Loss of functional nephrons induces compensatory glomerular hyperfiltration and hypertrophy, leading to the progression of chronic kidney disease. Krüppel-like factor 2 (KLF2), a shear-stress-inducible transcription factor, confers protection against endothelial injury. Because glomerular hyperfiltration is associated with shear stress, we hypothesized that KLF2 may be an important factor in the compensatory response to unilateral nephrectomy (UNX). To test this hypothesis, endothelial cell-specific Klf2 heterozygous knockout mice (KO) and their wild-type littermate control (WT) underwent either UNX or sham-operation. WT-UNX mice developed compensatory renal hypertrophy as expected, whereas KO-UNX mice did not. KO-UNX mice exhibited higher blood pressure, reduced glomerular filtration rate, and significant increase in proteinuria and glomerulosclerosis compared to WT-UNX. Expression of endothelial nitric oxide synthase (official name Nos3), a known transcriptional target gene of KLF2, was significantly reduced and dysregulation of other endothelial genes was also observed in the glomeruli of KO-UNX when compared to WT-UNX and sham-operated mice. Furthermore, both podocyte number and expression of podocyte markers were also significantly reduced in KO-UNX glomeruli, indicating a potential cross talk between glomerular endothelial cells and podocytes. Finally, decreased renal expression of KLF2 in nephrectomy patients was associated with the progression of kidney disease. Taken together, our data demonstrate a protective role of KLF2 against glomerular endothelial cell injury and progression of chronic kidney disease in the model of compensatory renal hypertrophy.