Candesartan ameliorates the functional renal disorder in diabetic nephropathy induced by streptozotocin

Background Diabetic nephropaty (DN) occurs in approximately 40% of patients with diabetes mellitus, and is the most common cause of end-stage renal disease. The mechanisms of DN are not very clear more recently, but the renin-angiotensin system (RAS) plays an important role. It has been known that rennin-angiotensin system blockers have a renal protective effect. The present study was undertaken to evaluate the effects of the candesartan on functional renal tests in streptozotocin (STZ) induced DN in rats. Methods DM was induced by a single intraperitoneal injection (ip) injection of STZ (60 mg/kg). In order to develop DN the animals were left in diabetic condition during 4 weeks. The DM rats were randomly assigned to the two experimental groups (STZ and STZ+CAN). To estimate the symptoms and signs of DN, the STZ group of rats was left without treatment. For assessment of the effects of the AT1 antagonist, candesartan (CAN) (5 mg/kg/day) was administered from week 4 to week 12. Renal function was assessed by determination of serum creatinine, blood urea nitrogen (BUN) test, 24-hour urine volume and urine albumin. Results The administration of STZ have caused diabetes mellitus (DM) with symptoms and signs of DN including poor general condition, body weight loss, as well as abnormalities of serum and urinary renal function tests. In STZ group of rats, these symptoms have been more distinctly 8 and 12 weeks after administration of STZ. Conclusion The candesartan treatment, although not completely but to a great extent ameliorates the functional renal disorder induced by STZ and may be used as a first line drug in preventing DN.

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Predictors of Residual Renal Function Decline in Peritoneal Dialysis Patients: ThebalANZ Trial

Peritoneal Dialysis International ◽

10.3747/pdi.2016.00206 ◽

2017 ◽

Vol 37 (3) ◽

pp. 283-289 ◽

Cited By ~ 11

Author(s):

Htay Htay ◽

Yeoungjee Cho ◽

Elaine M. Pascoe ◽

Darsy Darssan ◽

Carmel Hawley ◽

...

Keyword(s):

Renal Function ◽

Peritoneal Dialysis ◽

Demographic Data ◽

Urine Volume ◽

Renin Angiotensin System ◽

Residual Renal Function ◽

Angiotensin System ◽

Low Glucose ◽

Glucose Exposure

ObjectivePreservation of residual renal function (RRF) is associated with improved survival. The aim of the present study was to identify independent predictors of RRF and urine volume (UV) in incident peritoneal dialysis (PD) patients.MethodsThe study included incident PD patients who were balANZ trial participants. The primary and secondary outcomes were RRF and UV, respectively. Both outcomes were analyzed using mixed effects linear regression with demographic data in the first model and PD-related parameters included in a second model.ResultsThe study included 161 patients (mean age 57.9 ± 14.1 years, 44% female, 33% diabetic, mean follow-up 19.5 ± 6.6 months). Residual renal function declined from 7.5 ± 2.9 mL/min/1.73 m2at baseline to 3.3 ± 2.8 mL/min/1.73 m2at 24 months. Better preservation of RRF was independently predicted by male gender, higher baseline RRF, higher time-varying systolic blood pressure (SBP), biocompatible (neutral pH, low glucose degradation product) PD solution, lower peritoneal ultrafiltration (UF) and lower dialysate glucose exposure. In particular, biocompatible solution resulted in 27% better RRF preservation. Each 1 L/day increase in UF was associated with 8% worse RRF preservation ( p = 0.007) and each 10 g/day increase in dialysate glucose exposure was associated with 4% worse RRF preservation ( p < 0.001). Residual renal function was not independently predicted by body mass index, diabetes mellitus, renin angiotensin system inhibitors, peritoneal solute transport rate, or PD modality. Similar results were observed for UV.ConclusionsCommon modifiable risk factors which were consistently associated with preserved RRF and residual UV were use of biocompatible PD solutions and achievement of higher SBP, lower peritoneal UF, and lower dialysate glucose exposure over time.

