Targeted Deletion of Dicer from Proximal Tubules Protects against Renal Ischemia-Reperfusion Injury

Wei, Qingqing; Bhatt, Kirti; He, Hong; Mi, Qing Sheng; Haase, Volker H.; Dong, Zheng

doi:10.1681/asn.2009070718

Cited by 211 publications

(207 citation statements)

References 36 publications

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“…However, given the mostly ubiquitous tissue distribution of transcription factors, specific targeting to particular cell types in the kidney-although feasible in animal models-will be a challenge to translate to human studies. Recent studies have highlighted the importance of epigenetic modifications, including microRNAs, 13,14 as determinants for the outcome of AKI and the AKI-to-CKD transition. Oxidants and endonucleases such as deoxyribonuclease I and endonuclease G (both highly expressed in the kidney) can have effects on nuclear constituents causing DNA damage 15 and are also potential targets in acute tubular injury.…”

Section: Nucleusmentioning

confidence: 99%

Cellular and Molecular Mechanisms of AKI

Agarwal

Dong

Harris

et al. 2016

JASN

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180

151

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In this article, we review the current evidence for the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, using ischemic AKI as a model. Highlighted are the clinical relevance of cellular and molecular targets that have been investigated in experimental models of ischemic AKI and how such models might be improved to optimize translation into successful clinical trials. In particular, development of more context-specific animal models with greater relevance to human AKI is urgently needed. Comorbidities that could alter patient susceptibility to AKI, such as underlying diabetes, aging, obesity, cancer, and CKD, should also be considered in developing these models. Finally, harmonization between academia and industry for more clinically relevant preclinical testing of potential therapeutic targets and better translational clinical trial design is also needed to achieve the goal of developing effective interventions for AKI. Cellular and molecular mechanisms of AKI have been extensively investigated in a variety of experimental models, through which a number of candidate therapies for AKI have been identified. This article reviews the current evidence by dissecting the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, and using the example of ischemic AKI to describe our approach. Specifically, we reviewed the cellular and molecular epithelial cell targets that have been investigated in experimental models of ischemic AKI, and considered the clinical relevance of these models in human AKI and how such models might be improved to optimize translation into successful clinical trials. We have structured our review to answer two key questions:

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Section: Nucleusmentioning

confidence: 99%

Cellular and Molecular Mechanisms of AKI

Agarwal

Dong

Harris

et al. 2016

JASN

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180

151

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“…For this purpose, we tested the PT-Dicer Ϫ/Ϫ mouse model where Dicer (a key enzyme for microRNA biogenesis) was specifically ablated from kidney proximal tubule cells resulting in the depletion of the majority of microRNAs (21). Somewhat surprisingly, PT-Dicer Ϫ/Ϫ mice and PT-Dicer ϩ/ϩ mice showed similar degrees of kidney injury following cisplatin treatment.…”

Section: Mir-375 Is Up-regulated In In Vivo and In Vitro Models Ofmentioning

confidence: 99%

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Hao

Lou

Wei

et al. 2017

Journal of Biological Chemistry

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Edited by Joel GottesfeldNephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatininduced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatininduced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One upregulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-B attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-B in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1␤) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1␤ protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-B collaboratively induce miR-375 expression, which, in turn, represses HNF-1␤ activity, resulting in renal tubular cell apoptosis and nephrotoxicity.

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“…At the end of these experimental models different phenotypes have emerged. Based on these different results it was reported that miRNAs played role not only in kidney development and maintaining normal kidney functions but also in the pathogenesis of kidney disease [23][24][25][26][27][28][29][30][31] . As a limitation of our study, due to small sample size our results might not reflect the actual relation between DICER gene frequency and CAKUT.…”

Section: Discussionmentioning

confidence: 99%

Doğumsal Böbrek ve İdrar Yolları Anomalilerinde MicroRNA Gen Polimorfizmleri

Tezol¹,

Delibaş²,

Ay³

et al. 2015

Cukurova Medical Journal

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Pathogenesis of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is unknown. A strong genetic contribution is emphasized. In this study we investigated the role of microRNA gene polymorphism in CAKUT. Material and Methods: 147 patients with CAKUT [(Ureteropelvic junction obstruction n: 39, vesicoureteral reflux (VUR) (n: 37), renal parenchymal malformations (n:43), anomalies of renal embryonic migration (n: 28)] and 51 healthy children were enrolled in the study. RNASEN, DGCR8, XPO5, RAN, DICER1, GEMIN3 gene polymorphisms were studied. Results: When the patient and control group were compared by polymorphisms no statistically significant difference was found. But GEMIN3 mutant allel frequency was significantly higher in VUR group than renal parenchymal malformation group. Conclusions: Mutant alleles of the GEMIN3 gene might be related to VUR pathogenesis within the context of the CAKUT spectrum. But studies with larger number of patients are required to delineate the association between CAKUT pathogenesis and microRNA gene polymorphisms.

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Targeted Deletion of Dicer from Proximal Tubules Protects against Renal Ischemia-Reperfusion Injury

Cited by 211 publications

References 36 publications

Cellular and Molecular Mechanisms of AKI

Cellular and Molecular Mechanisms of AKI

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Doğumsal Böbrek ve İdrar Yolları Anomalilerinde MicroRNA Gen Polimorfizmleri

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