Adriamycin-induced nephropathy as a model of chronic progressive glomerular disease

Okuda, Seiya; Oh, Yukinori; Tsuruda, Hiroshi; Onoyama, Kaoru; Fujimi, Satoshi; Fujishima, Masatoshi

doi:10.1038/ki.1986.28

Cited by 229 publications

(194 citation statements)

References 11 publications

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“…A long term study demonstrated severe renal damage with extensive glomerular sclerosis and tubulointerstitial degeneration in ADR-treated rats (3). ADR-induced glomerulosclerosis in the rat is a progressive glomerulosclerosis model similar to human focal segmental glomerulosclerosis (3,4). In the advanced stages of the ADR model there is a severe interstitial infiltration of mononuclear cells (3), and in our preliminary experiments we found that there is also a significant infiltration of ␥␦ T cells in the ADR kidney (4).…”

Section: Infiltration Of Canonical V␥4/v␦1 ␥␦ T Cells In Anmentioning

confidence: 62%

Infiltration of Canonical Vγ4/Vδ1 γδ T Cells in an Adriamycin-Induced Progressive Renal Failure Model

Ando

Watson

et al. 2001

The Journal of Immunology

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We have previously reported an infiltration of renal interstitial γδ T cells in Adriamycin-induced progressive glomerulosclerosis in the rat kidney. The TCR repertoire and sequences used by these γδ T cells have now been studied. Two injections of Adriamycin 14 days apart caused segmental glomerulosclerosis, massive interstitial infiltration of mononuclear cells, and end-stage renal failure. Flow cytometry of lymphocyte subpopulations with Abs to CD3, the γδ TCR, and the αβ TCR showed that γδ T cells as a proportion of CD3+ cells were increased in Adriamycin-treated kidneys (8.5 ± 5.4%), but not in lymph nodes (1.3 ± 0.4%). A semiquantitative score of glomerular damage (r = 0.65; p < 0.01) and creatinine (r = 0.62; p < 0.01) correlated significantly with the presence of γδ T cells. TCR Vγ repertoire analysis by RT-PCR and Southern blotting showed that Vγ2 was the dominant subfamily in lymph nodes, whereas Vγ4 became the predominant subfamily in advanced stages of the rat Adriamycin-treated kidney. Sequencing of the Vγ4-Jγ junctional region showed an invariant sequence. The amino acid sequence of the junctional region of the Vγ4 TCR was the same as the reported mouse canonical Vγ4 TCR sequence. Analysis of the kidney Vδ repertoire showed dominant expression of Vδ1, and sequencing again revealed the selective expression of a canonical Vδ1 gene. Semiquantitative RT-PCR for cytokine gene expression showed that γδ T cells from the kidneys expressed TGF-β, but not IL-4, IL-10, or IFN-γ. These results suggest that the predominant γδ T cells in the Adriamycin kidney use an invariant Vγ4/Vδ1 receptor.

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Section: Infiltration Of Canonical V␥4/v␦1 ␥␦ T Cells In Anmentioning

confidence: 62%

Infiltration of Canonical Vγ4/Vδ1 γδ T Cells in an Adriamycin-Induced Progressive Renal Failure Model

Ando

Watson

et al. 2001

The Journal of Immunology

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“…Adriamycin causes well-described podocyte injury in rats (21), but its nephrotoxicity in mice is strain dependent. Balb/C mice are susceptible to podocyte injury by Adriamycin (22,23), whereas other strains that have been tested normally are resistant (24).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Cyclooxygenase-2 Predisposes to Podocyte Injury

