The kd/kd Mouse Is a Model of Collapsing Glomerulopathy
Laura Barisoni*,
Michael P. Madaio,
Maria Eraso,
David L. Gasser and
Peter J. Nelson
* Department of Pathology and Division of Nephrology, New York University School of Medicine, New York, New York; and the Renal Electrolyte & Hypertension Division, and Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Address correspondence to: Dr. Peter J. Nelson, Division of Nephrology, New York University School of Medicine, OBV-CD696, 550 First Avenue, New York, NY 10016. Phone: 212-263-7681; Fax: 212-263-7683; E-mail: nelsop02{at}popmail.med.nyu.edu
Collapsing glomerulopathy (CG) is associated with disordersthat markedly perturb the phenotype of podocytes. The kd/kdmouse has been studied for immune and genetic causes of microcystictubulointerstitial nephritis with little attention to its glomerularlesion. Because histologic examination revealed classic morphologicfeatures of CG, the question arises whether podocytes in kd/kdmice exhibit additional phenotypic criteria for CG. UtilizingTg26 mice as a positive control, immunohistochemical profilingof the podocyte phenotype was conducted simultaneously on bothmodels. Similar to Tg26 kidneys, podocytes in kd/kd kidneysshowed de novo cyclin D1, Ki-67, and desmin expression withloss of synaptopodin and WT-1 expression. Electron micrographsshowed collapsed capillaries, extensive foot process effacement,and dysmorphic mitochondria in podocytes. These results indicatethat the kd/kd mouse is a model of CG and raise the possibilitythat human equivalents of the kd susceptibility gene may existin patients with CG.
Since its first clinicopathologic descriptions in the 1980s,collapsing glomerulopathy (CG) is increasingly recognized asthe cause of renal failure in humans and experimental animals(1–7). In addition to the unique glomerular morphologyof hyperplastic and hypertrophic podocytes overlying collapsedcapillary loops (1,2), a consistent feature of CG is the markedperturbation to the mature phenotype of podocytes in diseasedglomeruli (8–13). This dysregulated podocyte phenotypeis captured by select immunohistochemical markers and segregatesthe podocyte injury in CG from other podocytopathies (8–13).Indeed, the application of these morphologic and immunohistochemicalcriteria has been instrumental in characterizing several newmurine models with similarities to human CG over the last twoyears (3–7), each in turn furthering knowledge that disruptionof normal podocyte function, whether from intrinsic or extrinsicinsults, is a critical step in the development of CG.
The kd/kd mouse was first described over three decades ago asa distinctive model of spontaneous proliferative disease ofrenal epithelium in a subline of CBA/CaH mice (14). Since then,the kd/kd mouse has been studied for immune and genetic causesof its prominent microcystic tubulointerstitial nephritis withlittle attention to the accompanying glomerular lesion (15–19).Recently, the susceptibility gene for renal disease in kd/kdmice was mapped and found to encode a prenyltransferase-likemitochondrial protein (PLMP) with shared homology to human transprenyltransferase,human geranylgeranyl pyrophosphate synthase, and a putativehuman tumor suppressor protein (16,19). C57BL/6 (B6) mice bredhomozygous for this mutant allele manifest a tubulointerstitialdisease identical to the founder strain with variable onsetno earlier than 8 wk of age that ultimately progresses to end-stagerenal disease by 16 to 40 wk of age (18,19). Introduction ofa wild-type PLMP transgene into B6 kd/kd mice can rescue thisrenal disease (19), suggesting that the kd susceptibility geneis required, but perhaps not sufficient alone, for the developmentof nephropathy in this model. Because histologic examinationof glomeruli in diseased B6 kd/kd mice revealed glomerular collapseand extensive glomerulosclerosis with hypertrophy and hyperplasiaof overlying podocytes (Figure 1), we asked whether the additionalimmunohistochemical and ultrastructural criteria that defineCG exist in B6 kd/kd mice. Using heterozygous Tg26 mice as apreviously characterized positive control for murine CG (20,21),quantitative profiling of the phenotype of podocytes was conductedsimultaneously across the two models.
