SerpinE2 deficiency exacerbates glomerular Injury in diabetic nephropathy through dysregulated angiogenesis and inflammatory responses

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 to 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 to WT. Consistent with the previously demonstrated anti-angiogenic 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 -/- than in WT mice. In addition, we measured higher mRNA levels of inflammatory cytokines and of midkine in diabetic SerpinE2 -/- kidneys compared to WT. 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.