Mechanisms for Renal Blood Flow Control Early in Diabetes as Revealed by Chronic Flow Measurement and Transfer Function Analysis

Bell, Tracy; DiBona, Gerald F.; Wang, Ying; Brands, Michael

doi:10.1681/asn.2006030216

Cited by 36 publications

(39 citation statements)

References 45 publications

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“…It has been shown that chronic but not acute inhibition of phosphodiesterase-5 may enhance insulin action and improve energy balance in vivo. 19 Varma et al reported that chronic treatment with tadalafil improved fasting glucose levels and reduced infarct size following ischemia-reperfusion injury in diabetic rat hearts. 9 Although the mechanism is not fully clear but it has been shown that in STZ-induced diabetes and due to hyperglycemia the renal autoregulation is impaired in the early stage leading to a rapid and progressive increase in RBF which is significantly dependent upon an increase in NO activity.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of tadalafil in diabetic nephropathy induced rat model

Elhawary

Allah

2017

Int J Basic Clin Pharmacol

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INTRODUCTIONDiabetes mellitus (DM) is a major global health problem that causes several micro-and macro-vascular complications. Among these is diabetic nephropathy (DN). DN is the main cause of end-stage renal disease and is associated with a high morbidity and mortality. It develops due to a complex interaction between metabolic and haemodynamic pathophysiological factors, which lead to renal damage. In the earliest stage of DN, patient usually presents with an increase in urinary albumin excretion (microalbuminuria) which progress to macroalbuminuria (more than 300 mg in a 24-hour collection) and later renal insufficiency. 1Among the various mechanisms involved in the pathogenesis of diabetic nephropathy, abnormalities in renal nitric oxide (NO) generation has attracted a lot of attention. NO is postulated to play a protective role towards ischemic injuries of vascular tissues including renal vascular endothelium, an action mediated via cyclic guanosine monophosphate (cGMP) which initiates renal vascular smooth muscle relaxation.2 NO plays numerous physiological roles in the kidney, including control of renal and glomerular hemodynamics, dilates both the ABSTRACT Background: Among various mechanisms involved in the pathogenesis of diabetic nephropathy (DN), abnormalities in renal nitric oxide (NO) generation has attracted a lot of attention. Tadalafil, a competitive inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 commonly used in the treatment of erectile dysfunction was suggested to play a potential prophylactic role for DN. However, this role has not been fully elucidated. The present study was designed to explore the potential beneficial effect of low-dose tadalafil on the progression of diabetic nephropathy in streptozotocin (STZ) induced diabetic rat model. Methods: After injection of STZ and verifying establishment of diabetes, rats were divided into 4 groups: control, diabetic-control, tadalafil-treated nondiabetic, and tadalafil-treated diabetic groups. Biochemical and hemodynamic parameters affecting the renal function such as blood glucose level, serum level of urea and creatinine, renal blood flow, urine volume, urinary albumin excretion, Na+ and K+ excretion, renal level of nitrite and nitrate, plus renal tissues antioxidant parameters (total antioxidant capacity, superoxide dismutase activity and glutathione content) were detected 8 weeks after administration of tadalafil. Histopathological and electron microscopy examination were performed. Results: Our results demonstrated that tadalafil attenuated the glycemic, renal biochemical, microscopic and ultramicroscopic changes/injuries caused by STZ-induced diabetes. Tadalafil could effectively increase renal blood flow and ameliorate glomerular basement membrane thickening. Conclusions: From the results it can be concluded that tadalafil protects rats against streptozotocin-induced DN possibly, in part, through its effect on renal nitric oxide level and its antioxidant activity.

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Section: Discussionmentioning

confidence: 99%

Protective effect of tadalafil in diabetic nephropathy induced rat model

Elhawary

Allah

2017

Int J Basic Clin Pharmacol

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“…At t ϭ 0, 0.3 g/kg BW glucose (50% dextrose, 454 mg/ml; B Braun, Irvine, CA) was injected into a peripheral vein. Additional samples were taken at 2,3,4,5,6,8,10,12,14,16, and 19 min. At t ϭ 20 min, a bolus of 0.03 U/kg porcine insulin was injected into a peripheral vein followed by sampling at 22,23,24,25,30,40,50,60,70,80,90,100,120,140,160, and 180 min.…”