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Impact of Hyperglycemia on the Renin Angiotensin System in Early Human Type 1 Diabetes Mellitus

Journal of the American Society of Nephrology ◽

10.1681/asn.v1081778 ◽

1999 ◽

Vol 10 (8) ◽

pp. 1778-1785

Author(s):

JUDITH A. MILLER

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Renal Function ◽

Blood Glucose ◽

Mean Arterial Pressure ◽

Arterial Pressure ◽

Type 1 Diabetes Mellitus ◽

Renin Angiotensin System ◽

Angiotensin System

Abstract. It has been demonstrated previously that moderate hyperglycemia without glucosuria can increase plasma renin activity and mean arterial pressure in young healthy males with early uncomplicated type 1 diabetes mellitus. This study was conducted to extend these observations by testing the hypothesis that mild to moderate hyperglycemia can affect renal function by increasing renin angiotensin system (RAS) activity in diabetic humans. The study included 10 men and women with early, uncomplicated type 1 diabetes (duration <5 yr), all ingesting a controlled sodium and protein diet. They were studied on four separate occasions, during a subdepressor dose of the angiotensin II (AngII) receptor blocker losartan, and during graded AngII infusion, 1.5 and 2.5 ng/kg per min, while euglycemic (blood glucose 4 to 6 mmol/L) and again while hyperglycemic without glucosuria (blood glucose 9 to 11 mmol/L), according to a randomized crossover design. Outcome measures included mean arterial pressure (MAP), GFR, effective renal plasma flow (ERPF), renal vascular resistance (RVR), filtration fraction (FF), and urine sodium excretion (UNaV) at baseline and in response to the above maneuvers. During hyperglycemic conditions, MAP was significantly higher compared with euglycemia, as were RVR and FF. After the administration of losartan, a significant renal and peripheral depressor effect was noted, with decreases in MAP, RVR, and FF, whereas during euglycemia the responses to losartan were minimal. AngII infusion resulted in elevations in MAP, RVR, and FF and a decline in UNaV during both glycemic phases, but the responses during hyperglycemia, most significantly at the 1.5 ng/kg per min infusion rate, were blunted. These data support the hypothesis that hyperglycemia affects renal function by activating the RAS. The mechanism remains obscure, but these contrasting responses may provide a link between the observations that maintenance of euglycemia and blockade of the RAS prevent or delay diabetic kidney disease, and furthermore, may clarify the mechanism whereby high glucose promotes renal disease progression in diabetes.

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Renal function and the renin-angiotensin system in the isolated perfused kidney

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1967.213.4.928 ◽

1967 ◽

Vol 213 (4) ◽

pp. 928-934 ◽

Cited By ~ 16

Author(s):

HD Berkowitz ◽

LD Miller ◽

HD Itskovitz

Keyword(s):

Renal Function ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Isolated Perfused Kidney ◽

Renin Angiotensin ◽

Perfused Kidney

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UPREGULATION OF RENIN ANGIOTENSIN SYSTEM IN TYPE 1 DIABETES MELLITUS ASSOCIATED WITH HYPERTENSION

Journal of Hypertension ◽

10.1097/00004872-201106001-01112 ◽

2011 ◽

Vol 29 ◽

pp. e377-e378

Author(s):

L. Morais ◽

I. Watanabe ◽

M. Franco ◽

D. Arita ◽

M. Gabbay ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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Preoperative Renin-Angiotensin System Inhibitors Protect Renal Function in Aging Patients Undergoing Cardiac Surgery

Journal of Surgical Research ◽

10.1016/j.jss.2009.11.702 ◽

2011 ◽

Vol 167 (2) ◽

pp. e63-e69 ◽

Cited By ~ 27

Author(s):

Viachaslau Barodka ◽

Scott Silvestry ◽

Ning Zhao ◽

Xiangyin Jiao ◽

David J. Whellan ◽

...

