12. Fisher, G. J. & Voorhes, J. J. (1996) Molecular mechanisms of retinoid action in skin. FASEB J. 10:1002-1013.[Abstract]
13. Sado, Y., Kagawa, M., Kishiro, Y., Sugihara, K., Naito, I., Seyer, J. M., Sugimoto, M., Oohashi, T. & Ninomiya, Y. (1995) Establishment by the rat lymph node method of epitope-defined monoclonal antibodies recognizing the six different chains of human type IV collagen. Histochem. Cell Biol. 104:267-275.[Medline]
14. Barber, T., Borrás, E., Torres, L., García, C., Cabezuelo, F., Lloret, A., Pallardó, F. V. & Viña, J. R. (2000) Vitamin A deficiency causes oxidative damage to liver mitochondria in rats. Free Radic. Biol. Med. 29:1-7.[Medline]
15. Estornell, E., Tormo, J. R., Marín, P., Renau-Piqueras, J., Timoneda, J. & Barber, T. (2000) Effects of vitamin A deficiency on mitochondrial function in rat liver and heart. Br. J. Nutr. 84:927-934.[Medline]
16. Williams, M. (1977) Stereological techniques. Glauert, A. M. eds. Practical Methods in Electron Microscopy 6:1-225 North Holland/American Elsevier Amsterdam, the Netherlands. .
17. Renau-Piqueras, J., Guasch, R., Azorín, I., Segui, J. M. & Guerri, C. (1977) Prenatal alcohol exposure affects galactosyltransferase activity and glycoconjugates in the Golgi apparatus of fetal rat lipocytes. Hepatology 25:343-350.
18. Arnaud, J., Fortis, I., Blachier, S., Kia, D. & Favier, A. (1991) Simultaneous determination of retinol, alpha-tocopherol and beta-carotene in serum by isocratic high-performance liquid chromatography. J. Chromatogr. 572:103-116.[Medline]
19. Podda, M., Weber, C., Traber, M. G., Milbradt, R. & Packer, L. (1999) Sensitive high-performance liquid chromatography techniques for simultaneous determination of tocopherols, tocotrienols, ubiquinols and ubiquinones in biological samples. Methods Enzymol. 299:330-341.[Medline]
20. Barua, A. B. & Olson, J. A. (1998) Reversed-phase gradient high-performance chromatographic procedure for simultaneous analysis of very polar to nonpolar retinoids, carotenoids and tocopherols in animal and plant samples. J. Chromatogr. B. Biomed. Sci. Appl. 707:67-79.
21. Laemmli, U. K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature (Lond.) 227:680-685.[Medline]
22. Miner, J. H. & Sanes, J. R. (1994) Collagen IV 3, 4, and 5 chains in rodent basal laminae: sequence, distribution, association with laminins, and developmental switches. J. Cell Biol. 127:879-891.
23. Ryan, J. J., Katbamna, I., Mason, P. J., Pusey, C. D. & Turner, A. N. (1998) Sequence analysis of the ’Goodpasture antigen’ of mammals. Nephrol. Dial. Transplant. 13:602-607.
24. Oohashi, T., Sugimoto, M., Mattei, M. G. & Ninomiya, Y. (1994) Identification of a new collagen IV chain, alpha 6(IV), by cDNA isolation and assignment of the gene to chromosome Xq22, which is the same locus for COL4A5. J. Biol. Chem. 269:7520-7526.
25. Hayat, M. A. (1992) Quantitation of inmunogold labelling. Micron 23:1-16.
26. Noel, L. H. (2000) Renal pathology and ultrastructural findings in Alport’s syndrome. Renal Fail 22:751-758.[Medline]
27. Tsilibary, E. C. (2003) Microvascular basement membranes in diabetes mellitus. J. Pathol. 200:537-546.[Medline]
28. Bergijk, E. C., Van Alderwegen, I. E., Baelde, H. J., De Heer, E., Funabiki, K., Miyai, H., Killen, P. D., Kalluri, R. K. & Bruijn, J. A. (1998) Differential expression of collagen IV isoforms in experimental glomerulosclerosis. J. Pathol. 184:307-315.[Medline]
29. Van Vliet, A., Van Alderwegen, I. E., Baelde, H. J., De Heer, E., Killen, P. D., Kalluri, R. K., Bruijn, J. A. & Bergijk, E. C. (1999) Differential expression of collagen type IV alpha-chains in the tubulointerstitial compartment in experimental chronic serum sickness nephritis. J. Pathol. 189:279-287.[Medline]
30. Yagame, M., Kim, Y., Zhu, D., Suzuki, D., Eguchi, K., Nomoto, Y., Sakai, H., Groppoli, T., Steffes, M. W. & Mauer, S. M. (1995) Differential distribution of type IV collagen chains in patients with diabetic nephropathy in non-insulin-dependent diabetes mellitus. Nephron 70:42-48.[Medline]
31. Wang, L., Tankersley, L. R., Tang, M., Potter, J. J. & Mezey, E. (2002) Regulation of the murine 2(I) collagen promoter by retinoic acid and retinoid X receptors. Arch. Biochem. Biophys. 401:262-270.[Medline]
32. Pollner, R., Schmidt, C., Fisher, G., Kühn, K. & Pöschl, E. (1997) Cooperative and competitive interaction of regulatory elements are involved in the control of divergent transcription of human COL4A1 and COL4A2 genes. FEBS Lett. 405:31-36.[Medline]
33. Shimada, J., Suzuki, Y., Kim, S. J., Wang, P. C., Matsumura, M. & Kojima, S. (2001) Transactivation via RAR/RXR-Sp1 interaction: characterization of binding between Sp1 and GC box motif. Mol. Endocrinol. 15:1677-1692.
