Proteinuria triggers renal lymphangiogenesis prior to the development of interstitial fibrosis

Saleh Yazdani*, Fariba Poosti, Andrea B. Kramer, Katarina Mirkovic, Arjan J. Kwakernaak, Menno Hovingh, Maartje C. J. Slagman, Klaas A. Sjollema, Martin H. de Borst, Gerjan Navis, Harry van Goor, Jacob van den Born

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Scopus)
210 Downloads (Pure)

Abstract

Proteinuria is an important cause of progressive tubulo-interstitial damage. Whether proteinuria could trigger a renal lymphangiogenic response has not been established. Moreover, the temporal relationship between development of fibrosis, inflammation and lymphangiogenesis in chronic progressive kidney disease is not clear yet. Therefore, we evaluated the time course of lymph vessel (LV) formation in relation to proteinuria and interstitial damage in a rat model of chronic unilateral adriamycin nephrosis. Proteinuria and kidneys were evaluated up to 30 weeks after induction of nephrosis. LVs were identified by podoplanin/VEGFR3 double staining. After 6 weeks proteinuria was well-established, without influx of interstitial macrophages and myofibroblasts, collagen deposition, osteopontin expression (tubular activation) or LV formation. At 12 weeks, a ∼3-fold increase in cortical LV density was found (p<0.001), gradually increasing over time. This corresponded with a significant increase in tubular osteopontin expression (p<0.01) and interstitial myofibroblast numbers (p<0.05), whereas collagen deposition and macrophage numbers were not yet increased. VEGF-C was mostly expressed by tubular cells rather than interstitial cells. Cultured tubular cells stimulated with FCS showed a dose-dependent increase in mRNA and protein expression of VEGF-C which was not observed by human albumin stimulation. We conclude that chronic proteinuria provoked lymphangiogenesis in temporal conjunction with tubular osteopontin expression and influx of myofibroblasts, that preceded interstitial fibrosis.

Original languageEnglish
Article numbere50209
Number of pages12
JournalPLoS ONE
Volume7
Issue number11
DOIs
Publication statusPublished - 26-Nov-2012

Keywords

  • PROXIMAL TUBULAR CELLS
  • GROWTH FACTOR-C
  • NF-KAPPA-B
  • LYMPHATIC VESSELS
  • EPITHELIAL-CELLS
  • INFLAMMATION
  • INJURY
  • ALBUMIN
  • DAMAGE
  • RATS

Cite this