The kd/kd Mouse Is a Model of Collapsing Glomerulopathy

Abstract

Collapsing glomerulopathy (CG) is associated with disorders that markedly perturb the phenotype of podocytes. The kd/kd mouse has been studied for immune and genetic causes of microcystic tubulointerstitial nephritis with little attention to its glomerular lesion. Because histologic examination revealed classic morphologic features of CG, the question arises whether podocytes in kd/kd mice exhibit additional phenotypic criteria for CG. Utilizing Tg26 mice as a positive control, immunohistochemical profiling of the podocyte phenotype was conducted simultaneously on both models. Similar to Tg26 kidneys, podocytes in kd/kd kidneys showed de novo cyclin D1, Ki-67, and desmin expression with loss of synaptopodin and WT-1 expression. Electron micrographs showed collapsed capillaries, extensive foot process effacement, and dysmorphic mitochondria in podocytes. These results indicate that the kd/kd mouse is a model of CG and raise the possibility that human equivalents of the kd susceptibility gene may exist in patients with CG.J Am Soc Nephrol 16: 2847-2851. doi: 10.1681 S ince its first clinicopathologic descriptions in the 1980s, collapsing glomerulopathy (CG) is increasingly recognized as the cause of renal failure in humans and experimental animals (1-7). In addition to the unique glomerular morphology of hyperplastic and hypertrophic podocytes overlying collapsed capillary loops (1,2), a consistent feature of CG is the marked perturbation to the mature phenotype of podocytes in diseased glomeruli (8 -13). This dysregulated podocyte phenotype is captured by select immunohistochemical markers and segregates the podocyte injury in CG from other podocytopathies (8 -13). Indeed, the application of these morphologic and immunohistochemical criteria has been instrumental in characterizing several new murine models with similarities to human CG over the last two years (3-7), each in turn furthering knowledge that disruption of normal podocyte function, whether from intrinsic or extrinsic insults, is a critical step in the development of CG.The kd/kd mouse was first described over three decades ago as a distinctive model of spontaneous proliferative disease of renal epithelium in a subline of CBA/CaH mice (14). Since then, the kd/kd mouse has been studied for immune and genetic causes of its prominent microcystic tubulointerstitial nephritis with little attention to the accompanying glomerular lesion (15)(16)(17)(18)(19). Recently, the susceptibility gene for renal disease in kd/kd mice was mapped and found to encode a prenyltransferase-like mitochondrial protein (PLMP) with shared homology to human transprenyltransferase, human geranylgeranyl pyrophosphate synthase, and a putative human tumor suppressor protein (16,19). C57BL/6 (B6) mice bred homozygous for this mutant allele manifest a tubulointerstitial disease identical to the founder strain with variable onset no earlier than 8 wk of age that ultimately progresses to end-stage renal disease by 16 to 40 wk of age (18,19). Introduction of a wild-type PLMP transgene into...

Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis

“…Desmin is normally expressed in mesangial cells but not in podocytes. However, expression in podocytes is triggered by injury, and it has therefore been used as a reliable marker of podocyte damage (33,34). As can be seen in Figure 8, modest and equivalent levels of desmin staining were seen in the glomerular mesangial cells from the kidneys in each experimental group, confirming the technical adequacy of staining.…”

ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption

“…Interestingly, the histology of affected individuals (1146, Pt5496, and Pt5497) with ADCK4 mutations showed cFSGS. In addition, mutant kd/kd mice, which have a missense mutation in Pdss2 and present with isolated nephropathy, have features of cFSGS (33). Therefore, it will be important to investigate whether nephropathy resulting from CoQ 10 deficiency results in cFSGS, because this may be a phenotypic criterion with which to choose individuals with SRNS that should be screened for genes involved in CoQ 10 biosynthesis, such as COQ2, COQ6, PDSS2, and ADCK4.…”

SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus

“…Archival formalin-fixed, paraffin-embedded kidneys from pre-natal mice at embryonic day 18 (E18), cyclin D1 À/À mice, diseased Tg26 mice (Tg26), diseased mice with nephrotoxic nephritis (NTN), diseased rats with passive Heymann nephritis (PHN), diseased rats with puromycin aminonucleoside nephrosis (PAN), and diseased mice with adriamycin nephrosis (AN), and the development of C57Bl/6 SSeCKS À/À and SSeCKS þ / þ (wild-type) mice, are described previously. 7,[19][20][21][22] Kidneys from male SSeCKS þ / þ and male SSeCKS À/À mice at 15 weeks of age were fixed in Karnovsky's solution for imaging glomerular ultrastructure by the University of Washington Pathology Research Service Laboratory on a Tecnai G2 Spirit Bio Twin Electron Microscope. Magnetic-bead isolation of capsulated and decapsulated glomeruli from wild-type mice following differential size sieving of digested kidneys was performed as described previously, 23 with isolated glomeruli immediately lysed in RIPA buffer (Teknova, Hollister, CA, USA) containing Complete Protease Inhibitor (Roche, Indianapolis, IN, USA), 50 mM sodium fluoride and 0.1 mM sodium orthovanadate at 41C to collect total protein.…”

“…[3][4][5] We therefore studied the expression of SSeCKS in archival tissue from models with existing glomerular disease representing a spectrum of podocytopathies, 30 specifically the following: Tg26 (a model of collapsing glomerulopathy), 20 mice with passive NTN (a model of crescentic glomerulonephritis), 24 rats with PAN (a model of minimal change disease), 24 rats with PHN (a model of membranous nephropathy), 24 and mice with AN (a model of focal segmental glomerulosclerosis). 24 Examination of these diseased models suggests that SSeCKSpositive PECs are major constituents of extracapillary glomerular lesions.…”