Figure 1. Collapsing glomerulopathy in B6 kd/kd mice. (A) Normal glomerulus in a B6 wild-type mouse. (B) Normal glomerulus in a nontransgenic Tg26 mouse. (C) B6 kd/kd mouse with glomerular collapse and podocyte hypertrophy and hyperplasia; focal injury to the parietal epithelium is also noted. (D) Tg26 heterozygote with glomerular collapsing features and prominent podocyte hypertrophy and hyperplasia with pseudocrescent formation and bridging to parietal epithelial cells. (E) B6 kd/kd mouse showing glomerular collapse and pseudocrescent formation adjacent to severe tubulointerstitial damage with prominent, protein-filled microcysts. (F) Tg26 heterozygote showing glomerular collapse with pseudocrescent formation adjacent to severe tubulointerstitial damage with prominent microcysts. (G) Electron micrograph of a glomerular capillary in a B6 wild-type mouse shows glomerular basement membranes (GBM) that are normal in thickness and contour, as well as podocytes with well-preserved foot processes. (H) Electron micrograph of a glomerular capillary in a diseased B6 kd/kd mouse shows GBM that are wrinkled and folded (indicating collapse) with subocclusion of the capillary lumen. There is also extensive foot process effacement accompanied by condensation of the actin-based cytoskeleton and swelling of primary processes. (I) A healthy podocyte from a B6 wild-type mouse containing few normal mitochondria with regular matrix density (arrows). (J) A diseased podocyte from a B6 kd/kd mouse containing numerous abnormal mitochondria with compressed cristae forming truncated cisternae and granular-appearing matrix (arrows). Magnification, x400 in A through D, x100 in E and F, x25,000 in G through J. The sections in A through F are silver-stained.
Mice
All studies on Tg26 and B6 kd/kd tissues complied with InstitutionalAnimal Care and Use Committee regulations of the New York UniversitySchool of Medicine and the University of Pennsylvania Schoolof Medicine, respectively. Archival formalin-fixed, paraffin-embeddedkidneys from six homozygous B6 kd/kd mice ranging in ages from15 to 43 wk and from two 15-wk-old wild-type B6 controls werestudied. Archival formalin-fixed, paraffin-embedded kidneysfrom three 6-wk-old heterozygous Tg26 mice and from one 6-wk-oldnontransgenic littermate were used as positive and negativecontrols, respectively, for murine CG (20,21).
Histopathology
Three-µm thick serial sections from each specimen werestained with hematoxylin and eosin (H&E), trichrome, periodic-acidschiff (PAS), or silver. Quantitative histopathology for theextent of glomerular sclerosis, capillary tuft collapse withoverlying podocyte hypertrophy and hyperplasia, tubular microcysts,acute tubular injury, tubular atrophy, and interstitial inflammationand fibrosis, was singularly evaluated across the entirety ofeach section. This quantitation was performed as follows: Thepercent of all glomeruli with sclerosis (defined as segmentalor global solidification of the glomerular tuft on silver ortrichrome stain); the percent of all glomeruli with collapse(defined as wrinkling and folding of the glomerular basementmembranes of any portion of the capillary tuft on silver stain)with overlying podocyte hypertrophy and hyperplasia, scaledas zero (none), +/– (1 to 5%), 1+ (6 to 25%), 2+ (26 to50%), or 3+ (>51%); the percent area of the total tubulointerstitialcompartment with tubular microcysts (defined as tubules dilatedat least 4 times the normal diameter), acute tubular injury(defined as flattening of the tubular epithelium, loss of thebrush border, or blebbing of the cytoplasm and nuclear hyperchromasiawith prominent nucleoli), tubular atrophy (defined as thickenedtubular basement membranes with small cuboidal tubular cells),or interstitial inflammation and fibrosis, scaled as zero (none),+/– (1 to 5%), 1+ (6 to 25%), 2+ (26 to 50%), or 3+ (>51%).
