Irradiation Prolongs Survival of Alport Mice

Katayama, Kan; Kawano, M.; Naito, Ichiro; Ishikawa, Hitoshi; Sado, Yoshikazu; Asakawa, Nagisa; Murata, Tetsuya; Oosugi, Kazuki; Kiyohara, Michiyo; Ishikawa, Eiji; M, Ito; Nomura, Shinsuke

doi:10.1681/asn.2007070829

Cited by 44 publications

(41 citation statements)

References 24 publications

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“…35 To confuse matters further, another study with Col4a3 null mice in the 129 ϫ 1/SvJ strain showed no differences in disease severity or longevity between knockouts transplanted with marrow from either wildtype or knockout animals. 36 Moreover, there was no deposition of collagen ␣3(IV) in GBMs in either case. 36 The authors provided evidence that irradiation itself, through an unknown mechanism, can contribute to the prolonged survival of Col4a3 null mice.…”

Section: Discussionmentioning

confidence: 88%

“…36 The authors provided evidence that irradiation itself, through an unknown mechanism, can contribute to the prolonged survival of Col4a3 null mice. 36 As we learn more about GBM protein synthesis and secretion in general, and podocyte cell biology in particular, perhaps more effective therapies can be developed to repair collagen ␣3␣4␣5(IV) assembly by podocytes in Alport patients.…”

Section: Discussionmentioning

confidence: 99%

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Cellular Origins of Type IV Collagen Networks in Developing Glomeruli

Abrahamson

Hudson²,

Stroganova³

et al. 2009

Journal of the American Society of Nephrology

176

148

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Laminin and type IV collagen composition of the glomerular basement membrane changes during glomerular development and maturation. Although it is known that both glomerular endothelial cells and podocytes produce different laminin isoforms at the appropriate stages of development, the cellular origins for the different type IV collagen heterotrimers that appear during development are unknown. Here, immunoelectron microscopy demonstrated that endothelial cells, mesangial cells, and podocytes of immature glomeruli synthesize collagen ␣1␣2␣1(IV). However, intracellular labeling revealed that podocytes, but not endothelial or mesangial cells, contain collagen ␣3␣4␣5(IV). To evaluate the origins of collagen IV further, we transplanted embryonic kidneys from Col4a3-null mutants (Alport mice) into kidneys of newborn, wildtype mice. Hybrid glomeruli within grafts containing numerous host-derived, wildtype endothelial cells never expressed collagen ␣3␣4␣5(IV). Finally, confocal microscopy of glomeruli from infant Alport mice that had been dually labeled with anti-collagen ␣5(IV) and the podocyte marker anti-GLEPP1 showed immunolabeling exclusively within podocytes. Together, these results indicate that collagen ␣3␣4␣5(IV) originates solely from podocytes; therefore, glomerular Alport disease is a genetic defect that manifests specifically within this cell type. Basement membranes are thin sheets of extracellular matrix that underlie epithelial cells, including the vascular endothelium, and surround all muscle cells, Schwann cells, and adipocytes. They are composed of polymers of laminin and type IV collagen, and also contain nidogen/entactin, and proteoglycans. During glomerulogenesis, a basement membrane beneath developing endothelial cells fuses with a separate basement membrane layer beneath differentiating podocytes, to produce the glomerular basement membrane (GBM) shared on opposing surfaces by both cell types. 1 Unlike most basement membranes in the body, the laminin and collagen IV composition of the GBM changes temporally as the glomerulus develops. 2 The earliest GBMs of comma-and S-shaped nephrons contain laminin ␣1␤1␥1 (laminin 111), whereas those at later developmental stages and in adulthood contain laminin ␣5␤2␥1 (laminin 521). 2,3 Previously, we showed by postfixation immunoelectron microscopy that both endothelial cells and podocytes synthesize laminin ␣1 and ␤1 initially, and both cells then undergo a laminin isoform switch and synthesize laminin ␣5 and ␤2 as glomeruli mature. 4 The mechanism and reason why laminin replacement occurs are unknown, but

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Cellular Origins of Type IV Collagen Networks in Developing Glomeruli

Abrahamson

Hudson²,

Stroganova³

et al. 2009

Journal of the American Society of Nephrology

176

148

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“…Our previous report demonstrated that lymphocyte ablation improves renal interstitial fibrosis in Col4a3/Rag-1 double-KO mice on C57BL/6 background 16 as a result of diminished interstitial infiltrates. Recently, Katayama et al 13 provided evidence for an increase in the survival of Col4A3 knockout mice on 129Sv background, associated with improvement in renal function and histologic findings after total body irradiation; however, that study does not conclusively negate the specific therapeutic potential of BM-derived cells in the recovery of the renal phenotype.…”

mentioning

confidence: 97%

“…Nonetheless, a disease-modulating effect of total body irradiation on the progression of the kidney disease was recently suggested in Col4A3 knockout mice on the 129Sv genetic background. 13 Unlike the human disease, kidney disease progression in Col4A3 knockout mice involves significant immune infiltration; therefore, a case can be made that total body irradiation and subsequent BM transplantation in Col4A3 knockout mice could modulate disease progression by diminishing renal immune infiltration. Our previous report demonstrated that lymphocyte ablation improves renal interstitial fibrosis in Col4a3/Rag-1 double-KO mice on C57BL/6 background 16 as a result of diminished interstitial infiltrates.…”

mentioning

confidence: 99%

Stem Cell Therapies Benefit Alport Syndrome

LeBleu

Sugimoto²,

Mundel³

et al. 2009

Journal of the American Society of Nephrology

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Patients with Alport syndrome progressively lose renal function as a result of defective type IV collagen in their glomerular basement membrane. In mice lacking the ␣3 chain of type IV collagen (Col4A3 knockout mice), a model for Alport syndrome, transplantation of wild-type bone marrow repairs the renal disease. It is unknown whether cell-based therapies that do not require transplantation have similar potential. Here, infusion of wild-type bone marrow-derived cells into unconditioned, nonirradiated Col4A3 knockout mice during the late stage of disease significantly improved renal histology and function. Furthermore, transfusion of unfractionated wild-type blood into unconditioned, nonirradiated Col4A3 knockout mice improved the renal phenotype and significantly improved survival. Injection of mouse and human embryonic stem cells into Col4A3 knockout mice produced similar results. Regardless of treatment modality, the improvement in the architecture of the glomerular basement membrane is associated with de novo expression of the ␣3(IV) chain. These data provide further support for testing cell-based therapies for Alport syndrome.

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“…[2][3][4][5][6][7][8][9][10] Improved renal outcomes were reported in a number of these studies, although it is debated whether this is the result of cytokines or secreted factors produced by the BMDCs or the consequence of transdifferentiation of BMDCs into specific renal cell types. In regard to the latter, studies suggested variable abilities of these cells to transdifferentiate into renal endothelial, tubular, and glomerular epithelial cell lineages.…”

mentioning

confidence: 99%