A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse

Zheng, Zongyu; Schmidt‐Ott, Kai M.; Chua, Streamson C.; Foster, Kirk A.; Frankel, Rachelle Z.; Pavlidis, Paul; Barasch, Jonathan; D’Agati, Vivette D.; Gharavi, Ali G.

doi:10.1073/pnas.0409786102

Cited by 93 publications

(93 citation statements)

References 33 publications

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“…In recent preliminary studies, we also found that our transgenic mice are susceptible to puromycin injury, so it is likely that increased podocyte COX-2 expression may predispose podocytes to a variety of injury. Recent studies suggested that susceptibility to Adriamycin nephropathy in mice may link to a gene locus on chromosome 16 (31). Although this locus is distinct from the COX-2 gene, which is found on chromosome 1, when the specific predisposing gene products are identified, it would be interesting to investigate potential interactions with COX-2 expression.…”

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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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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“…After 3 days of VPA treatment the urinary podocin mRNA level has already dropped significantly compared with that of the ADR group. (#P Ͻ 0.001; **P Ͻ 0.01) BASIC RESEARCH www.jasn.org thelium in proteinuria 34 in a less susceptible mouse strain 35 requiring a high ADR dose. Besides glomerular apoptosis, podocytes can be lost in the urine because of detachment.…”

Section: Discussionmentioning

confidence: 99%

Valproic Acid Attenuates Proteinuria and Kidney Injury

Beneden

Geers

Pauwels

et al. 2011

Journal of the American Society of Nephrology

117

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Inhibitors of histone deacetylase (HDAC) have anti-inflammatory and antifibrotic effects in several organs and tissues, but their effect on the progression of renal disease is unknown. Here, we studied the effect of valproic acid in adriamycin-induced nephropathy in mice. Administration of valproic acid before kidney injury prevented the development of proteinuria and the onset of glomerulosclerosis. Even after postponing treatment until the peak of adriamycin-induced proteinuria, valproic acid rapidly decreased the quantity of proteinuria and attenuated the progression of renal disease. Valproic acid abrogated the decrease in glomerular acetylation observed during adriamycin-induced nephropathy. Furthermore, valproic acid attenuated the significant upregulation of profibrotic and proinflammatory genes, the deposition of collagen, and the infiltration of macrophages into the kidney. Valproic acid decreased glomerular apoptosis and proliferation induced by adriamycin. Ultrastructural studies further supported the protective effect of valproic acid on podocytes in this model. Taken together, these data suggest that HDACs contribute to the pathogenesis of renal disease and that HDAC inhibitors may have therapeutic potential in CKD.

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“…It is possible that distinct substrates are methylated in different fashions by this enzyme. A study that focused on identifying loci that impart susceptibility to drug-induced nephropathy has implicated PRMT7 as a candidate (Zheng et al, 2005). Also, PRMT7 plays a role in male germline imprinted gene methylation through its interaction with CTCFL (a protein that associates with the imprinting control region) and subsequent methylation of histone 4 Arg3 (Jelinic et al, 2006).…”

Section: Prmt7mentioning

confidence: 99%