Enhanced renal sensitivity to angiotensin actions in diabetes mellitus in the rat

Kennefick, Thomas M.; Oyama, T; Thompson, Michele M.; Vora, Jiten; Anderson, Sharon

doi:10.1152/ajprenal.1996.271.3.f595

Cited by 24 publications

(31 citation statements)

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“…25 In models of nondiabetic renal disease, castration reduces albuminuria by downregulating the activity of the reninangiotensin system. 26 It is conceivable that, in the setting of diabetes, castration is insufficient to reduce renal activity, which is upregulated in the face of persistent hyperglycemia, 27 leading to the development of albuminuria. Further studies are needed to examine the effects of castration on the renin-angiotensin system expression and activity.…”

Section: Discussionmentioning

confidence: 99%

Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Wells

Garman

et al. 2008

Hypertension

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Abstract-Studies suggest that the presence of testosterone exacerbates, whereas the absence of testosterone attenuates, the development of nondiabetic renal disease. However, the effects of the absence of testosterone in diabetic renal disease have not been studied. The study was performed in male Sprague-Dawley nondiabetic, streptozotocin-induced diabetic, and streptozotocin-induced castrated rats (nϭ10 to 11 per group) for 14 weeks. Diabetes was associated with the following increases: 3.2-fold in urine albumin excretion, 6.3-fold in glomerulosclerosis, 6.0-fold in tubulointerstitial fibrosis, 1.6-fold in collagen type I, 1.2-fold in collagen type IV, 1.3-fold in transforming growth factor-␤ protein expression, and 32.7-fold in CD68-positive cell abundance. Diabetes was also associated with a 1.3-fold decrease in matrix metalloproteinase protein expression and activity. Castration further exacerbated all of these parameters. Diabetes was also associated with a 4.7-fold decrease in plasma testosterone, 2.9-fold increase in estradiol, and 2.1-fold decrease in plasma progesterone levels. Castration further decreased plasma testosterone levels but had no additional effects on plasma estradiol and progesterone. These data suggest that diabetes is associated with abnormal sex hormone levels that correlate with the progression of diabetic renal disease. Most importantly, our results suggest an important role for sex hormones in the pathophysiology of diabetic renal complications. (Hypertension. 2008;51:1218-1224.)Key Words: diabetes Ⅲ kidney Ⅲ sex hormones Ⅲ glomerulosclerosis Ⅲ tubulointerstitial fibrosis E pidemiological studies show that the incidence and the rate of progression of nondiabetic renal disease are greater in men compared with age-matched women. 1,2 These observations lead to the belief that the male sex is a risk factor and/or that the female sex is a protective factor against the development of renal disease. In the setting of diabetes, however, this relationship is not so clear. Although some studies indicate that the male sex is still a risk factor for the development of diabetic nephropathy and progression to end-stage renal disease, 3,4 other studies suggest either no difference 5,6 or that females progress at a faster rate. 7,8 The actual truth is that the existing data are inadequate for the precise determination of whether sex differences, which clearly exist in nondiabetic renal disease, exist or "disappear" in the setting of diabetes.Our previous studies have shown that diabetes is associated with reduced plasma levels of estradiol in the female streptozotocin (STZ)-induced diabetic rat. 9 Supplementation of estradiol in these animals either from the onset 10,11 or 2 months after the induction of diabetes 12 attenuates the development of renal disease. Clinical studies indicate that diabetes is associated with decreased testosterone levels in men with diabetes, 13,14 suggesting that testosterone deficiency may contribute or at least be associated with the development of diabetic renal disea...

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Section: Discussionmentioning

confidence: 99%

Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Wells

Garman

et al. 2008

Hypertension

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“…It has been widely reported that RAS is implicated in hemodynamic maladaptations of the diabetic kidney [21,22,28] , and the changes of ACE, ACE2, as well as Ang II, have been investigated in STZ-induced diabetic rats [23][24][25] . Previous investigations have shown that Ang (1-7) serves a protective role by counteracting the effects of locally-generated Ang II in cardiovascular research [26] .…”

Section: Discussionmentioning

confidence: 99%

Chronic angiotensin (17) injection accelerates STZ-induced diabetic renal injury¹

