Inflammation and Fibrosis in ADPKD

Mun, Hyowon; Park, Jong Hoon

doi:10.1007/978-981-10-2041-4_4

Cited by 12 publications

(13 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[5][6][7] These cytokines promote fibrosis by activating lamina propria fibroblasts to produce collagen and fibronectin, increasing eosinophil adherence to tissue and enhancing fibroblast contractility. 6,8 Additionally, cross-talk between esophageal epithelial cells and fibroblasts leads to robust fibroblast production of TNF-a, 8,9 a profibrogenic cytokine that has been implicated in fibrotic disease conditions of the liver, intestine, and kidney [10][11][12] ; however, the pathogenic role of TNF-a in patients with EoE remains elusive. In response to these cytokines, stromal fibroblasts are activated to deposit and construct networks of excess collagen and fibronectin in the lamina propria, leading to increased esophageal stiffness.…”

mentioning

confidence: 99%

Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α

Kasagi¹,

Dods²,

Wang³

et al. 2019

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

(to K.A.W. and H.N.). J.M.S. is funded by the Stuart Starr Endowed Chair, Food Allergy Research and Education. J.M.S. and A.B.M. are funded in part by the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). CEGIR (U54 AI117804) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), and is funded through collaboration between the National Institute of Allergy and Infectious Diseases (NIAID), NIDDK, and NCATS. CEGIR is also supported by patient advocacy groups, including APFED, CURED, and EFC. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

show abstract

mentioning

confidence: 99%

Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α

Kasagi¹,

Dods²,

Wang³

et al. 2019

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

show abstract

“…7A). Macrophages surrounding cysts consist of a heterozygous population of M1-like and M2-like macrophages, with the latter of the two thought to promote cyst growth 40,41 . Q-PCR analysis showed that the markers of the pathogenic M2-like macrophages, Arg1 and Mrc1, were decreased by 67.2%%, and 34.9%.…”

Section: Anti-mir-17mentioning

confidence: 99%

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

View full text Add to dashboard Cite

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

show abstract

“…Therapies currently in clinical trials focus on increased total kidney volume (TKV) as an indicator of disease severity, with decreased TKV reflecting the success of treatment[ 8 - 10 ]. However, an essential feature of the disease is interstitial inflammation and fibrosis[ 11 - 13 ]. Such interstitial changes lead to decreased TKV and strongly correlate with a decline in kidney function.…”

Section: Introductionmentioning

confidence: 99%

“…Renal fibrosis is the key determinant of the progression of all renal disease including ADPKD, irrespective of the original cause, and dictates the eventual outcome[ 11 , 13 , 14 ]. As cystic lesions enlarge, they compress both normal renal parenchyma and vascular elements between multiple cysts, creating a peri-cystic local microenvironment (PLM) that becomes fibrotic over time.…”

Section: Introductionmentioning

confidence: 99%

“…As cystic lesions enlarge, they compress both normal renal parenchyma and vascular elements between multiple cysts, creating a peri-cystic local microenvironment (PLM) that becomes fibrotic over time. The decline of renal function and the development of ESRD correlate with the progression of fibrosis in ADPKD[ 13 , 15 , 16 ]. Despite this link of ESRD to fibrosis, there is virtually no therapy specifically targeting fibrosis in ADPKD.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Unique interstitial miRNA signature drives fibrosis in a murine model of autosomal dominant polycystic kidney disease

Patil¹,

Sweeney

Pan³

et al. 2018

WJN

View full text Add to dashboard Cite

AIMTo delineate changes in miRNA expression localized to the peri-cystic local microenvironment (PLM) in an orthologous mouse model of autosomal dominant polycystic kidney disease (ADPKD) (mcwPkd1(nl/nl)).METHODSWe profiled miRNA expression in the whole kidney and laser captured microdissection (LCM) samples from PLM in mcwPkd1(nl/nl) kidneys with Qiagen miScript 384 HC miRNA PCR arrays. The three times points used are: (1) post-natal (PN) day 21, before the development of trichrome-positive areas; (2) PN28, the earliest sign of trichrome staining; and (3) PN42 following the development of progressive fibrosis. PN21 served as appropriate controls and as the reference time point for comparison of miRNA expression profiles.RESULTSLCM samples revealed three temporally upregulated miRNAs [2 to 2.75-fold at PN28 and 2.5 to 4-fold (P ≤ 0.05) at PN42] and four temporally downregulated miRNAs [2 to 2.75 fold at PN28 and 2.75 to 5-fold (P ≤ 0.05) at PN42]. Expression of twenty-six miRNAs showed no change until PN42 [six decreased (2.25 to 3.5-fold) (P ≤ 0.05) and 20 increased (2 to 4-fold) (P ≤ 0.05)]. Many critical miRNA changes seen in the LCM samples from PLM were not seen in the contralateral whole kidney.CONCLUSIONPrecise sampling with LCM identifies miRNA changes that occur with the initiation and progression of renal interstitial fibrosis (RIF). Identification of the target proteins regulated by these miRNAs will provide new insight into the process of fibrosis and identify unique therapeutic targets to prevent or slow the development and progression of RIF in ADPKD.

show abstract

Inflammation and Fibrosis in ADPKD

Cited by 12 publications

References 55 publications

Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α

Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α

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

Unique interstitial miRNA signature drives fibrosis in a murine model of autosomal dominant polycystic kidney disease

Contact Info

Product

Resources

About