Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats

Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue Po2. Recent observations have indicated that increased tubular Na+-glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon Po2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline Po2 in both the cortex and medulla. SGLT inhibition improved cortical Po2 in the diabetic kidney, whereas it reduced medullary Po2 in both groups. SGLT inhibition reduced Na+ transport efficiency [tubular Na+ transport (TNa)/renal O2 consumption (Qo2)] in the control kidney, whereas the already reduced TNa/Qo2 in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex Po2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary Po2 in both control and diabetic kidneys during the inhibition of proximal Na+ reabsorption suggests the redistribution of active Na+ transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia.

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Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney

Journal of Endocrinology ◽

10.1677/joe.0.1700647 ◽

2001 ◽

Vol 170 (3) ◽

pp. 647-651 ◽

Cited By ~ 58

Author(s):

C Hill ◽

A Flyvbjerg ◽

R Rasch ◽

M Bak ◽

A Logan

Keyword(s):

Diabetic Nephropathy ◽

Growth Factor ◽

Western Blotting ◽

Transforming Growth Factor ◽

Rat Kidney ◽

Human Monoclonal Antibody ◽

Diabetic Rats ◽

Diabetic Rat ◽

Diabetic Kidney ◽

In The Diabetic Kidney

Diabetic nephropathy is characterised by an increase in glomerular and tubular fibrosis that compromises kidney function. The transforming growth factor-betas (TGF-betas) have been shown to play a major role in fibrosis and we have shown that TGF-beta2, in particular, increases co-ordinately with fibrogenesis in the diabetic kidney. The aim of this study was to investigate the changes in expression of extracellular matrix molecules in the diabetic kidney, with and without systemic administration of a recombinant human monoclonal antibody to TGF-beta2. Streptozotocin-induced diabetic rats were split into two groups. The first were treated with 5 mg/kg irrelevant control IgG4 (placebo) and the second treated with 5 mg/kg isoform-specific recombinant monoclonal anti-TGF-beta2 IgG4 (termed CAT-152) systemically every second day for 14 days. A further group of six non-diabetic rats was also used as a control. Various biological parameters were measured daily throughout the experimental period, and on termination of the experiment at 14 days Western blotting was performed on kidney cortices for procollagen-I C-propeptide, which is an indicator of the rate of collagen-I synthesis within the kidney. In the placebo-treated diabetic rats, blood glucose, food consumption, urinary albumin excretion (UAE) and kidney weights were all significantly higher than in the non-diabetic group (P<0.05, n=24, by ANOVA). In the anti-TGF-beta2-treated diabetic rats, kidney weights and UAE levels were decreased when compared with those in placebo-treated diabetics. Western blotting for the procollagen-I C-propeptide in kidney cortices showed a significant increase in levels in placebo-treated diabetic rats compared with non-diabetic controls over the 14 day diabetic period, indicating initiation of fibrogenesis. By contrast, in anti-TGF-beta2-treated diabetic rats, levels of the propeptide remained at non-diabetic levels. In summary, a significant suppression of kidney fibrosis was seen in anti-TGF-beta2-treated diabetic rats, compared with placebo-treated diabetic rats. We conclude that systemic delivery of CAT-152, a neutralising anti-TGF-beta2 antibody, during the acute stages of diabetic nephropathy reduces the rate of pathogenic fibrosis in the kidney.

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Nitric oxide originating from NOS1 controls oxygen utilization and electrolyte transport efficiency in the diabetic kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00229.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. F416-F420 ◽

Cited By ~ 18

Author(s):

Fredrik Palm ◽

Angelica Fasching ◽

Peter Hansell ◽

Örjan Källskog

Keyword(s):

