SerpinE2 deficiency exacerbates glomerular injury in diabetic nephropathy through dysregulated angiogenesis and...

Diabetic nephropathy (DN) is a multifactorial disease in which inflammation and angiogenesis play a crucial role. SerpinE2, or protease nexin-1 (PN-1), is a protease inhibitor of the serpin family, expressed by vascular and inflammatory cells. In this study, we addressed the role of SerpinE2 in DN, using the models of streptozotocin-induced type-1 and db/db type-2 diabetes. Our results indicated that SerpinE2^-/- diabetic mice presented histological features of an aggravated nephropathy compared with wild-type (WT) mice, with higher hypertrophy of glomeruli, greater collagen IV accumulation, and reduced nephrin expression. Moreover, renal function was worsened in SerpinE2^-/- diabetic mice with urine albumin-to-creatinine ratio much higher compared with WT. Consistent with the previously demonstrated antiangiogenic properties of SerpinE2, we observed that glomerular vascularization was higher in SerpinE2^-/- than in WT diabetic mice in early type-1 diabetes, associated with increased proliferation of glomerular cells. Accordingly, renal blood flow reduction in response to diabetes was lower in SerpinE2^-/- mice than in WT mice. In addition, we measured higher mRNA levels of inflammatory cytokines and of midkine in the kidneys of diabetic SerpinE2^-/- mice compared with WT mice. Altogether, our results indicate that SerpinE2 may play a protective role in the development of DN by limiting glomerular damage throughout regulation of early process in angiogenesis and inflammation.NEW & NOTEWORTHY In two different models of diabetes, SerpinE2 deficiency exacerbated nephropathy, as evidenced by increased glomerular hypertrophy and collagen expression, reduced nephrin, and impaired kidney function. Increased angiogenesis and upregulated cytokines were involved. This study is the first to demonstrate a role of SerpinE2 in DN progression by modulating early disease mechanisms.