Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes

Background. More than half of the new patients admitted to dialysis therapy in some centers are diagnosed with type IIb diabetes, that is, diabetes as sociated with obesity. This study searched for a common final pathway of re nal damage in this progressive renal disease. Methods. The evolution of biochemical and morphological renal changes was e xamined in 6- to 60-week-old Zucker rats (fa/fa-rats), a model of obesity a ssociated with type II diabetes. Results, fa/fa-rats exhibited pronounced hyperinsulinemia and hyperlipidemi a at 6 weeks and became diabetic after 14 weeks of age. Significant focal s egmental glomerulosclerosis was first noted in 18-week-old fa/fa-rats and t ubulointerstitial damage and proteinuria in 40-week-old fa/fa-rats. A compa rison of kidneys of six-week-old fa/fa-and lean control (Fn/?) rats by immu nohistology revealed a 1.8-fold increase in glomerular monocyte/macrophage counts in fa/fa-rats and a significant increase in de novo desmin expressio n in podocytes. Electron microscopy demonstrated an increase in the number of podocyte mitochondria and intracytoplasmic protein and fat droplets. Pod ocyte desmin scores markedly increased until week 18 in fa/fa-rats, whereas glomerular monocyte/macrophage counts peaked at 3.2-fold at week 14. Podoc yte desmin expression, but not glomerular macrophage infiltration, correlat ed with damage in adjacent tubular cells, as evidenced by their de novo exp ression of vimentin. Progressive glomerular hypertrophy was detected in fa/ fa-rats after 10 weeks. GEM width was significantly increased in 14-week-ol d fa/fa-rats as compared with lean controls. Mesangial cell activation (de novo expression of alpha-smooth muscle actin) and proliferation was low to absent throughout the observation period in fa/fa-rats. Renal cell death co unts (TUNEL) remained unchanged in 6- to 40-week-old fa/fa-rats. Tubulointe rstitial myofibroblast formation and matrix accumulation occurred late duri ng the study duration in fa/fa-rats. Conclusion. These data suggest that early progressive podocyte damage and m acrophage infiltration is associated with hyperlipidemia and type IIb diabe tes mellitus, and antedates both the development of glomerulosclerosis and tubulointerstitial damage.