MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

Lakhia, Ronak; Hajarnis, Sachin; Williams, Darren R.; Aboudehen, Karam; Yheskel, Matanel; Xing, Chao; Hatley, Mark E.; Torres, Vicente E.; Wallace, Darren P.; Patel, Vishal

doi:10.1681/asn.2015060634

Cited by 66 publications

(63 citation statements)

References 57 publications

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“…The expression of the miR-17~92 cluster, consisting of miR-17, -18a, 19a, -20a, -19b1 and -92a1, seems to be essential for normal nephrogenesis since ablation of the cluster in a mouse model resulted in reduced numbers of nephrons (Marrone, et al, 2014). Furthermore, miR-21 and miR-150 were found highly enriched in kidney cysts of patients with polycystic kidney disease and kidney biopsies from patients with lupus nephritis, respectively (Lakhia, et al, 2015; H. Zhou, et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs and drug-induced kidney injury

Pavkovic

Vaidya

2016

Pharmacology & Therapeutics

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Drug-induced kidney injury (DIKI) is a severe complication in hospitalized patients associated with higher probabilities of developing progressive chronic kidney disease or end-stage renal diseases. Furthermore, DIKI is a problem during preclinical and clinical phases of drug development leading to high rates of project terminations. Understanding the molecular perturbations caused by DIKI would pave the way for a new class of therapeutics to mitigate the damage. Yet, another approach to ameliorate DIKI is identifying sensitive and specific translational biomarkers that outperform the current diagnostic analytes like serum creatinine and facilitate early diagnosis. MicroRNAs (miRNAs), a class of non-coding RNAs, are increasingly being recognized to have a two-pronged approach towards DIKI management: 1) miRNAs have a regulatory role in gene expression and signaling pathways thereby making them novel interventional targets and 2) miRNAs enable diagnosis and prognosis of DIKI because of their stable presence in biofluids. In this review, apart from summarizing the literature on miRNAs in DIKI, we report small RNA sequencing results showing miRNA expression profiles at baseline in normal kidney samples from mice and humans. Additionally, we also compared the miRNA expression in biopsies of normal human kidneys to patients with acute tubular necrosis, and found 76 miRNAs significantly downregulated and 47 miRNAs upregulated (FDR adjusted p<0.05, +/−2-fold change). In summary, we highlight the transformative potential of miRNAs in therapeutics and translational medicine with a focus on drug-induced kidney damage.

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Section: Introductionmentioning

confidence: 99%

MicroRNAs and drug-induced kidney injury

Pavkovic

Vaidya

2016

Pharmacology & Therapeutics

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“…Up-regulation of miR-21 in the kidneys of the PKD/ mhm (cy/+) rat model of ADPKD, compared with that in wild-type controls, has been reported and indicates that miR-21 may be involved in cell proliferation by regulating programmed cell death-4 expression (18). Recent studies have suggested a critical role for miRs in the effort to identify potential therapeutic targets in ADPKD (19)(20)(21). The miR-17-92 miR cluster and miR-21 may promote manifestation of renal cyst growth in PKD mouse models.…”

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confidence: 99%

“…In Kif3a-KO mice, the miR-17-92 cluster and miR-21 were up-regulated. Cyst growth was reported to be reduced in Kif3a-miR-17-92and Pkd2-miR-21-double-knockout mice compared with Kif3a-and Pkd2-KO mice (19,20). Furthermore, anti-miR-17 treatment attenuated cyst growth in PKD mouse models (21).…”

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confidence: 99%

Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease

et al. 2018

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Altered miRNA (miR) expression occurs in various diseases. However, the therapeutic effect of miRNAs in autosomal dominant polycystic kidney disease (ADPKD) is unclear. Genome‐wide analyses of miRNA expression and DNA methylation status were conducted to identify crucial miRNAs in end‐stage ADPKD. miR‐192 and ‐194 levels were down‐regulated with hypermethylation at these loci, mainly in the intermediate and late stages, not in the early stage, of cystogenesis, suggesting their potential impact on cyst expansion. Cyst expansion has been strongly associated with endothelial‐mesenchymal transition (EMT). Zinc finger E‐box‐binding homeobox‐2 and cadherin‐2, which are involved in EMT, were directly regulated by miR‐192 and ‐194. The therapeutic effect of miR‐192 and ‐194 in vivo and in vitro were assessed. Restoring these miRs by injection of precursors influenced the reduced size of cysts in Pkd1 conditional knockout mice. miR‐192 and ‐194 may act as potential therapeutic targets to control the expansion and progression of cysts in patients with ADPKD.—Kim, D. Y., Woo, Y. M., Lee, S., Oh, S., Shin, Y., Shin, J.‐O., Park, E. Y., Ko, J. Y., Lee, E. J., Bok, J., Yoo, K. H., Park, J. H. Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease. FASEB J. 33, 2870–2884 (2019). http://www.fasebj.org

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“…To further rule out cross reactivity, we analyzed the expression of miR-21, an abundantly expressed, pathogenic miRNA in PKD. 8,11,14,25 miR-21 levels did not change in kidneys from mice treated with PBS compared to kidneys from mice treated with either anti-miR-17, 18, 19, or 25 mixtures ( Fig. 2E).…”

Section: Expression Of Mirnas Produced By the Mir-17~92 And Related Cmentioning

confidence: 90%

“…miRNAs belonging to the one family have redundant biological functions because they target the same mRNAs. In diseases such as cancer [6][7][8][9] , and as we have recently shown in ADPKD 10,11 , aberrant activation of miRNAs can drive disease progression. Accordingly, synthetic oligonucleotides known as anti-miRs have emerged as a novel therapeutic platform to inhibit pathogenic miRNAs.…”

Section: Introductionmentioning

confidence: 94%

Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth

Yheskel

Lakhia

Flaten

et al. 2018

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of renal failure. We have recently shown that inhibiting miR-17~92 is a potential novel therapeutic approach for ADPKD. However, miR-17~92 is a polycistronic cluster that encodes microRNAs (miRNAs) belonging to the miR-17, miR-18, miR-19 and miR-25 families, and the relative pathogenic contribution of these miRNA families to ADPKD progression is unknown. Here we performed an in vivo anti-miR screen to identify the miRNA drug targets within the miR-17~92 miRNA cluster. We designed anti-miRs to individually inhibit miR-17, miR-18, miR-19 or miR-25 families in an orthologous ADPKD model. Treatment with anti-miRs against the miR-17 family reduced cyst proliferation, kidney-weight-to-body-weight ratio and cyst index. In contrast, treatment with anti-miRs against the miR-18, 19, or 25 families did not affect cyst growth. Anti-miR-17 treatment recapitulated the gene expression pattern observed after miR-17~92 genetic deletion and was associated with upregulation of mitochondrial metabolism, suppression of the mTOR pathway, induction of autophagy, and inhibition of cyst-associated inflammation. Our results argue against functional cooperation between the various miR-17~92 cluster families in promoting cyst growth, and instead point to miR-17 family is the primary therapeutic target for ADPKD. driver of kidney cyst growth

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MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

Cited by 66 publications

References 57 publications

MicroRNAs and drug-induced kidney injury

MicroRNAs and drug-induced kidney injury

Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease

Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth

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