Nitric Oxide ◽

Rat Kidney ◽

Diabetic Rats ◽

Electrolyte Transport ◽

Diabetic Rat ◽

Oxygen Utilization ◽

Diabetic Kidney ◽

Transport Efficiency ◽

In The Diabetic Kidney

Nitric oxide (NO) is a potent regulator of both vascular tone and cellular oxygen consumption (Qo2). Diabetic kidneys have reduced NO availability and increased Qo2. However, the exact nitric oxide synthase (NOS) isoform regulating Qo2, hemodynamics, and excretory function in the diabetic kidney remains unclear. We therefore investigated the effects of both selective neuronal NOS (NOS1) inhibition and nonselective NOS inhibition. Oxygen utilization, electrolyte transport efficiency [tubular Na+ transport (TNa)/Qo2], renal blood flow (RBF), glomerular filtration rate (GFR), and mean arterial pressure (MAP) were measured in vivo in control and streptozotocin-diabetic rats before and after administration of the selective NOS1 inhibitor S-methyl-l-thiocitrulline (SMTC) or the nonselective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME). Diabetic rats had higher baseline Qo2 and GFR than control rats, although RBF was similar in the groups. SMTC and l-NAME increased Qo2 and reduced TNa/Qo2 only in the diabetic animals, whereas both inhibitors increased MAP and reduced RBF in both groups. GFR was reduced by l-NAME, but SMTC had no effect in either group. Carbachol increased RBF and decreased MAP in SMTC-treated rats, whereas it had no effect in l-NAME-treated rats, indicating that SMTC selectively inhibited NOS1. In conclusion, NO regulates RBF and GFR similarly in both control and diabetic rats. However, selective NOS1 inhibition increased Qo2 and reduced TNa/Qo2 in the diabetic rat kidney, indicating a pivotal role of NO produced by NOS1 in maintaining control of Qo2 and tissue oxygenation in these kidneys.

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Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation

AJP Renal Physiology ◽

10.1152/ajprenal.00288.2005 ◽

2007 ◽

Vol 292 (4) ◽

pp. F1141-F1150 ◽

Cited By ~ 145

Author(s):

Sakiko Ohga ◽

Kenichi Shikata ◽

Kosuke Yozai ◽

Shinichi Okada ◽

Daisuke Ogawa ◽

...

Keyword(s):

Endothelial Cells ◽

Transforming Growth Factor ◽

Diabetic Rats ◽

Pyrrolidine Dithiocarbamate ◽

Sprague Dawley ◽

Diabetic Kidney ◽

Ppar Γ ◽

Glomerular Endothelial Cells ◽

Anti Inflammatory ◽

In The Diabetic Kidney

Thiazolidinedione (TZD), a ligand for peroxisome proliferator-activated receptor-γ (PPAR-γ), exerts anti-inflammatory effects independently of the insulin-sensitizing effect. In the present study, we tested the hypothesis that TZD prevents the progression of diabetic nephropathy by modulating the inflammatory process. Five-week-old Sprague-Dawley rats were divided into three groups: 1) nondiabetic control rats (non-DM), 2) diabetic rats (DM), and 3) diabetic rats treated with pioglitazone (DM+pio). Diabetes was induced by injection with streptozotocin (STZ). The DM+pio group received 0.0002% pioglitazone mixed in chow for 8 wk after induction of diabetes. Blood glucose and HbA1c were elevated in diabetic rats but did not change by treatment with pioglitazone. Pioglitazone reduced urinary albumin excretion and glomerular hypertrophy, suppressed the expression of transforming growth factor (TGF)-β, type IV collagen, and ICAM-1, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, renal NF-κB activity was increased in diabetic rats and reduced by pioglitazone. PPAR-γ was expressed in glomerular endothelial cells in the diabetic kidney and in cultured glomerular endothelial cells. High-glucose conditions increased the expression of ICAM-1 and the activation of NF-κB in cultured glomerular endothelial cells. These changes were reduced by pioglitazone, ciglitazone, and pyrrolidine dithiocarbamate, an inhibitor of NF-κB. However, pioglitazone did not show the changes in the presence of PPAR-γ antagonist GW9662. Our results suggest that the preventive effects of pioglitazone may be mediated by its anti-inflammatory actions, including inhibition of NF-κB activation, ICAM-1 expression, and macrophage infiltration in the diabetic kidney.

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Anomalous decrease in dextran sulfate clearance in the diabetic rat kidney

AJP Renal Physiology ◽

10.1152/ajprenal.1998.274.4.f700 ◽

1998 ◽

Vol 274 (4) ◽

pp. F700-F708 ◽

Cited By ~ 4

Author(s):

Melissa J. Burne ◽

Yalçin Adal ◽

Neale Cohen ◽

Sianna Panagiotopoulos ◽

George Jerums ◽

...

