Course of Renal Injury in the Mpv17-Deficient Transgenic Mouse
THOMAS O'BRYAN*,
HANS WEIHER,
HELMUT G. RENNKE,
STEFAN KREN* and
THOMAS H. HOSTETTER*
*Renal Division, University of Minnesota, Minneapolis Minnesota Institut für Diabetes Forschung, Munich,
Germany Department of Pathology, Brigham and Women's Hospital, Boston,
Massachusetts.
Correspondence to Dr. Thomas H. Hostetter, Renal Division, Box 736 UMHC, 420
Delaware Street SE, Minneapolis, MN 55455. Phone: 612-624-6917; Fax:
612-626-3840; E-mail:
hoste002{at}maroon.tc.umn.edu
Abstract. The mutant Mpv17 mouse is a transgenic strain thatfails
to express a protein that is normally expressed in thekidney and that is
associated with peroxisomes. The presentstudies provide a quantitative
examination of renal functionand structure in this strain compared to its
control CFW strain.By 52 wk of age, the mutant strain developed proteinuria
(urinaryprotein to creatinine ratio: 25 ± 14 versus 3
±1, mutant versus control), albuminuria (urinary albumin to
creatinineratio: 23 ± 15 versus 0.1 ± 0.1, mutant
versuscontrol), and hypoalbuminemia (2.1 ± 0.4
versus 2.5 ±0.2 G/dl, mutant versus control), but
without arterial hypertensionor major reduction in filtration (serum
creatinine 0.14 ±0.04 versus 0.18 ± 0.12 mg/dl, mutant
versus control).The Mpv17 glomeruli were enlarged (0.98 ±
0.12 versus0.52 ± 0.02 µm3 x
106, mutant versus control).Glomerular sclerosis became
widespread (95 ± 3 versus23 ± 32%, mutant
versus control) and was preceded bymesangiolysis and microaneurysms.
Tubulointerstitial diseasewas conspicuous by its absence. The intrarenal
vasculature wasnormal in the mutant mice. Electron microscopy demonstrated
focalfoot process fusion and mesangiolysis. Thus, this mutant strainof mouse
develops proteinuria and a distinct glomerulopathyincluding mesangiolysis but
little interstitial injury all dueto the loss of expression of a single
gene.
Transgenic mouse lines have been developed previously to serveas models of
glomerular sclerosis. In these cases, over-productionof a transgene such as
Sv40, growth hormone, or growth hormonereleasing factor produced the observed
phenotype
(1,2).
In contrast,the Mpv17 strain is a recessive mutant involving a single gene
whoseloss of function results in the development of disease. In thisstrain,
a transgenic line was produced by insertional mutagenesis,and it develops
nephrosis and severe glomerular injury
(3).Genetically, this strain
is characterized by a deletion of a1.7-kb gene transcript coding for a
hydrophobic peroxisomalmembrane protein
(4).
The present study was undertaken to further define the pathophysiologyof
this model of glomerular injury. Herein we provide more detailedfunctional
and structural quantification of the Mpv17 transgenicmouse strain.
Animal Model
Two breeding pairs of transgenic mice homozygous for the Mpv17insertion
were maintained by continuous breeding from the originalstock and were the
origins of mice used in these studies
(3).Their genotype was
verified (see below). All Mpv17-deficientmice used in the present study were
bred in the animal facilityof the University of Minnesota. Individual mice in
each studygroup were siblings. The original mutation was on an outbredCFW
background; therefore, age-matched CFW mice (Charles River,Boston, MA) were
used as controls. All animals were given freeaccess to water and standard
rodent chow.
Functional Measurements
Systolic blood pressure (SBP) was measured by the tail-cuffmethod in
conscious mice. Urine was obtained by placing micein metabolic cages for 2 to
3 h. All collections were controlledfor the time of day and conducted between
8 a.m. and 2 p.m.Blood was obtained from the tail vein. Serum and urine total
proteinwere determined using the Coomassie dye method. Serum and urine
albuminwere determined by rate nephelometry using anti-mouse albumin
antibodies(Cappel Laboratories, Malvern, PA and Bethyl Laboratories,
Montgomery,TX). Serum and urine creatinine were determined using a
modificationof the Jaffe reaction with a Beckman analyzer. The ratio of
urinaryprotein and albumin to creatinine concentrations were used asindices
of urinary excretion. The left kidney and heart wereremoved and weighed after
renal perfusion.