34. Douthwaite, J. A., Johnson, T. S., Haylor, J. L., Watson, P. & El Nahas, A. M. (1999) Effects of transforming growth factor-ß1 on renal extracellular matrix components and their regulating proteins. J. Am. Soc. Nephrol. 10:2109-2119.
35. Morath, C., Dechow, C., Lehrke, I., Haxsen, V., Waldherr, R., Floege, J., Ritz, E. & Wagner, J. (2001) Effects of retinoids on the TGF-ß system and extracellular matrix in experimental glomerulonephritis. J. Am. Soc. Nephrol. 12:2300-2309.
36. Iglesias-De la Cruz, M. C., Ruiz-Torres, P., Alcami, J., Diez-Marques, L., Ortega-Velazquez, R., Chen, S., Rodríguez-Puyol, M., Ziyadeh, F. N. & and Rodríguez-Puyol, D. (2001) Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells. Kidney Int. 59:87-95.[Medline]
37. De Rubertis, F. R., Craven, P. A., Melhem, M. F. & Salah, E. M. (2004) Attenuation of renal injury in db/db mice overexpressing superoxide dismutase: evidence for reduced superoxide-nitric oxide interaction. Diabetes 53:762-768.
38. Misseri, R., Meldrum, D. R., Dagher, P., Hile, K., Rink, R. C. & Meldrum, K. K. (2004) Unilateral ureteral obstruction induces renal tubular cell production of tumor necrosis factor- independent of inflammatory cell infiltration. J. Urol. 172:1595-1599.[Medline]
39. Mou, L., Lankford-Turner, P., Leander, M. V., Bissonnette, R. P., Donahoe, R. M. & Royal, W. (2004) RXR induced TNF- suppression is reversed by morphine in activated U937 cells. J. Neuroimmunol. 147:99-105.[Medline]
40. Camp, T. M., Smiley, L. M., Hayden, M. R. & Tyagi, S. C. (2003) Mechanism of matrix accumulation and glomerulosclerosis in spontaneously hypertensive rats. J. Hypertens. 21:1719-1727.[Medline]
41. Twining, S. S., Schulte, D. P., Zhou, X., Wilson, P. M., Fish, B. L. & Moulder, J. E. (1997) Changes in rat corneal matrix metalloproteinases and serine proteinases under vitamin A deficiency. Curr. Eye Res. 16:158-165.[Medline]
42. Mao, J. T., Tashkin, D. P., Belloni, P. N., Baileyhealy, I., Baratelli, F. & Roth, M. D. (2003) All-trans retinoic acid modulates the balance of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in patients with emphysema. Chest 124:1724-1732.
43. Hamano, Y., Grunkemeyer, J. A., Sudhakar, A., Zeisberg, M., Cosgrove, D., Morello, R., Lee, B., Sugimoto, H. & Kalluri, R. (2002) Determinants of vascular permeability in the kidney glomerulus. J. Biol. Chem. 277:31154-31162.
This article has been cited by other articles:
|
|
 |
|
  R. D.W. Klemm, A. B. Labrique, P. Christian, M. Rashid, A. A. Shamim, J. Katz, A. Sommer, and K. P. West Jr Newborn Vitamin A Supplementation Reduced Infant Mortality in Rural Bangladesh Pediatrics, July 1, 2008; 122(1): e242 - e250. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Zaragoza, A. Gimeno, V. J. Miralles, E. R. Garcia-Trevijano, R. Carmena, C. Garcia, M. Mata, I. R. Puertes, L. Torres, and J. R. Vina Retinoids induce MMP-9 expression through RAR{alpha} during mammary gland remodeling Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1140 - E1148. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
