Abstract
Fms-like tyrosine kinase-1 (Flt-1) is a receptor for vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) and, playing a crucial role in angiogenesis and inflammation pathways. Soluble Flt-1 (sFlt-1) acts as a decoy for both VEGF and PlGF, regulating Flt-1-mediated angiogenesis and inflammation. We investigated the involvement of sFlt-1 in the transition from acute kidney injury to chronic kidney disease (CKD).
Wild-type (WT) and sFlt-1 knock-out (KO) mice underwent ischemia-reperfusion injury (IRI) treatment. A unilateral 23-minute IRI and contralateral nephrectomy were performed to examine kidney function (AKI to CKD) for 2 weeks. To explore the downstream signaling pathway for sFlt-1 in the kidney, a unilateral 28-minute IRI was performed, and angiogenesis and cytokine expression arrays (Proteome Profiler Array Kits) were used to compare the relative expressions between 28-minute IRI and the contralateral untreated kidney cortices in both WT and sFlt-1 KO mice.
A plasma sFlt-1 concentration was elevated just after IRI and reached its peak after 12 hours. Blood urea nitrogen (BUN) and plasma creatinine (pCre) levels peaked at 24 hours after IRI. The peak levels of BUN and pCre were significantly lower in sFlt-1 KO compared to those in WT mice (BUN 43.23 ± 5.9 mg/dL and 82.7 ± 13.0 mg/dL, p = 0.008, pCre 0.18 ± 0.03 mg/dL and 0.31 ± 0.04 mg/dL, p = 0.008 in KO and WT mice, respectively). Urinary KIM-1 (uKIM-1) levels 12 hours after IRI in WT mice were higher than those in sFlt-1 KO mice (WT vs sFlt-1 KO; uKIM-1 4.82 ± 0.83 pg/day vs 2.39 ± 0.98 pg/day, p = 0.09). Histopathological evaluation of the kidneys showed reduced monocyte infiltration in sFlt-1 KO mice compared to WT mice 14 days after IRI. In cytokine expression assay of kidney cortices 3 days after IRI, IRI-induced increased expressions of tissue repairs and immune response proteins such as TIMP-1, C5/C5a, and TREM-1 were alleviated in sFlt-1 KO mice compared to those in WT mice. In the Angiogenesis expression array of kidney cortices 1 day after IRI, there were no significant differences in the levels of IRI-induced increased expression of anti-/pro-angiogenesis factors, including TIMP-1, Cyr61, SerpinE1, angiogenin, platelet factor 4, collagen factor 3, MMP-9, and SDF-1, between WT and sFlt-1 KO mice.
The acute and chronic kidney damages after IRI was reduced in sFlt-1 KO mice compared to WT mice. The protective effect on the kidneys by eliminating sFlt-1 would be associated with immune response signaling such as TIMP-1, C5/C5a, and TREM-1 but not with anti-/pro-angiogenesis factors.
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