Structural Measurements
The kidney was perfusion-fixed with buffered 1.25% glutaraldehyde.The
percentage of glomeruli showing any sclerosis (mesangialexpansion by hyaline
and with capillary collapse) or any mesangiolysiswas calculated using
hematoxylin and eosin staining with examinationof at least 100 glomerular
profiles. For measurement of meanglomerular volume (MGV), a grid containing a
tessellation ofpoints 6.0 mm apart was used. The morphometric measurements
weremade as described previously in rats
(5). The MGV was definedas
follows: MGV = (P x A)3/2 x B/k, where P is
the average numberpoints per profile, A is the area in square micrometers
representedby each point, B equals 1.38 and represents a correction factor
thatassumes glomeruli and spherical, and k equals 1.01 and assumes
thevariation in glomerular volume has a coefficient of variationof 10%. For
the measurement of percent of interstitial volume,grid tessellations were 4.0
cm apart. The coarse to fine pointratio was 1/9. Percent interstitial volume
is equal to the sumof fine points falling on interstitium (excluding tubules
andluminal space) divided by the sum of fine points falling onwhole kidney
profile. Blood vessels were excluded and only thecortex was examined.
Electron microscopy was performed on plasticembedded sections from cortical
tissue obtained from the micemaintained for 52 wk.
Genetic Analysis
Total genomic DNA from a 1-cm segment of the mouse tail wasisolated and
purified in standard (Easy-DNA kit; Invitrogen,San Diego, CA) and digested
with BamHI. Qualitative Southernblot analysis, using the
radiolabeled (Prime-It II; Stratagene,La Jolla, CA) Mpv17 cDNA probe, was
used to confirm genotype.Total RNA from mouse kidney was isolated using a
modificationof the guanidine HCl procedure
(6). Aliqots of total RNA were
electrophoresedin a 1% formaldehyde gel and transferred to nylon membranes.
Autoradiographswere obtained (Kodak XAR-5) after nonstringent prehydrization
andhybridization protocol.
Statistical Analyses
Statistical analyses were performed using unpaired t test. All
resultsare expressed as mean ± SD.
Figure 1 demonstrates
Northern analysis of whole kidney RNAand Southern analysis of genomic DNA
from Mpv17-deficient mice.Isolated and BamH1-digested DNA from
homozygous or heterozygousor wild-type mice is depicted in the right panel.
As shown,a 3-kb band is detected in the wild-type DNA, a 6-kb band inthe
Mpv17 DNA, while DNA from the heterozygous animals showsboth bands. On the
left, a 1.7-kb transcript is detected inthe wild-type but absent in the Mpv17
RNA extracted from kidney.
Figure 1. (Left Panel) Northern analysis of both kidney RNA demonstrating a 1.7-kb
transcript in wild-type CFW mice and its absence in RNA from two Mpv17
mutants. (Right Panel) Southern analysis demonstrated the expected
BamHI digests with a 3-kb band detected in DNA from wild-type CFW
mice and a 6-kb band in the DNA from the Mpv homozygous mutants. Also, DNA
from heterozygous animals are shown illustrating both bands.
Table 1 compares general and
physiologic parameters of Mpv17mice versus wild-type CFW control
mice at the ages of 52 and8 wk. Compared with controls at 52 wk of age,
Mpv17-deficientmice demonstrated increased kidney weight, decreased serum
albumin,and elevated urinary protein and albumin excretion relativeto
creatinine. There were no demonstrable differences in bodyweight, heart
weight, SBP, hematocrit, serum creatinine, orserum total protein between the
two groups. To gain furtherinsight into the pathophysiology of this model of
glomerulosclerosis,another cohort of mice at 8 wk of age were studied. The
1-yr-oldmice had extensive glomerular pathology (see below). Therefore,we
studied another cohort at 8 wk of age. We reasoned that furtherinsight would
be gained by examining an earlier phase of pathogenesis.Surprisingly, in this
cohort, significant proteinuria and albuminuriawas evident even by 8 wk.
However, histopathology was of lesserdegree than at 52 wk (see below).
Table 1. General and physiologic parameters of Mpv17 mice versus
wild-type CFW control micea
Figure 2 displays protein
excretion as a function of time inweeks for the cohort maintained for 52 wk.
