To investigate the functional and structural renal changes in a long-term liver-specific glucokinase knockout mouse, a model was developed of maturity-onset diabetes of the young (MODY2). Hemizygous glucokinase (gck) knockout mice, gck^w/– groups, were compared at 6, 10, and 14 months with their age-matched normal littermates, gck^w/w groups. To examine changes, we compared body weight, fasting blood glucose, serum insulin, and creatinine levels, as well as 24-h urine samples that were collected for urine volume and protein analysis between the 2 groups. Renal tissues were collected and stained with hemotoxylin-eosin and periodic-acid Schiff for light microscopic observation. The expression of renal transforming growth factor β1 (TGF-β1) was determined by Western blot. Our results show that fasting blood glucose levels were significantly higher in gck^w/– mice compared with gck^w/w mice (P < 0.01) for all age groups. Compared with age-matched gck^w/w mice, 10-month old gck^w/– mice have significantly elevated body weights (P < 0.01) and protein contents (P < 0.001). A gradual increase in mesangial matrix and a thickening of the glomerular basement membrane was observed in gck^w/- mice at 10 and 14 months. The levels of renal TGF-β1 expression are increasing in both gck^w/– and gck^w/w mice. Our results indicate that renal changes occur in the liver-specific glucokinase knockout mouse model of MODY2 and suggest that TGF-β1 may play a key role in pathogenesis of these renal changes.