Untangling the Knot in Diabetic Nephropathy: The Unanticipated Role of Glycocalyx in the Antiproteinuric Effect of Endothelin Receptor Antagonists.

Diabetes is a devastating disease that is imposing itself as one of the largest health emergencies of the 21st century, and high blood glucose is the third-highest risk factor for premature mortality (1). In 2015, almost 5 million people aged 20–79 years died from diabetes and its related complications, which accounted for almost 15% of the overall causes of mortality among people in this age-group (1). With no effective prevention and management programs, the incidence of diabetes and its complications is dramatically increasing worldwide, imposing a substantial impact on the economy. Diabetic nephropathy (DN) affects 30– 40% of patients with diabetes (2) and induces a progressive deterioration of renal function. Albuminuria independently associates with increased vascular mortality and morbidity in patients with diabetes (3), in patients with hypertension (4), and in the general population (5), and therefore is not only a sign of renal impairment and a key pathogenic element of renal disease progression but also a marker of more generalized vascular damage. Many studies have linked albuminuria with cardiovascular disease (CVD). A linear relationship was observed between albumin excretion and CVD risk (6), but the exact significance and mechanism of such a relationship are not yet understood. Microalbuminuria not only denotes renal capillary damage but also represents an early biological marker of vascular injury (7). Endothelial dysfunction has been implicated as a potential major mechanism for vascular disease, and microalbuminuria has been linked to markers of endothelial dysfunction in patients with and without diabetes (8). Several experimental studies provided evidence of a pathogenic role for endothelin 1 (ET-1) in DN. Pioneering investigations documented preservation of renal function and limitation of long-term renal histological changes in diabetic rats after administration of selective endothelin A receptor (ETAR) antagonists (9,10). The effectiveness of ETAR antagonism has been attributed to the preservation of the renal microvascular architecture together with a protection against podocyte loss (11), a typical feature of overt diabetes. ET-1 directly affects podocytes as revealed by less proteinuria and protection from podocyte dysfunction and glomerulosclerosis in diabetic mice with a podocyte-specific double deletion of ETAR and ETBR (12). In this issue of Diabetes, Boels et al. (13) confirm the renoprotective action of atrasentan, a selective ETAR antagonist, in streptozotocin-induced diabetic apolipoprotein E (apoE) knockout mice. Notably, atrasentan reduced the urinary albumin-to-creatinine ratio without affecting systemic blood pressure, glomerular hypertrophy, or podocyte number. The latter data are not surprising considering that diabetic apoE knockout mice did not faithfully replicate typical features of overt diabetic nephropathy, and, as already observed in experimental early diabetes, renal nitric oxide levels increased in this model (14). The novelty proposed by Boels et al. is the intriguing mechanism through which atrasentan may preserve the glomerular endothelial glycocalyx, thus exerting its antiproteinuric effect. In the diabetic apoE knockout mice, proteinuria was associated with a reduction of glomerular endothelial glycocalyx coverage and glomerular basement membrane (GBM) thickness (13). The endothelial glycocalyx is a mesh-like, hydrated structure comprising glycoproteins and proteoglycans anchored to the endothelium. In different glomerular diseases including DN, low expression of heparan sulfate proteoglycans in the GBM inversely correlated with the degree of proteinuria (15). In line with these findings, Boels et al.