In addition to having
blood glucose-lowering effects, inhibitors of
sodium glucose cotransporter 2 (SGLT2) afford renoprotection in diabetes. We sought to investigate which components of the glomerular filtration barrier could be involved in the antiproteinuric and renoprotective effects of SGLT2 inhibition in diabetes. BTBR (black and tan, brachyuric) ob/ob mice that develop a type 2
diabetic nephropathy received a standard diet with or without
empagliflozin for 10 weeks, starting at 8 weeks of age, when animals had developed
albuminuria.
Empagliflozin caused marked decreases in
blood glucose levels and
albuminuria but did not correct glomerular hyperfiltration. The protective effect of
empagliflozin against
albuminuria was not due to a reduction in podocyte damage as
empagliflozin did not affect the larger podocyte filtration slit pore size nor the defective expression of
nephrin and
nestin.
Empagliflozin did not reduce the thickening of the glomerular basement membrane. In BTBR ob/ob mice, the most profound abnormality seen using electron microscopy was in the endothelial aspect of the glomerular capillary, with significant loss of endothelial fenestrations. Remarkably,
empagliflozin ameliorated the subverted microvascular endothelial ultrastructure. Caveolae and bridging diaphragms between adjacent endothelial fenestrae were seen in diabetic mice and associated with increased expression of
caveolin-1 and the appearance of PV-1. These endothelial abnormalities were limited by the
SGLT2 inhibitor. Although no expression of SGLT2 was found in glomerular endothelial cells, SGLT2 was expressed in the podocytes of diabetic mice.
VEGF-A, which is a known stimulus for endothelial
caveolin-1 and PV-1, was increased in podocytes of BTBR ob/ob mice and normalized by
SGLT2 inhibitor treatment. Thus,
empagliflozin's protective effect on the glomerular endothelium of diabetic mice could be due to a limitation of the paracrine signaling of podocyte-derived
VEGF-A that resulted in a reduction of the abnormal endothelial
caveolin-1 and PV-1, with the consequent preservation of glomerular endothelial function and permeability. © 2022 The Pathological Society of Great Britain and Ireland.