Abnormal renal structural alterations during the development of diabetes mellitus in Otsuka Long‐Evans Tokushima Fatty rats*

Abstract

The aim of this study was to investigate the renal structural properties in diabetic nephropathy. Flow-pressure and pressure-glomerular filtration rate (GFR) relationships were determined for maximally vasodilated kidneys at 10 (pre-diabetic stage) and 42 weeks of age (diabetic stage) in Otsuka Long-Evans Tokushima Fatty rats (OLETF), an animal model of type 2 diabetes mellitus, using age-matched Long-Evans Tokushima Otsuka rats (LETO) as non-diabetic controls (n = 9 of each age for each strain). Kidneys were then perfusion-fixed for histological analysis. At 10 weeks of age, the slope of flow-pressure relationship (minimal renal vascular resistance, reflecting overall luminal dimensions of preglomerular and postglomerular vasculature) was steeper in OLETF than in LETO. In contrast, the threshold pressure for beginning filtration (preglomerular-to-postglomerular vascular resistance ratio) at pressure-GFR relationship did not differ between the two strains; however, the slope of the relationship (glomerular filtration capacity) was lower in OLETF than in LETO. Thus, in the kidneys of 10-week-old OLETF rats, vascular narrowing and impaired glomerular filtration capacity already existed with no abnormalities in preglomerular-to-postglomerular vascular resistance ratio. From the age of 10-42 weeks, the following results were obtained: (1) Minimal renal vascular resistance decreased in both strains, but it diminished markedly in OLETF. (2) The pressure for beginning filtration increased in LETO, but remained unchanged in OLETF. (3) Glomerular filtration capacity decreased to the similar extent in both strains. (4) Histologically, the vascular lumen and wall thickness increased in the interlobular arteries of both strains. However, vascular luminal widening was more pronounced in OLETF, resulting in the reduction in wall to lumen ratio. (5) Glomerular injuries and increased blood pressure occurred only in OLETF. In conclusion, during progression from the prediabetic to diabetic stage of OLETF, the pre-existing vascular narrowing was markedly attenuated without the concomitant increase in preglomerular-to-postglomerular vascular resistance ratio. Combined with increased blood pressure, these renal structural alterations could lead to the elevation of intraglomerular pressure in OLETF.