Note the near baselinerate of excretion until approximately week 40. This is
in contrastto the 8-wk cohort, which demonstrated significant proteinuriaby
8 wk (Table 1).
Figure 2. Time course of urine protein to urine creatinine concentration ratios in
homozygous Mpv17-deficient mice. The CFW control mice demonstrated urine
protein to urine creatinine ratios of only three at the final measurements of
52 wk and are not shown here.
Table 2 presents structural
and morphometric analysis of Mpv17and CFW kidneys. At 52 wk of age, Mpv17
mice demonstrated widespreadglomerular sclerosis. They had increased
glomerular volume aswell. At 8 wk of age, similar results were obtained.
However,the magnitude of differences between control and Mpv17 micewere
substantially less than at 52 wk. At neither age was fractionalinterstitial
volume different between Mpv17 and controls. Mesangiolysiswas notable only in
the Mpv17 mice and was more prevalent at52 wk than at 8 wk.
Table 2. Structural and morphometric analysis of Mpv17 and CFW
kidneysa
Figure 3 is an example of a
CFW control glomerulus at 52 wk.Note the patent capillary loops and intact
mesangium. The tubularlumens are open, and no interstitial expansion or
infiltrateis observed. In contrast, glomeruli from Mpv17-deficient mice
(Figure 4)showed
glomerulosclerosis. This glomerulus (Figure
4) displayscollapse of the capillaries, an increase in mesangial
matrix,and deposition of hyaline material. Capillary walls also appear
thickened.Global sclerosis was also observed in mutant mice at 52 wk
(Figure 5).Mesangiolysis
(Figure 6) and microaneurysms
(Figure 7) werealso notable.
Interestingly, there was no evidence of inflammatorycell infiltrate or
tubulointerstitial disease in the mutantmice despite the striking glomerular
lesions and proteinuria.In the glomeruli from Mpv17 mice examined at 8 wk,
some glomerularsclerosis occurred but the predominant lesion was
mesangiolysis.Glomeruli at this earlier stage also displayed microaneurysms.
Theintrarenal vasculature was unremarkable
(Figure 8). Electronmicroscopy
of the glomerular capillary walls revealed focalareas of foot process fusion
but no other abnormalities (Figure 9, A and
B).Mesangiolysis was readily apparent by electronmicroscopy,
suggesting that the aneurysm formation proceededupon breakdown of the
structural integrity of the mesangium
(Figure 10, A and B,and
Figure 11).
Figure 4. A glomerulus from Mpv17-deficient mouse at 52 wk demonstrates evidence of
glomerulosclerosis with collapse of capillaries, increase in mesangial matrix,
and deposition of hyaline material.
Figure 5. Occasional glomeruli in Mpv17-deficient mice at 52 wk demonstrated total
sclerosis as demonstrated by this example. The absence of inflammatory cell
infiltrates and tubulointerstitial disease was consistent in mice even at this
stage.
Figure 6. A glomerulus of Mpv17-deficient mice at 52 wk demonstrates severe
mesangiolysis. The lack of matrix accumulation or inflammatory cell infiltrate
is notable. These lesions were observed both at 52 wk and 8 wk, but were the
predominant lesions at the earlier interval.
Figure 9. (A) The glomerular capillary wall of a CFW mouse at 52 wk was normal. (B)
The glomerular capillary wall from an Mp17 mutant mouse showed focal areas of
foot process fusion. Magnification, x30,000.
Figure 10. (A) The capillary-mesangial attachments were normal in CFW mice at 52 wk.
(B) Mesangiolysis led to separation of mesangial areas from basement membrane
and endothelial layers in Mpv17 mutant mice at 52 wk. The mesangium at the
upper right demonstrates rarefication and cleavage at the mesangial waist.
Magnification, x6600.
Figure 11. A capillary loop from an Mpv17 mutant at 52 wk shows a true lumen with its
endothelial cell (arrow) to the left and dissolution of mesanguim with
aneurysm formation with a trapped erythrocyte (arrowhead) to the right.
Magnification, x6600.
