Renal injury in streptozotocin-diabetic Ren2-transgenic rats is mainly dependent on hypertension, not on diabetes

Abstract

Hartner A, Cordasic N, Klanke B, Wittmann M, Veelken R, Hilgers KF. Renal injury in streptozotocin-diabetic Ren2-transgenic rats is mainly dependent on hypertension, not on diabetes. Am J Physiol Renal Physiol 292: F820 -F827, 2007. First published October 3, 2006; doi:10.1152/ajprenal.00088.2006.-Induction of streptozotocin (STZ) diabetes in hypertensive rats transgenic for the mouse ren-2 gene (TGR) has been described as a model of progressive diabetic nephropathy. We investigated the long-term course of STZ diabetes in TGR and appropriate Sprague-Dawley control rats (SD) and tested the role of angiotensin-dependent hypertension by treating rats with the angiotensin II type 1 receptor blocker losartan (1 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) via osmotic minipumps. Five weeks after STZ injection, diabetes developed in TGR and SD. Urinary albumin excretion was increased by diabetes and, to a much higher degree, by hypertension. The effects of hypertension and diabetes were not additive, and only the effects of hypertension were ameliorated by losartan. A similar pattern was observed for cell proliferation and macrophage infiltration in the kidney. In contrast, the effects of hypertension and diabetes on glomerular collagen IV accumulation were additive 5 wk after STZ injection. In a long-term study for 20 wk after STZ, survival was better in STZ-treated TGR than in normoglycemic TGR, whereas all SD survived. Impaired creatinine clearance and increased macrophage infiltration as well as glomerular and interstitial matrix deposition were prominent in TGR compared with SD, regardless of the presence or absence of diabetes. In conclusion, STZ diabetes in TGR may be useful to study glomerular and interstitial matrix deposition early in the course of diabetes. However, the long-term course of this animal model resembles severe hypertensive nephrosclerosis, rather than progressive diabetic nephropathy.angiotensin; nephrosclerosis; macrophages; glomerulosclerosis DIABETIC NEPHROPATHY is the most common cause of end-stage renal failure in developed countries, and its incidence continues to rise (32). In most patients with diabetic nephropathy, hypertension is present and contributes significantly to the progression of renal failure in diabetes (32). Studies in diabetic rats as well as in human volunteers with hyperglycemia have indicated that activation of the intrarenal renin-angiotensin system (RAS) plays a key role in the development of the hemodynamic abnormalities in early diabetic nephropathy (1, 13). Angiotensin (ANG) II contributes to systemic and glomerular capillary hypertension in diabetic nephropathy (1) and may exert additional nonhemodynamic effects such as promotion of inflammation and fibrosis (39). The role of ANG II in the development and progression of diabetic nephropathy is supported by clinical trials with ANG II antagonists (22, 30).There is a long-standing debate as to what extent the available rodent models represent human diabetic nephropathy, in particular nephropathy of patients with type 2 diabetes (4, 15)....

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

“…In these animals, renal pathology has been reported to be far more dependent on hypertension than on diabetes, with the contribution of diabetes to glomerular pathology being limited to additive effects on MME. 7 It is possible that the diabetic effects we observed have been hitherto overlooked because of the almost exclusive focus of earlier glomerular assessments of diabetic (mREN-2)27 rats on the incidence of glomerulosclerosis and degree of MME. 6,7 It is also possible that hypertensive lesions were much more prominent in one of the earlier renal histopathological assessments of diabetic (mREN-2)27 rats because of diabetes having been induced in rats that were likely to have been hypertensive for several weeks longer than those used in our study.…”

“…7 It is possible that the diabetic effects we observed have been hitherto overlooked because of the almost exclusive focus of earlier glomerular assessments of diabetic (mREN-2)27 rats on the incidence of glomerulosclerosis and degree of MME. 6,7 It is also possible that hypertensive lesions were much more prominent in one of the earlier renal histopathological assessments of diabetic (mREN-2)27 rats because of diabetes having been induced in rats that were likely to have been hypertensive for several weeks longer than those used in our study. 7 Mesangiolysis was the most prominent diabetes-specific phenomenon identified in our study.…”

“…[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.…”

“…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 that are not dominated by hypertensive lesions.…”

“…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 that are not dominated by hypertensive lesions. 7 An equally plausible possibility, which is the focus of this study, is that the effect of diabetes in males has been overlooked because the types of renal damage typically assessed do not adequately capture the subtlety and extent of diabetic injury. As the (mREN-2)27 rat exhibits the elevated prorenin levels and high tissue renin-angiotensin system (RAS) activity that characterize DN in human beings, [9][10][11][12][13][14][15][16][17] investigating this possibility is important lest a potentially valuable model be prematurely dismissed.…”