Section: Metabolic Assessmentsmentioning

confidence: 99%

“…Visceral adipose tissue was defined as the fat located in the intra-and retroperitoneal region, and this region was separated from the subcutaneous adipose tissue by manual trace. For each slice, the area was calculated in cm 2 (area of 226 ϫ 256 pixels equivalent to 34.9 ϫ 34.9 cm 2 ) and multiplied by the thickness of the slice to obtain the volume.…”

Section: Calculationsmentioning

confidence: 99%

Novel canine models of obese prediabetes and mild type 2 diabetes

Ionut¹,

Liu²,

Mooradian³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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(T2DM) is often characterized by obesity-associated insulin resistance (IR) and ␤-cell function deficiency. Development of relevant large animal models to study T2DM is important and timely, because most existing models have dramatic reductions in pancreatic function and no associated obesity and IR, features that resemble more T1DM than T2DM. Our goal was to create a canine model of T2DM in which obesity-associated IR occurs first, followed by moderate reduction in ␤-cell function, leading to mild diabetes or impaired glucose tolerance. Lean dogs (n ϭ 12) received a high-fat diet that increased visceral (52%, P Ͻ 0.001) and subcutaneous (130%, P Ͻ 0.001) fat and resulted in a 31% reduction in insulin sensitivity (S I) (5.8 Ϯ 0.7 ϫ 10 Ϫ4 to 4.1 Ϯ 0.5 ϫ 10 Ϫ4 U ⅐ ml Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.05). Animals then received a single low dose of streptozotocin (STZ; range 30 -15 mg/kg). The decrease in ␤-cell function was dose dependent and resulted in three diabetes models: 1) frank hyperglycemia (high STZ dose); 2) mild T2DM with normal or impaired fasting glucose (FG), 2-h glucose Ͼ200 mg/dl during OGTT and 77-93% AIR g reduction (intermediate dose); and 3) prediabetes with normal FG, normal 2-h glucose during OGTT and 17-74% AIR g reduction (low dose). Twelve weeks after STZ, animals without frank diabetes had 58% more body fat, decreased ␤-cell function (17-93%), and 40% lower S I. We conclude that high-fat feeding and variable-dose STZ in dog result in stable models of obesity, insulin resistance, and 1) overt diabetes, 2) mild T2DM, or 3) impaired glucose tolerance. These models open new avenues for studying the mechanism of compensatory changes that occur in T2DM and for evaluating new therapeutic strategies to prevent progression or to treat overt diabetes.obesity; animal models; streptozotocin; insulin secretion TYPE 2 DIABETES MELLITUS (T2DM) is a highly prevalent disease with an enormous public and individual health impact. According to the Centers for Disease Control National Diabetes Fact Sheet, in 2007 23.6 million people in the US (7.8% of population) had diabetes, and an estimated 57 million people had prediabetes [impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both] (10). The disease's increasing prevalence requires adequate and strong intervention for prevention of new cases and new or improved therapeutic tools for the existing cases (11). T2DM is characterized by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response and is usually associated with obesity (15). Increased body fat and especially visceral fat accumulation have been shown to be risk factors for the development of IGT or diabetes (14). The mechanisms of the initial alterations in the development of T2DM, related to fat deposition and the associated changes in liver, muscle, and adipocyte, are not fully elucidated. Studying the relationship between insulin resistance and hyperinsulinemic compensation (or failure thereof) and the change from normal glucose tolerance to IGT ...

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“…This suggests that the characteristic decline in renal filtration function in diabetes-and hypertension-related renal disease follows changes in renal vascular compliance. Early hyperfiltration in diabetes is mediated by enhanced proximal tubule reabsorption which reduces sodium concentration at the distal tubule and thereby leads to tubuloglomerular feedback-induced afferent arteriolar vasodilation (5).…”

Section: Discussionmentioning

confidence: 99%

Renal autoregulation and passive pressure-flow relationships in diabetes and hypertension

Hill

Findon

Appelhoff

et al. 2010

American Journal of Physiology-Renal Physiology

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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...

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Mechanisms for Renal Blood Flow Control Early in Diabetes as Revealed by Chronic Flow Measurement and Transfer Function Analysis

Cited by 36 publications

References 45 publications

Protective effect of tadalafil in diabetic nephropathy induced rat model

Protective effect of tadalafil in diabetic nephropathy induced rat model

Novel canine models of obese prediabetes and mild type 2 diabetes

Renal autoregulation and passive pressure-flow relationships in diabetes and hypertension

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