In this article, we provide more detailed physiologic measurementsand
structural quantification of the previously described Mpv17transgenic mouse
strain (3). In addition, two
separate cohortsof distinct age difference were studied to gain further
insightinto the pathogenesis of glomerulosclerosis. Mpv17-deficientmice at 1
yr of age demonstrated decreased serum albumin andelevated urinary total
protein and albumin excretions consistentwith nephrosis. Proteinuria was not
manifest in this group until40 wk of age. The were no major reductions in
glomerular filtration,at least as evidenced by similar serum creatinine
levels. However,renal and glomerular hypertrophy was striking, and severe
glomerularpathology was widespread. Glomerular microaneurysms and
mesangiolysiswere precursors to the sclerotic lesions. The essentially total
absenceof tubulointerstitial disease in the presence of severe glomerular
destructionwas surprising, because in the vast majority of clinical and
experimentalglomerular disease, associated chronic interstitial change is
readilyapparent
(7,8,9).
By contrast with the group followed for 52wk, the other cohort studied for
only 8 wk demonstrated significantproteinuria and albuminuria at only 8 wk
(Figure 2). However,at this
early stage, the prevalence of sclerotic lesions wasless than at the later
interval.
The different age of onset of proteinuria in these two cohortsof mutant
mice was unexpected. Furthermore, the phenotypes forboth these cohorts were
considerably attenuated compared withthe original description of the Mpv17
strain. In that initialreport, 90% of the mutant mice were dead by 18 wk of
age (3).In our studies, there
were no deaths within the period of follow-up.Although the original
publication did not follow the quantitativecourse of proteinuria, it also
seems to have been considerablymore severe than in the present studies.
Differences in environmentalconditions such as diet seem unlikely to account
for the differentseverities among these observations. On the other hand, this
strainwas developed on the background of a wild-type CFW mouse, andit is
possible that some diminution in severity of phenotypeaccrued over time due
to the outbred nature of that strain.The variation between the present
cohorts is probably due tothis background genetic variation among our initial
breedingstock. Regarding the general mitigation of phenotype, compensating
(andunidentified) genes were likely selected unintentionally duringmultiple
generations of laboratory propagation. That is, theremay have been some
selection of animals with lesser diseasethrough successive breeding
generations either by differingfertility or simply survival. Nevertheless,
the mutant miceof both cohorts, while displaying less dramatic disease than
initiallydescribed, still demonstrated albuminuria and strikingly abnormal
glomerularstructure with both features progressing with age. The natureof
any compensating genes could also be of great interest inthemselves.
The protein encoded by the Mpv17 gene, and that fails to beexpressed in
the mutant mice, is normally expressed in the kidneyand has been detected in
glomerular epithelial cells
(3,10).
Itsfunction is not entirely clear, but it appears to be a peroxisomally
associatedprotein that has characteristics of a membrane constituent
(4).Furthermore, its absence
in fibroblasts grown from the mutantstrain leads to reduced production of
reactive oxygen species,consistent with a failure of peroxisomal generation
of suchspecies (4). Such a
failure might reside in defective transportof substrates into the peroxisome
or some defect of intraperoxisomalmetabolism. Injury to cells lacking the
protein, in particularthe glomerular epithelial cells, might arise from an
accumulationof such substrate(s) normally metabolized through peroxisomes.
Thenatural substrates of the glomerular epithelial peroxisomesare unknown.
However, normal functioning of epithelial peroxisomesis critical, at least in
the tubular epithelium, as witnessedby the severe renal microcystic disease
occurring in the Zellweger'ssyndrome, in which peroxisome formation in the
tubular epitheliumis absent
(11). Because glomerular
epithelial cells have a majorrole in determining glomerular permselectivity
to macromolecules,primary injury to this cell could easily be envisioned as
theinitial cause for proteinuria
(12).
