Abstract: TH-PO696
miR-210-3p Inhibition Decreases Fibrosis and Improves Renal Function in Murine ADPKD
Session Information
- ADPKD: Genetic and Model Studies
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidney
- 1001 Genetic Diseases of the Kidney: Cystic
Authors
- Patil, Ameya P., Medical College of Wisconsin, Wauwatosa, Wisconsin, United States
- Sweeney, William E., Medical College of Wisconsin, Wauwatosa, Wisconsin, United States
- Pan, Cynthia G., Children's Corporate Center, Milwaukee, Wisconsin, United States
- Avner, Ellis D., Medical College of Wisconsin, Wauwatosa, Wisconsin, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cystic enlargement. In mcwPkd1(nl/nl) hypomorphic mice, peri-cystic areas are hypoxic early in the disease course. These hypoxic areas are markedly positive for hypoxia inducible factor-1α (HIF-1α). These areas develop fibrosis with disease progression. miR-210-3p is HIF-1α inducible and increases in response to hypoxia. We hypothesize that peri-cystic hypoxia initiates a repair response via HIF-1α and miR-210-3p which contributes to interstitial fibrosis.
Methods
Cystic kidneys at weekly intervals starting at postnatal (PN) day 21, were sectioned and stained with trichrome and PCNA. RNA extracted from laser capture micro-dissection (LCM) trichrome (TC) positive peri-cystic regions at PN28, & 42 was examined for expression of miRNA 210-3p. PN21 peri-cystic regions negative for trichrome stain was used as a control. Anti-miR-210-3p was injected IP starting at PN21 Q 4 days till PN42. Untreated cystic kidneys were used as control. RNA was extracted from both cystic treated and untreated kidneys at PN42. Serum obtained at harvest was used to assess renal function.
Results
1. In LCM captured peri-cystic regions, miRNA-210-3p is upregulated 6-fold at PN28 and 5-fold at PN42 compared with PN21.
2. Anti-miR-210-3p treated cystic kidneys at PN42 compared with age-matched untreated cystic kidneys has: (a) 35% reduction in serum creatinine; (b) 75% decrease in trichrome positive/fibrotic areas; (c) proliferation (PCNA) is restricted to tubular epithelia vs both tubular epithelia and peri-cystic regions in untreated controls; (d) up-regulation of anti-fibrotic mRNA’s Hgf (19.22-fold), IFNg (7.95-fold), Il10 (523.68-fold), II13ra2 (31.99-fold) and down-regulation of pro-fibrotic mRNA’s Ctgf (-10.79) and II5 (-4.31) and ECM component Col1a2 (-94.86).
Conclusion
Conclusions-
1. We demonstrate that expression of miR-210-3p increases in hypoxic peri-cystic regions with disease progression at PN28 and PN42.
2. In vivo inhibition of miR-210-3p: improves kidney function; decreases interstitial fibrosis; reduces proliferation in peri-cystic regions; increases expression of anti-fibrotic mRNAs (Hgf, IFNg, II10, Il13ra2) and decreases profibrotic (Ctgf, II5) and ECM matrix component (Col1a2).