Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice.

Abstract

Expression of klotho, the renoprotective anti-aging gene, is decreased in diabetic model kidneys. We hypothesized that klotho protein attenuates renal hypertrophy and glomerular injury in a mouse model of diabetic nephropathy. Klotho transgenic (KLTG) mice were crossed with spontaneously diabetic Ins2Akita (AKITA) mice. Glomerular morphology, macrophage infiltration, urinary albumin excretion and urinary 8-hydroxy-2-deoxy guanosine excretion were examined. In vitro, human glomerular endothelial cells were stimulated with high glucose with or without recombinant klotho, and calpain activity and proinflammatory cytokine expressions were measured. We found that klotho protein overexpression attenuates renal hypertrophy and glomerular injury in this mouse model of diabetic nephropathy. Klotho overexpression attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, and endothelial glycocalyx loss in the AKITA mice. AKITA mice exhibit high levels of urinary 8-hydroxy-2-deoxy guanosine excretion. In the presence of klotho overexpression, this effect was reversed. In addition, the glomerular macrophage infiltration characteristic of AKITA mice was attenuated in KLTG-AKITA mice. In human glomerular endothelial cells, high glucose induced calpain activity. This effect was suppressed by expression of recombinant klotho, which also suppressed the induction of proinflammatory cytokines. Our data suggest klotho protein protects against diabetic nephropathy through multiple pathways.