Cheng¹,

Wang²,

Jo³

et al. 2007

Journal of the American Society of Nephrology

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Increased podocyte cyclooxygenase-2 (COX-2) expression is seen in rats after renal ablation and Thy-1 nephritis and in cultured murine podocytes in response to mechanical stress. For investigation of whether COX-2 overexpression plays a role in podocyte injury, transgenic B6/D2 mice in which COX-2 expression was driven by a nephrin promoter were established. Selective upregulation of COX-2 expression in podocytes of transgenic mouse kidneys was confirmed by immunoblotting and immunohistochemistry. Whether upregulation of podocyte-specific COX-2 expression enhanced sensitivity to the development of Adriamycin nephropathy was examined. Adriamycin administration induced dramatically more albuminuria and foot process effacement and reduced glomerular nephrin mRNA and immunoreactivity in transgenic mice compared with wild-type littermates. Adriamycin also markedly increased immunoreactive COX-2 expression in podocytes from transgenic mice compared with the wild-type mice. Reverse transcriptase-PCR indicated that this increase represented a stimulation of endogenous COX-2 mRNA expression rather than COX-2 mRNA driven by the nephrin promoter. Balb/C mice, which are susceptible to renal injury by Adriamycin, also increased podocyte COX-2 expression and reduced nephrin expression in response to administration of the drug. Long-term treatment with the COX-2-specific inhibitor SC58236 ameliorated the albuminuria that was induced by Adriamycin in the transgenic mice. SC58236 also reduced Adriamycin-induced foot process effacement in both the COX-2 transgenic mice and Balb/C mice. Therefore, overexpression of COX-2 may predispose podocytes to further injury.

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“…It offers the opportunity to study the effect of MSCs at various time points of the disease, model of nephrosis (2,24). Overall 55 rats were utilized, 14 for acute ADR, 33 for chronic ADR, and 8 were including a potential reparative effect when renal lesions have already developed.…”

Section: Mesenchymal Stem Cells In Chronic Adriamycin-induced Nephrosmentioning

confidence: 99%

“…ADR-induced renal failure is a well-accepted chronic Only cells between passage 4 and 10, positive for CD73, CD90, and CD105 surface markers (Pharmingen, disease model of progressive glomerulosclerosis in rats (1,2,24). It is characterized by rapid development of pro-BD Biosciences, Franklin Lakes, NJ, USA) and negative for CD45 (>95%) were utilized in all in vitro and in teinuria and glomerulosclerosis and evolves to renal fibrosis and renal failure.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Protective Effect in Adriamycin Model of Nephropathy

et al. 2008

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Mesenchymal stem cells (MSCs) may be of value in regeneration of renal tissue after damage; however, lack of biological knowledge and variability of results in animal models limit their utilization. We studied the effects of MSCs on podocytes in vitro and in vivo utilizing adriamycin (ADR) as a model of renal toxicity. The in vivo experimental approach was carried out in male Sprague-Dawley rats (overall 60 animals) treated with different ADR schemes to induce acute and chronic nephrosis. MSCs were given a) concomitantly to ADR in tail vein or b) in aorta and c) in tail vein 60 days after ADR. Homing was assessed with PKH26-MSCs. MSCs rescued podocytes from apoptosis induced by ADR in vitro. The maximal effect (80% rescue) was obtained with MSCs/podocytes coculture ratio of 1:1 for 72 h. All rats treated with ADR developed nephrosis. MSCs did not modify the clinical parameters (i.e., proteinuria, serum creatinine, lipids) but protected the kidney from severe glomerulosclerosis when given concomitantly to ADR. Rats given MSCs 60 days after ADR developed the same severe renal damage. Only a few MSCs were found in renal tubule-interstitial areas 1-24 h after injection and no MSCs were detected in glomeruli. MSCs reduced apoptosis of podocytes treated with ADR in vitro. Early and repeated MSCs infusion blunted glomerular damage in chronic ADR-induced nephropathy. MSCs did not modify proteinuria and progression to renal failure, which implies lack of regenerative potential in this model.

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Adriamycin-induced nephropathy as a model of chronic progressive glomerular disease

Cited by 229 publications

References 11 publications

Infiltration of Canonical Vγ4/Vδ1 γδ T Cells in an Adriamycin-Induced Progressive Renal Failure Model

Infiltration of Canonical Vγ4/Vδ1 γδ T Cells in an Adriamycin-Induced Progressive Renal Failure Model

Overexpression of Cyclooxygenase-2 Predisposes to Podocyte Injury

Mesenchymal Stem Cells Protective Effect in Adriamycin Model of Nephropathy

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