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. There are numerous rodent models of human diabetic nephropathy (DN), attesting to the uncertainty associated with many of them. 1,2 Streptozotocin (STZ), which induces hyperglycemia by selectively damaging pancreatic b cells, has been administered to genetically modified rodents to create a variety of DN models. [3][4][5][6] The validity of one of these models, the diabetic (mREN-2)27 rat, has been questioned because of the apparent overwhelming impact of its genetically mediated hypertension on renal pathology. 7 One group of investigators reported that STZ-induced diabetes in female heterozygous (mREN-2)27 rats recapitulates the proteinuria, nodular glomerulosclerosis, and progressive loss of renal function that are cardinal features of DN in human beings. 6 However, other investigators suggest that the survival and kidney pathology of male heterozygotes is determined more by hypertension than by diabetes, as the presence of diabetes in these animals seemed to exert little phenotypic effect. 7 A sexual dimorphism in hypertension is apparent from the lower blood pressure of female vs male (mREN-2)27 rats. 8 This dimorphism has been proposed to underlie the apparent gender-dependent variation in experimental outcome because the effects of diabetes might only be observed in kidneys ...

Hill JV, Findon G, Appelhoff RJ, Endre ZH. Renal autoregulation and passive pressure-flow relationships in diabetes and hypertension. Am J Physiol Renal Physiol 299: F837-F844, 2010. First published July 21, 2010 doi:10.1152/ajprenal.00727.2009.-We investigated renal hemodynamics in isolated, perfused kidneys from rat models of diabetes and hypertension. Autoregulation and passive vascular responses were measured using stepped pressure ramps in the presence of angiotensin II (pEC50) or papaverine (0.1 mM), respectively. Male diabetic heterozygote m(Ren2)27 rats were compared with three male control groups: nondiabetic, normotensive Sprague-Dawley (SD) rats; nondiabetic, hypertensive heterozygote m(Ren2)27 rats; and diabetic, normotensive SD rats. Kidney function (proteinuria, creatinine clearance) was monitored before induction and at monthly intervals. Vascular function was measured in vitro in rats of induction age (6 -8 wk) and at 2 and 4 mo postinduction. Renal flow correlated with age, but not diabetes or the Ren2 gene. Kidney weight-specific and body weightspecific renal flow differed between diabetic and nondiabetic rats because diabetic rats had higher kidney but lower body weights. Kidneys from all groups showed effective autoregulation in the presence of angiotensin II. The autoregulatory pressure threshold of m(Ren2)27 rats was higher, and the autoregulation pressure range was wider, compared with SD rats. When vascular smooth muscle activity was blocked with papaverine, pressure-flow responses differed between groups and with time. The m(Ren2)27 rat groups showed higher renal vascular resistance at lower pressures, suggesting greater vascular stiffness. In contrast, diabetic SD rat kidneys demonstrated reduced vessel stiffness. Flow was impaired in diabetic m(Ren2)27 rats at 4 mo, and this correlated with a decline in creatinine clearance. The results suggest that the characteristic late decline in renal filtration function in diabetes-and hypertension-related renal disease follows changes in renal vascular compliance. change in vascular conductance; vascular remodeling DIABETIC NEPHROPATHY (DN) is the most common cause of end-stage renal failure (ESRF) in the Western world (24). Clinical progression of DN follows a relatively well-defined course characterized by early microalbuminuria, renal hyperfiltration and hyperperfusion, and increased capillary permeability to macromolecules. DN occurs late in diabetes, generally becoming apparent 15-25 yr after onset (8). However, glomerular basement membrane thickening begins less than 2 yr after onset of diabetes and is followed by mesangial matrix expansion. The final stage leading to ESRF is a progressive decline in glomerular filtration rate (GFR) (8,24).Progressive deterioration of renal function is commonly due to diabetes and hypertension, both separately and together. The causes of hypertension are multifactorial and diabetes is characterized by multiple potential mediators of progressive renal injury, including hyperglycemia, hypertension, endothe...