The mesangiolysis observed as clearly as 8 wk was not notedin the original
studies on this strain, probably because thelesions were studied at a
relatively late phase. This lesionprogressed and was visible concurrently
with sclerosis in manyglomeruli by 52 wk. Mesangiolysis in other conditions
has usuallybeen associated with either primary mesangial injury, as inthe
anti-Thy.1 model, or primary endothelial injury, as in radiationnephropathy
or the thrombotic microangiopathies
(13). Giventhe current
provisional localization of the gene expressionfor Mpv17 in normal animals to
the glomerular epithelial cells,the early appearance of mesangiolysis is
intriguing. Despitethis localization, the possibility exists that mesangial
and/orendothelial cells do indeed normally express Mpv17 perhaps inlow
abundance and incur primary injury due to its absence. Alternatively,a
peroxisomal substrate that fails to be metabolized in themutant epithelial
cells might have toxic effects on the underlyingendothelium or adjacent
mesangium. Another potential mechanismwould derive from a primary defect to
the glomerular epithelialcells that would manifest not only as leakage of
macromolecules,but also as a reduction in the hydraulic conductivity of the
glomerularbarrier. In fact, proteinuric states are often associated witha
reduction of the ultrafiltration coefficient
(14). A fallin hydraulic
conductivity could lead to increases in glomerularpressure. The ensuing
mechanical stress might weaken mesangialattachments causing mesangiolysis and
microaneurysms. Additionally,the glomerular enlargement could further
contribute to mechanicalload by increasing wall tension, through the LaPlace
relationof tension to lumen radius
(15). This, too, could
predisposeto structural disruption including microaneurysms. Finally,the
observation of increased expression of matrix metalloproteinase-2(MMP-2) in
Mpv17-deficient mice provides an additional potentialexplanation for matrix
dissolution (16). The
biochemical linkbetween Mpv17 and MMP-2 is not yet clear, but an excess of
theprotease may contribute to the initial mesangiolytic process.Obviously,
these possibilities are speculative and not mutuallyexclusive. Additional
studies of the sites of expression ofthe Mpv17 protein and a more thorough
knowledge of its functionare required.
Glomerular sclerosis often follows glomerular enlargement
(1,15).
Severalpathogenetic schemes have been proposed as pathways from growthto
sclerosis, including the mechanical load imposed by an expandedcapillary
radius noted above. However, other factors in additionto glomerular
expansion, such as hypertension, seem necessarybefore full-blown sclerosis
supersedes on benign enlargement.For example, in comparing the sclerosis
sustained by two differentstrains of mice each bearing a copy of a mutant
gene that leadsto syndacticism, oligonephronia, and glomerular
sclerosis—theOs (oligosydactycism) mutant gene—the ROP strain
developedmuch more sclerosis than the C57 strain
(17). This differencewas
obtained despite the similarity in glomerular hypertrophyin the two
heterozygote strains compared to their wild-typecontrols. Also of note, the
oligonephronia of Os heterozygotesseems unlikely in the Mpv17 model, as
kidney weights were notdifferent between Mpv17 mutants and CFW. However, we
have notenumerated the glomeruli by direct methods. In the Os heterozygote,
thereduced nephron number is accompanied by a proportionately smallerkidney
than in its control. Thus, a predisposition to glomerularenlargement does not
seem to be a sufficient explanation forthe sclerosis entailed by Mpv17
deficiency. Of note, the CFWmice did display a tendency to sclerosis with age
but not ofthe same magnitude as the Mpv17 mutants.
The absence of tubulointerstitial disease, even in the micefollowed for 1
yr, was a remarkable finding. In general, proteinuriais associated with
chronic tubulointerstitial disease, and glomerularleakage of proteins has
been proposed as causative of that interstitialinjury via a variety of
mechanisms
(7,8,9).
Although some exceptionsto this linkage are notable, particularly minimal
change diseasein children, the absence of chronic tubulointerstitial changes
ina disease culminating in glomerular sclerosis is, to our knowledge,unique.
Possibly this lack of association between glomerularsclerosis and chronic
interstitial disease is characteristicof the response of the murine kidney in
contrast to rat andhuman disease. However, chronic and severe interstitial
diseasecan be induced in mice
(18). Perhaps the diminished
productionof reactive oxygen species in fibroblasts from the mutant mice
invitro and/or the enhanced MMP-2 production of mutants may provide
protectionin the tubulointerstitial compartment
(4,16).
In summary, the Mpv17-deficient strain of mouse develops progressive
proteinuria.The glomerular lesions proceed from glomerular enlargement,
microaneurysms,and mesangiolysis to glomerular sclerosis. Tubulointerstitial
diseaseis notably absent.
Acknowledgments
This work was supported in part by a grant from the Deutsche
Forschungsgemeinschaft(to Dr. Weiher), a fellowship grant from the Juvenile
DiabetesFoundation (to Dr. O'Bryan), and a grant from the National Institute
ofDiabetes and Digestive and Kidney Diseases of the National Institutesof
Health (RO1 DK31437-15; to Dr. Hostetter). We thank PattyJohnson and Marilyn
Jones for excellent work on the manuscript.
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Received for publication February 1, 1999.
Accepted for publication September 17, 1999.
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Abstract
Introduction
