Abstract
Presence of tubulointerstitial fibrosis is predictive of progressive decline in kidney function, independent of its underlying cause. Injury to the renal microvasculature is a major factor in the progression of fibrosis and identification of factors that regulate endothelium in fibrosis is desirable as they might be candidate targets for treatment of kidney diseases. The current study investigates how loss of Angipoietin-1 (Angpt1), a ligand for endothelial tyrosine-kinase receptor Tek (also called Tie2), affects tubulointerstitial fibrosis and renal microvasculature. Inducible Angpt1 knockout mice were subjected to unilateral ureteral obstruction (UUO) to induce fibrosis, and kidneys were collected at different time points up to 10 days after obstruction. Staining for aSMA showed that Angpt1 deficient kidneys had significantly more fibrosis compared to wildtype mice 3, 6, and 10 days after UUO. Further investigation 3 days after UUO showed a significant increase of Col1a1 and vimentin in Angpt1 deficient mice, as well as increased gene expression of Tgfb1, Col1a1, Fn1, and CD44. Kidney injury molecule 1 (Kim1/Havcr1) was significantly more increased in Angpt1 deficient mice 1 and 3 days after UUO, suggesting a more severe injury early in the fibrotic process in Angpt1 deficient mice. Staining for endomucin showed that capillary rarefaction was evident 3 days after UUO and Angpt1 deficient mice had significantly less capillaries 6 and 10 days after UUO compared to UUO kidneys in wildtype mice. RNA sequencing revealed downregulation of several markers for endothelial cells 3 days after UUO, and that Angpt1 deficient mice had a further downregulation of Emcn, Plvap, Pecam1, Erg, and Tek. Our results suggest that loss of Angpt1 is central in capillary rarefaction and fibrogenesis and propose that manipulations to maintain Angpt1 levels may slow down fibrosis progression.
Original language | English (US) |
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Article number | e0189433 |
Journal | PloS one |
Volume | 13 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2018 |
Funding
The laboratory of M.J. is funded by Swedish Research Council grant 2012-865, by Åke Wiberg Foundation, by Magnus Bergwall Foundation, and by IGP Young Investigator grant. S.E.Q holds the Charles Mayo Chair of Medicine at the Feinberg School of Medicine and a Finnish Distinguished Professorship at the Oulu Biocenter. The laboratory of S.E.Q is funded by NIH/NHLBI grant HL1241200, by Canadian Institute of Health Research grants M0P62931 and M0P77756, by E-rare Joint Translation Call (JTC 2011) for European Research Projects on Rare Diseases, and by Terry Fox Foundation grant 016002. The laboratory of C. B. is funded by grants from the Swedish Research Council, the European Research Council and the Knut and Alice Wallenberg Foundation. We thank Jana Chmielniakova and Pia Peterson at Uppsala University for technical assistance. The authors would also like to acknowledge support of the National Genomics Infrastructure (NGI) / Uppsala Genome Center and UPPMAX for providing assistance in massive parallel sequencing and computational infrastructure. Work performed at NGI / Uppsala Genome Center has been funded by RFI / VR and Science for Life Laboratory, Sweden
ASJC Scopus subject areas
- General Agricultural and Biological Sciences
- General
- General Biochemistry, Genetics and Molecular Biology