Glycogen synthase kinase 3 (GSK3) plays an important role in the development of
diabetes mellitus and renal injury. GSK3 inhibition increases
glucose uptake in
insulin-insensitive muscle and adipose tissue, while it reduces
albuminuria and glomerulosclerosis in
acute kidney injury. The effect of chronic GSK3 inhibition in
diabetic nephropathy is not known. We tested the effect of
lithium, the only clinical GSK3 inhibitor, on the development of
diabetes mellitus and kidney injury in a mouse model of
diabetic nephropathy. Twelve-week old female BTBR-ob/ob mice were treated for 12 weeks with 0, 10 and 40 mmol LiCl/kg after which the development of diabetes and
diabetic nephropathy were analysed. In comparison to BTBR-WT mice, ob/ob mice demonstrated elevated bodyweight, increased
blood glucose/
insulin levels, urinary
albumin and
immunoglobulin G levels, glomerulosclerosis, reduced
nephrin abundance and a damaged proximal tubule brush border. The lithium-10 and -40 diets did not affect
body weight and resulted in blood
lithium levels of respectively <0.25 mM and 0.48 mM. The Li-40 diet fully rescued the elevated non-fasting
blood glucose levels. Importantly, glomerular filtration rate was not affected by
lithium, while urine
albumin and
immunoglobulin G content were further elevated. While
lithium did not worsen the glomerulosclerosis, proximal tubule function seemed affected by
lithium, as urinary NGAL levels were significantly increased. These results demonstrate that
lithium attenuates non-fasting
blood glucose levels in diabetic mice, but aggravates urinary
albumin and
immunoglobulin G content, possibly resulting from proximal tubule dysfunction.