Aims/hypothesis: Activation of endothelin receptor-A (ETA) increases glomerular permeability to albumin (Palb) and elevates pro-inflammatory markers in hyperglycaemic rats. Methods: Male Sprague-Dawley rats were given streptozotocin (n=32) or saline (sham; n=32). Half of the animals in each group received the ETA-selective antagonist, ABT-627 (atrasentan; orally), beginning immediately after hyperglycaemia was confirmed. Glomeruli were isolated by sieving techniques and Palb determined from the change in glomerular volume induced by oncotic gradients of albumin. Glomerular nephrin levels were assessed by immunofluorescence, whereas urinary nephrin was measured by immunoassay. Results: At 3 and 6 weeks after streptozotocin injection, proteinuria was significantly increased compared with sham controls and significantly reduced by ABT-627 treatment. Palb was also increased at 3 and 6 weeks post-streptozotocin. ABT-627 had no effect on Palb or protein excretion in sham control rats. In glomeruli isolated from hyperglycaemic rats, incubation with BQ-123, a selective ET A antagonist, reduced Palb, whereas BQ-788, a selective endothelin receptor-B antagonist had no effect (n=6 rats per group, 5-8 glomeruli per rat). Glomerular and plasma content of soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were significantly increased 6 weeks after streptozotocin (ELISA). ABT-627 attenuated these increases. After 6 weeks of hyperglycaemia, glomerular nephrin content was decreased with a concurrent increase in urinary nephrin excretion. ABT-627 prevented glomerular nephrin loss in hyperglycaemic rats (n=5-8 rats per group; eight groups). Conclusions/interpretation: These observations support the hypothesis that endothelin-1, via the ETA receptor, directly increases Palb, possibly via nephrin loss, as well as early inflammation in the hyperglycaemic rat. © 2010 Springer-Verlag.