Objectives: Our previous studies have disclosed that quiescent endothelium switches to activated phenotype since early phase of kidney injury, harboring angiogenesis response and proinflammatory transcriptome. We propose that VEGF isoform switch to ECM-bound VEGF188 predominance is one of the cardinal pathogenic mechanisms mediating endothelial phenotype change, inflammation, and kidney fibrosis. Methods: We used inducible knockout mice to delete VEGF188 in all cells or specifically in tubule cells to study the pathogenic mechanisms in kidney fibrosis focusing on microvasculature and inflammation. Results: In the murine model of unilateral ureteral obstruction, dysangiogenic VEGF188 increased as kidney fibrosis progressed. Inducible deletion of VEGF188 in all cells using Tg(UBC-CreERT2Cre/+);VEGF188F/F mice demonstrated decreased inflammation and attenuated fibrosis in unilateral ureteral obstruction. In addition, inducible deletion of VEGF188 also lead to improved functional impairment in adenine-induced tubulointerstitial nephropathy. Furthermore, tubule cell-specific deletion of VEGF188 by Tg(Pax8-rtTA/LC1rtTA-Cre/+);VEGF188F/F mice demonstrated improved inflammation, tubule damage and kidney fibrosis in ischemia-reperfusion injury and adenine-induced tubulointerstitial nephropathy. VEGF188 mainly expressed in tubule cells by in situ hybridization. Immunoprecipitation also implicated that VEGF188 may interact with extracellular matrix and neuropilin receptor leading to the release of proinflammatory and proangiogenic growth factors, such as fibroblast growth factor. Conclusions: VEGF188 deletion improves inflammation, tubule injury, kidney fibrosis and functional impairment in different models of chronic kidney disease. Therapeutic strategies targeting VEGF188 will be a convincing treatment to improve chronic kidney disease.