Proteinuria Triggers Renal Lymphangiogenesis Prior to the Development of Interstitial Fibrosis

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.

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

“…We therefore analyzed the effect of PPB-PEG-IFN-g on PTC density by quantifying the number of CD31 + PTCs expressed as the percent CD31 + surface area. Moreover, we and others have shown earlier that renal fibrosis is associated with increased lymph vessel formation in different renal disease models (36)(37)(38)(39)(40). This led us to hypothesize that UUO-induced renal lymphangiogenesis might be attenuated by PPB-PEG-IFN-g. By use of antibodies against CD31 and podoplanin, we were able to discriminate between PTCs and lymphatics because virtually no podoplanin + lymphatic vessels showed CD31 positivity (Fig.…”

dl-propargylglycine reduces blood pressure and renal injury but increases kidney weight in angiotensin-II infused rats

“…However, in our study renal lymphatic vessel function (number and/or size) was not affected after PAG treatment. Probably the increase in lymph vessel number (lymphangiogenesis) and size in AngIIinfused rats is caused by proteinuria as this has also been reported in adriamycin-induced CKD with protein excretion higher than 200mg/24h [30]. Furthermore, no tubular dilation was observed suggesting that obstruction of nephrons or the urinary tract was not involved.…”

“…Sections were stained with primary antibodies for desmin (mouse anti-desmin NCL-DES-DER11, 1:500, Novacastra, Rijswijk, the were categorized by size in extra small, small, medium and large vessels [30]. Histological analysis was performed in a blinded fashion.…”

Interactions between osteopontin and vascular endothelial growth factor: Implications for skeletal disorders

“…Specifically, OPN is involved in the regulation of dystrophic calcification and contributes to inflammatory pathways as a chemo-attractant for macrophages, dendritic cells and T-lymphocytes [87]. Chronic proteinuria-derived renal lymphangiogenesis is accompanied by tubular expression of OPN and VEGF-C and precedes interstitial fibrosis [88]. In progressive renal failure, VEGF treatment decreases fibrosis by reducing the OPN expression levels in the renal tubules [89].…”