Immunohistochemistry on 3-µm thick serial sections fromeach specimen to detect changes to the phenotype of mature podocyteswas performed using primary antibodies to mark podocyte cell-cycleengagement (cyclin D1, clone SP4, Lab Vision, Fremont, CA),podocyte cell-cycle progression (Ki-67, clone SP6, Lab Vision),the state of podocyte differentiation (synaptopodin, mouse monoclonal,gift of Dr. Peter Mundel, Mount Sinai School of Medicine, NewYork, NY; WT-1, clone 6F-H2, NovoCastra, Newcastle, UK), andpodocyte injury (desmin, clone D33, DAKO, Carpinteria, CA) asdescribed previously on Tg26 kidneys (20,21). Sections stainedfor synaptopodin or desmin were counterstained with hematoxylin,and sections stained with cyclin D1, Ki-67, or WT-1 were counterstainedwith PAS. Quantitation of the change in podocyte phenotype ineach mouse was calculated as the percent of all nongloballysclerotic glomeruli containing podocytes with cyclin D1 in oneor more nuclei, Ki-67 in one or more nuclei, desmin in at leastone segmental distribution, loss of WT-1 in at least one segmentaldistribution, or with trace or less synaptopodin in the cytoplasm.Globally sclerotic glomeruli were excluded in the analysis dueto the absence of podocytes.
Ultrastructural Analysis
Small samples of renal cortex from B6 kd/kd mice were fixedin 2.5% glutaraldehyde and 2.0% paraformaldehyde in 0.1 M sodiumcacodylate buffer, pH 7.4, overnight at 4°C. Samples werepostfixed with 2.0% osmium tetroxide in 0.1 M cacodylate bufferfor 1 h at 4°C. After additional washing in 0.1 M cacodylatebuffer and distilled H2O, samples were stained with 2% aqueousuranyl acetate for 30 min at room temperature. Samples werethen rinsed in distilled H2O, dehydrated, infiltrated, and embeddedin Embed 812 (Electron Microscopy Science, Fort Washington,PA). Sections were examined in a JEOL100CX electron microscope.Digital images recorded on a Hamamatsu camera were analyzedfor the presence of folding and wrinkling of the glomerularbasement membrane and foot process effacement.
The glomerular lesion of collapsing glomerulopathy is definedmorphologically by the presence of hyperplastic and hypertrophicpodocytes overlying collapsed capillary loops in either a segmentalor global distribution within the glomerular tuft (1,2). Thesediseased podocytes undergo a marked perturbation in their mature,quiescent phenotype, characterized by proliferation and dedifferentiation,which is not observed in other proteinuric lesions (8–13).Concurrent examination and quantitation of the morphologic injurywithin glomeruli of B6 kd/kd and Tg26 mice, coupled with quantitativeprofiling of the podocyte phenotype by immunohistochemical markers,demonstrate that the renal disease in B6 kd/kd mice fulfillsthe criteria for CG (Figures 1 and 2; Table 1). Similar to CGin Tg26 mice (20,21), diseased glomeruli in B6 kd/kd mice showsegmental and global sclerosis and collapse of capillary loopswith folding and wrinkling of the glomerular basement membrane,extensive foot process effacement with marked condensation ofthe actin cytoskeleton and focal loss of primary processes ofpodocytes, and hyperplastic and hypertrophic podocytes withde novo cyclin D1, Ki-67, and desmin expression and reducedsynaptopodin and WT-1 expression. In addition to these significantalterations to podocytes, focal injury to the parietal epitheliumlining Bowman’s capsule is evident in B6 kd/kd mice. Despitethe variable, age-dependent penetrance of CG in B6 kd/kd mice,there appears to be a positive correlation suggesting causalitybetween the extent of glomerular injury and the downstream tubulointerstitialdisease in each animal. Together, these data indicate that theB6 kd/kd mouse is a previously unrecognized model of CG. Moreover,similar to prior observations of changes to the morphology ofmitochondria in the tubular epithelium of B6 kd/kd mice (19),abnormal mitochondria are also found in diseased podocytes.
