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

Abstract

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.

Keywords: KLF2; eNOS; endothelial cells; glomerular hyperfiltration; shear stress.

Graphical abstract

Figure 1.

Krüppel-like factor 2 (KLF2) expression in human kidneys. Kidney single-cell transcriptomic dataset showing KLF2 expression (healthy reference samples: n = 28) from the Kidney Precision Medicine Project (https://www.kpmp.org; accessed July 1st, 2024). ATL, ascending thin limbs; B, B cell; CCD, cortical collecting duct; CNT, connecting tubule; C-TAL, cortical thick ascending limb; cycT, T cell (cycling); DCT, distal convoluted tubule; dFIB, fibroblast (degenerative); DTL, descending thin limb; dVSMC, vascular smooth muscle cell (degenerative); EC-AEA, afferent/efferent arteriole endothelial cell; EC-AVR, ascending vasa recta endothelial cell; EC-GC, glomerular capillary endothelial cell; EC-LYM, lymphatic endothelial cell; EC-PT, peritubular capillary endothelial cell; IMCD, inner medullary collecting duct; MDC, monocyte-derived cell; MON, monocyte; M-TAL, medullary thick ascending limb; ncMON, nonclassical monocyte; NK1, natural killer cell type 1; NKT, natural killer T cell; PL, plasma cell; T, T cell; T-CYT, cytotoxic T cell; UMAP, Uniform Manifold Approximation and Projection.

Figure 2.

Krüppel-like factor 2 (KLF2) is regulated by glomerular hyperfiltration-induced shear stress. KLF2 expression is increased in the glomeruli of unilateral nephrectomy mice but suppressed in diabetic kidney disease (DKD). This could be due to disturbed shear stress in the diabetic kidney. KLF2 is also negatively regulated by high glucose and inflammatory cytokines in DKD.

Figure 3.

Renoprotective effects of Krüppel-like factor 2 (KLF2) in diabetic kidney disease (DKD). KLF2 has antiangiogenic, antithrombotic, anti-inflammatory, antioxidant, and vasodilatory effects in endothelial cells. KLF2 also has anti-inflammatory effects via the regulation of immune cell function.