Keyword(s):

Renal Function ◽

Cardiac Surgery ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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Mechanism of and Therapeutic Strategy for Atrial Fibrillation Associated with Diabetes Mellitus

The Scientific World JOURNAL ◽

10.1155/2013/209428 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 18

Author(s):

Yubi Lin ◽

Hairui Li ◽

Xianwu Lan ◽

Xianghui Chen ◽

Aidong Zhang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Atrial Fibrillation ◽

Catheter Ablation ◽

Sinus Rhythm ◽

Renin Angiotensin System ◽

Hypoglycemic Agents ◽

Angiotensin System ◽

Low Levels ◽

Upstream Therapy

Diabetes mellitus (DM) is one of the most important risk factors for atrial fibrillation (AF) and is a predictor of stroke and thromboembolism. DM may increase the incidence of AF, and when it is combined with other risk factors, the incidence of stroke and thromboembolism may also be higher; furthermore, hospitalization due to heart failure appears to increase. Maintenance of well-controlled blood glucose and low levels of HbA1c in accordance with guidelines may decrease the incidence of AF. The mechanisms of AF associated with DM are autonomic remodeling, electrical remodeling, structural remodeling, and insulin resistance. Inhibition of the renin-angiotensin system is suggested to be an upstream therapy for this type of AF. Studies have indicated that catheter ablation may be effective for AF associated with DM, restoring sinus rhythm and improving prognosis. Catheter ablation combined with hypoglycemic agents may further increase the rate of maintenance of sinus rhythm and reduce the need for reablation.

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Synergistic Expression of Angiotensin-Converting Enzyme (ACE) and ACE2 in Human Renal Tissue and Confounding Effects of Hypertension on the ACE to ACE2 Ratio

Endocrinology ◽

10.1210/en.2006-1287 ◽

2007 ◽

Vol 148 (5) ◽

pp. 2453-2457 ◽

Cited By ~ 68

Author(s):

Shigeyuki Wakahara ◽

Tadashi Konoshita ◽

Shinichi Mizuno ◽

Makoto Motomura ◽

Chikako Aoyama ◽

...

Keyword(s):

Renal Function ◽

Angiotensin Converting Enzyme ◽

Pairwise Comparison ◽

Renin Angiotensin System ◽

Mrna Levels ◽

Converting Enzyme ◽

Gene Expressions ◽

Angiotensin System ◽

Renin Angiotensin ◽

Clinicopathological Variables

Angiotensin-converting enzyme (ACE) 2, a newly emerging component of the renin-angiotensin system, is presumed to be a counterregulator against ACE in generating and degrading angiotensin II. It remains to be elucidated how mRNA levels of these two genes are quantitatively regulated in the kidney and also what kind of clinicopathological characteristics could influence the gene expressions in humans. Seventy-eight cases of biopsy-proven renal conditions were examined in detail. Total RNA from a small part of each renal cortical biopsy specimen was reverse transcribed, and the resultant cDNA was amplified for ACE, ACE2, and glyceraldehyde-3-phosphate dehydrogenase with a real-time PCR system. Then we investigated the relationship between clinicopathological variables and mRNA levels adjusted for glyceraldehyde-3-phosphate dehydrogenase. Statistically significant correlation was not observed between any clinicopathological variables and either of the gene expressions by pairwise comparison. However, a strong correlation was observed between the gene expressions of ACE and those of ACE2. Moreover, the ACE to ACE2 ratio was significantly higher in subjects with hypertension (HT) than that in subjects without HT. Whereas parameters of renal function, e.g. urinary protein excretion (UPE) and creatinine clearance (Ccr), are not significantly related to the ACE to ACE2 ratio as a whole, the HT status may reflect disease-induced deterioration of renal function. That is, UPE and Ccr of subjects with HT are significantly different from those without HT, in which a significant correlation is also observed between UPE and Ccr. Finally, stepwise regression analysis further revealed that only the HT status is an independent confounding determinant of the ACE to ACE2 ratio among the variables tested. Our data suggest that ACE2 might play an important role in maintaining a balanced status of local renin-angiotensin system synergistically with ACE by counterregulatory effects confounded by the presence of hypertension. Thus, ACE2 may exert pivotal effects on cardiovascular and renal conditions.

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