Figure 2. Comparison of the podocyte phenotype between B6 wild-type and B6 kd/kd mice. Synaptopodin stains strongly in the cytoplasm of podocytes in B6 wild-type mice indicating the normal, differentiated state, whereas there is a marked loss of synaptopodin expression in diseased podocytes in B6 kd/kd mice. An identical change is observed in the nuclear staining of WT-1, a second marker of podocyte differentiation. Nuclear staining of Ki-67, a marker of cell-cycle progression, is not detected in glomeruli of B6 wild-type mice, but is focally positive in glomerular epithelial cells forming pseudocrescents in B6 kd/kd mice. Likewise, nuclear staining of cyclin D1, a marker of cell-cycle engagement, is diffusely negative in podocytes of B6 wild-type mice (but positive in some intracapillary cells), whereas it is detected in podocytes in B6 kd/kd mice in areas of podocyte hypertrophy and hyperplasia. Glomerular staining of desmin is found only in mesangial cells in B6 wild-type mice, but is markedly upregulated in injured podocytes in B6 kd/kd mice. Magnification, x400.
Table 1. Collapsing glomerulopathy in B6 kd/kd and Tg26 mice: Morphologic injury and changes to the podocyte phenotype
The exact pathogenic steps whereby mutant PLMP causes CG inB6 kd/kd mice are not known. Antisera to PLMP localize to dysmorphicmitochondria in renal epithelium of B6 kd/kd mice (19). Thissuggests that mutant PLMP might directly alter mitochondrialfunction in podocytes, lowering the threshold to injury fromenergetic stress. This is an attractive hypothesis as CG andfocal segmental glomerulosclerosis can develop in patients withgenetically-acquired mitochondrial cytopathies (22,23). Furthermore,CG is associated with a growing list of disease stresses (1).If this is indeed correct, B6 kd/kd mice would represent thefirst model of CG due to a mitochondrial disorder, providinga ready system to investigate how environmental factors mayinfluence the manifestation of this abnormality within podocytes.Interestingly, bisphosphonate drugs, small molecules linkedto podocyte injury and CG in humans (24,25), can perturb mitochondrialfunction (26), and human mitochondrial transprenyltransferasessharing homology with PLMP contain specificity determining residuesfor bisphosphonate binding (i.e., the amino acid sequence DDXXD).However, the extent to which bisphosphonates interact with andinhibit human transprenyltransferases is still unclear (EricOldfield, University of Illinois at Urbana-Champaign, personalcommunication).
Alternatively but not mutually exclusively, an aberrant autoimmune-likeresponse to renal parenchymal damage specific to B6 mice maydictate the development of CG in this model, as suggested byprior studies on B6 kd/kd mice (18). Although the phenotypicmanifestation of renal disease after transfer of the kd susceptibilitygene to B6 mice, a strain biased toward T-helper type 1 immunity(27), appears to be identical to that of the founder strain,we do not know if the degenerate glomeruli, glomerulosclerosis,and albuminuria noted in the original report on CBA/CaH kd/kdmice (14) is a product of the same podocytopathy reported here(i.e., CBA/CaH kd/kd tissues are no longer available). Indeed,although specific genes that may modify the nephropathy in B6kd/kd have not been identified, the CG in B6 kd/kd mice mayultimately be attributable to background genetic differencesbetween strains of mice. For example, using a mouse geneticsapproach with Tg26 mice to investigate the racial predilectionof HIV-induced CG, Gharavi et al. identified susceptibilityloci and strain-specific modifications to specific featuresof the renal disease in this model (28), including ameliorationby BALB/C mice, a strain biased toward T-helper type 2 immunity(27). These intriguing observations regarding what is likelyto be a polygenic disease raise the possibility that human equivalentsof the kd susceptibility gene may exist and predispose somepatients to develop CG. Further studies on B6 kd/kd mice, thefirst model of CG caused by a spontaneously occurring mutationidentified through forward genetics, not a product of reversegenetics (3,4,6,7,20), and of patients with CG will help answerthese questions.
Acknowledgments
We thank Ali Gharavi and David B. Thomas for critical readingof the manuscript, Ke Lin for excellent technical support, RayMeade from the Biomedical Imaging Core of the University ofPennsylvania for the electron microscopy, and David B. Thomas,J. Charles Jennette, and Surya Seshan for reviewing the pathologyin a blinded fashion. This work was supported by National Institutesof Health grants DK55852 (D.L.G.) and DK065498 (P.J.N.).
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org
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Abstract
Introduction
