Differential contribution of diabetes and the Ren2 gene to glomerular pathology in diabetic (mREN-2)27 rats

The effect of diabetes mellitus vs the effect of the Ren2 gene on the glomerular pathology of (mREN-2)27 heterozygous male rats is controversial. As discrete diabetes-induced glomerular lesions may have been overlooked, we performed a detailed morphometric analysis of glomeruli in diabetic and non-diabetic heterozygous male (mREN-2) 27 rats and their normotensive (non-diabetic and diabetic Sprague-Dawley) controls. Glomeruli were scored by light microscopy for nine discrete histological parameters, some of which were graded for extent and/or severity. Mesangiolysis, segmental hypocellularity, and severe tuft-to-capsule adhesions were specific to diabetes; severe mesangial matrix expansion, glomerulosclerosis, thickening of Bowman's capsule, and dilatation of the urinary space were specific to the Ren2 gene. Hyalinosis and hypercellularity were associated with both diabetes and the Ren2 gene: the effect was additive for hyalinosis and synergistic for hypercellularity. The histological parameters were then combined with two physiological indices (systolic blood pressure and proteinuria) and principle components analysis (PCA) was used to detect correlations between the variables. Four discrete patterns of pathology were identified; three were statistically associated with diabetes and/or the Ren2 gene. These findings suggest that both diabetes and the Ren2 gene make significant, albeit different, contributions to the glomerular pathology of diabetic heterozygous male (mREN-2) 27 rats. Despite defining the contribution of diabetes, our work does not support the (mREN-2) 27 rat as a model of diabetic nephropathy (DN). Rather, it suggests that these animals remain useful for investigating a particular and limited constellation of DN features. Laboratory Investigation (2010) 90, 1225-1235; doi:10.1038/labinvest.2010.96; published online 10 May 2010