Krüppel-like factor 2 is an endoprotective transcription factor in diabetic kidney disease

• Published in: American Journal of Physiology: Cell Physiology Vol. 327; no. 2; pp. C477 - C486
• Main Authors: Min, Lulin, Zhong, Fang, Gu, Leyi, Lee, Kyung, He, John Cijiang
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2024
• Subjects: Angiogenesis; Animals; Cardiovascular diseases; Cell activation; Cytokines; Diabetes; Diabetes mellitus; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Humans; Immunosuppressive agents; Inflammation; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Krueppel-like factor; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Microvasculature; Nephrectomy; Nephropathy; Shear stress; Transcription factors; Tumor necrosis factor-α; eNOS; endothelial cells; shear stress; glomerular hyperfiltration; KLF2
• ISSN: 0363-6143; 1522-1563; 1522-1563
• DOI: 10.1152/ajpcell.00222.2024

Diabetic kidney disease (DKD) is a microvascular complication of diabetes, and glomerular endothelial cell (GEC) dysfunction is a key driver of DKD pathogenesis. Krüppel-like factor 2 (KLF2), a shear stress-induced transcription factor, is among the highly regulated genes in early DKD. In the kidney, KLF2 expression is mostly restricted to endothelial cells, but its expression is also found in immune cell subsets. KLF2 expression is upregulated in response to increased shear stress by the activation of mechanosensory receptors but suppressed by inflammatory cytokines, both of which characterize the early diabetic kidney milieu. KLF2 expression is reduced in progressive DKD and hypertensive nephropathy in humans and mice, likely due to high glucose and inflammatory cytokines such as TNF-α. However, KLF2 expression is increased in glomerular hyperfiltration-induced shear stress without metabolic dysregulation, such as in settings of unilateral nephrectomy. Lower KLF2 expression is associated with CKD progression in patients with unilateral nephrectomy, consistent with its endoprotective role. KLF2 confers endoprotection by inhibition of inflammation, thrombotic activation, and angiogenesis, and thus KLF2 is considered a protective factor for cardiovascular disease (CVD). Based on similar mechanisms, KLF2 also exhibits renoprotection, and its reduced expression in endothelial cells worsens glomerular injury and albuminuria in settings of diabetes or unilateral nephrectomy. Thus KLF2 confers endoprotective effects in both CVD and DKD, and its activators could potentially be developed as a novel class of drugs for cardiorenal protection in diabetic patients.