Proteinuria Triggers Renal Lymphangiogenesis Prior to the Development of Interstitial Fibrosis

• Published in: PloS one Vol. 7; no. 11; p. e50209
• Main Authors: Yazdani, Saleh, Poosti, Fariba, Kramer, Andrea B., Mirković, Katarina, Kwakernaak, Arjan J., Hovingh, Menno, Slagman, Maartje C. J., Sjollema, Klaas A., de Borst, Martin H., Navis, Gerjan, van Goor, Harry, van den Born, Jacob
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.11.2012; Public Library of Science (PLoS)
• Subjects: Albumin; Angiotensin-Converting Enzyme Inhibitors - administration & dosage; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Anthracyclines; Antigens; Biocompatibility; Biology; Biomedical materials; Cell activation; Cell Line; Collagen; Deposition; Disease Models, Animal; Fibrosis; Gene expression; Gene Expression Regulation; Humans; Inflammation; Interstitial cells; Kidney diseases; Kidney Diseases - etiology; Kidney Diseases - genetics; Kidney Diseases - pathology; Kidney transplantation; Kidney Tubules - pathology; Kidneys; Lisinopril - administration & dosage; Lisinopril - pharmacology; Lymphangiogenesis - drug effects; Lymphangiogenesis - genetics; Lymphatic Vessels - pathology; Lymphedema; Macrophages; Male; Medical prognosis; Medicine; mRNA; Nephrology; Osteopontin; Pathogenesis; Pathology; Proteinuria; Proteinuria - drug therapy; Rats; RNA; Rodents; Transplants & implants; Urine; Vascular endothelial growth factor; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor C - metabolism; Vascular endothelial growth factor receptors; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0050209

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.