Shao

Zhou

et al. 2008

Acta Pharmacologica Sinica

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Aim: The renin-angiotensin system (RAS) plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. In the past few years, angiotensin (Ang) (1-7) has been reported to counteract the effects of Ang II and was even considered as a new therapeutical target in RAS. The present study aimed to investigate the effect of Ang (1-7) administration on a diabetic animal model and the modulation on local RAS. Methods: Streptozotocin (STZ) injection-induced diabetic rats were used in the experiment. The animals were divided into 3 groups: (1) control; (2) STZ-induced diabetes; and (3) STZ-induced diabetes with chronic Ang (1-7) treatment [D+Ang (1-7)]. In the D+Ang(1-7) group, a dose of 25 µg·kg of Ang (1-7) was continually injected through the jugular vein by embedding miniosmotic pump for 6 weeks. Plasma glucose, ratio of kidney to body weight, and 24 h urine protein and serum creatinine were monitored by conventional measurement. Plasma and renal Ang II levels were measured by radioimmunoassay. Ang-converting enzyme (ACE), ACE2, Ang II type 1 (AT1) receptor, Ang II type 2 (AT2) receptor, Ang (1-7) Mas receptor, and TGF-β1 mRNA levels were measured by real time PCR; ACE, ACE2, and TGF-β1 protein levels were analyzed by Western blotting. Results:The renal function of diabetic rats was significantly retrogressed when compared with that of control rats. After the treatment by constant Ang (1-7) vein injection for 6 weeks, renal function was found to be even worse than diabetic rats, and both TGF-β1 mRNA and protein levels were elevated in the D+Ang(1-7) group compared with the diabetic rats. The real-time PCR result also showed an increase in ACE mRNA expression and decrease in ACE2 mRNA level in the D+Ang(1-7) group when compared with diabetic rats. The number of AT1 receptors increased in the Ang (1-7)-injected group, while the number of AT2 and Mas receptors decreased. Conclusion: Exogenous Ang (1-7) injection did not ameliorate STZinduced diabetic rat renal injury; on the contrary, it accelerated the progressive diabetic nephropathies.

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“…However, this reduction in Ang II receptor expression does not indicate that the AT1 receptor is not functionally as active in the diabetic context because these techniques do not address postreceptor signaling events. Indeed, it has been demonstrated that there is an increase in sensitivity to Ang II in the diabetic kidney, both in experimental and clinical studies (50,51), and this has been postulated to partly explain the renoprotective effects that have been amply demonstrated in both experimental and human diabetes.…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy with the Advanced Glycation End Product Cross-Link Breaker, Alagebrium, and Angiotensin Converting Enzyme Inhibitors in Diabetes: Synergy or Redundancy?

Coughlan¹,

Thallas‐Bonke²,

Pete³

et al. 2007

Endocrinology

118

111

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Blockade of advanced glycation end product (AGE) accumulation with alagebrium with concomitant angiotensin converting enzyme inhibition was tested for effects on renal function and on other postulated mediators of diabetic renal disease including the renin-angiotensin system, AGEs, mitochondrial and cytosolic oxidative stress, and intracellular signaling molecules. Sprague Dawley rats were rendered diabetic with streptozocin and followed consecutively for 32 wk with nondiabetic controls. Groups were treated with ramipril (1 mg/kg⅐d; wk 0 -32); alagebrium (10 mg/kg⅐d; wk 16 -32); or a combination of both. Although individual treatments had significant effects on albuminuria, no further improvements were seen with combination therapy. Changes in urinary vascular endothelial growth factor excretion mirrored those seen in albuminuria. Diabetes was associated with suppression of circulating angiotensin II in the context of increased circulating and renal levels of the AGE, carboxymethyllysine. All treatments attenuated circulating but not renal carboxymethyllysine levels. The renal gene expression of AGE receptor 1 and soluble receptor for advanced glycation end products were markedly reduced by diabetes and normalized with alagebrium. Diabetes induced renal mitochondrial oxidative stress, which was reduced with alagebrium. In the cytosol, both therapies were equally effective in reducing reactive oxygen species production. Increases in membranous protein kinase C activity in diabetes were attenuated by all treatments, whereas diabetes-associated increases in nuclear factor-B p65 translocation remained unaltered by any therapy. It is evident that renin-angiotensin system blockade and AGE inhibition have specific effects. However, many of their downstream effects appear to be similar, suggesting that their renoprotective benefits may ultimately involve common pathways and key points of convergence, which could be important targets for new therapies in diabetic nephropathy. (Endocrinology 148: 886 -895, 2007)

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Enhanced renal sensitivity to angiotensin actions in diabetes mellitus in the rat

Cited by 24 publications

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Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Chronic angiotensin (17) injection accelerates STZ-induced diabetic renal injury¹

Combination Therapy with the Advanced Glycation End Product Cross-Link Breaker, Alagebrium, and Angiotensin Converting Enzyme Inhibitors in Diabetes: Synergy or Redundancy?

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Enhanced renal sensitivity to angiotensin actions in diabetes mellitus in the rat

Cited by 24 publications

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Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Chronic angiotensin (17) injection accelerates STZ-induced diabetic renal injury1

Combination Therapy with the Advanced Glycation End Product Cross-Link Breaker, Alagebrium, and Angiotensin Converting Enzyme Inhibitors in Diabetes: Synergy or Redundancy?

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Chronic angiotensin (17) injection accelerates STZ-induced diabetic renal injury¹