Endothelial Kallikrein-Related Peptidase 8 Promotes Diabetic Nephropathy via Reducing SDC4 Expression and Enhancing LIF Release

The molecular mechanisms underlying diabetic nephropathy (DN) are poorly defined. We sought to investigate the roles of kallikrein-related peptidases (KLKs) in DN pathogenesis. Screening of renal tissue from diabetic mice revealed KLK8 as the most highly induced gene in KLK family. KLK8 expression was greater in glomerular endothelial cells (GECs) than other glomerular cells in DN patients and diabetic mice. The rats with KLK8 overexpression exhibited proteinuria, reduced glomerular filtration rate (GFR), and mesangial expansion, podocytopenia, glomerulosclerosis and interstitial fibrosis in renal tissues. In contrast, global KLK8 deficiency reversed streptozotocin-induced hallmark of DN features including proteinuria, reduced GFR, glomerular hypertrophy, glycocalyx loss in GECs, podocytopenia, leukocyte infiltration, glomerulosclerosis, and interstitial fibrosis in mice. Moreover, endothelial KLK8 ablation also blocked streptozotocin-induced hallmark of DN features. Mechanically, elevated KLK8 in GECs promoted endothelial hyperpermeability, glycocalyx injury, and monocyte recruitment and adhesion through downregulation and shedding of syndecan-4 (SDC4). KLK8 upregulation in GECs stimulated mesangial cell proliferation and activation via increasing leukemia inhibitory factor (LIF) release. Moreover, circulatory KLK8 levels correlated positively with LIF and SDC4 in diabetic nephropathy patients. Our study identifies KLK8 as a novel driver of DN development and progress and highlight potential therapeutic strategies targeting KLK8 for DN.