Keyword(s):

Dextran Sulfate ◽

Rat Kidney ◽

Cell Receptor ◽

Diabetic Rats ◽

High Rate ◽

Diabetic Rat ◽

Sprague Dawley ◽

Charge Selectivity ◽

Sprague Dawley Rats ◽

Charge Interaction

The anomalous increase in charge selectivity as previously observed with reduced dextran sulfate clearances in diabetic rats (L. D. Michels, M. Davidman, and W. F. Keane. Kidney Int. 21: 699–705, 1982) was confirmed in 4-wk streptozotocin (STZ) diabetic Sprague-Dawley rats using the isolated perfused kidney technique. The apparent charge selectivity in both control and diabetic rats could be abolished by increasing the dextran sulfate concentration to 200 μg/ml in the perfusate. This was demonstrated by a high rate of processing of dextran sulfate (∼1,700 ng ⋅ min−1 ⋅ kidney−1) by glomeruli in both control and diabetic kidneys and by the fact that charge interaction could not explain the concentration dependence. The amount of urinary desulfation of dextran sulfate was also found to be significantly less in the diabetic kidney as was glomerular sulfatase activity compared with controls. Dextran sulfate glomerular processing is therefore altered in the STZ diabetic rat kidney but could be rationalized in terms of previous models of endothelial cell receptor-mediated uptake of dextran sulfate. The results are consistent with recent work demonstrating that there is little or no electrostatic charge interaction operating on dextran sulfate or other negatively charged molecules at the glomerular capillary wall.

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Cigarette smoke inhalation aggravates diabetic kidney injury in rats

Toxicology Research ◽

10.1039/c9tx00201d ◽

2019 ◽

Vol 8 (6) ◽

pp. 964-971 ◽

Cited By ~ 2

Author(s):

Songling Jiang ◽

Do Van Quan ◽

Jae Hyuck Sung ◽

Moo-Yeol Lee ◽

Hunjoo Ha

Keyword(s):

Kidney Disease ◽

Cigarette Smoke ◽

Density Lipoprotein ◽

Kidney Injury ◽

Diabetic Rats ◽

Smoke Inhalation ◽

Lipoprotein Cholesterol ◽

Sprague Dawley ◽

Experimental Conditions ◽

Diabetic Kidney

Abstract Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Epidemiological studies have demonstrated that cigarette smoke or nicotine is a risk factor for the progression of chronic kidney injury. The present study analyzed the kidney toxicity of cigarette smoke in experimental rats with DKD. Experimental diabetes was induced in 7-week-old Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin (60 mg kg−1). Four weeks after the induction of diabetes, rats were exposed to cigarette smoke (200 μg L−1), 4 h daily, and 5 days per week for 4 weeks. Cigarette smoke did not affect the levels of plasma glucose, hemoglobin A1c, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol or non-esterified fatty acids in both control and diabetic rats under the experimental conditions. Cigarette smoke, however, significantly increased diabetes-induced glomerular hypertrophy and urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion, suggesting exacerbation of diabetic kidney injury. Cigarette smoke promoted macrophage infiltration and fibrosis in the diabetic kidney. As expected, cigarette smoke increased oxidative stress in both control and diabetic rats. These data demonstrated that four weeks of exposure to cigarette smoke aggravated the progression of DKD in rats.

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Alterations in neurogenically mediated contractile responses of urinary bladder in rats with diabetes

AJP Renal Physiology ◽

10.1152/ajprenal.00449.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. F1220-F1226 ◽

Cited By ~ 61

Author(s):

Guiming Liu ◽

Firouz Daneshgari

Keyword(s):

Urinary Bladder ◽

Unknown Origin ◽

Electrical Field Stimulation ◽

Diabetic Rats ◽

Diabetic Rat ◽

Detrusor Muscle ◽

Sprague Dawley ◽

Contractile Responses ◽

Bladder Detrusor ◽

Induced Changes

Diabetic bladder dysfunction (DBD) is among the most common and bothersome complications of diabetes mellitus. Autonomic neuropathy has been counted as the cause of DBD. In the present study, we compared the alterations in the neurogenically mediated contractile responses of urinary bladder in rats with streptozocin-induced diabetes, 5% sucrose-induced diuresis, and age-matched controls. Male Sprague-Dawley rats were divided into three groups: 9-wk diabetic rats, diuretic rats, and age-matched controls. Micturition and morphometric characteristics were evaluated using metabolic cage and gross examination of the bladder. Bladder detrusor muscle strips were exposed to either periodic electrical field stimulation (EFS) or to EFS in the presence of atropine, α,β-methylene adrenasine 5′-triphosphate, or tetrodotoxin. The proportions of cholinergic, purinergic, and residual nonadrenergic-noncholinergic (NANC) components of contractile response were compared among the three groups of animals. Diabetes caused a significant reduction of body weight compared with diuresis and controls, although the bladders of diabetic and diuretic rats weighed more than the controls. Both diabetes and diuresis caused significant increase in fluid intake, urine output, and bladder size. Diabetes and diuresis caused similarly increased response to EFS and reduced response to cholinergic component compared with controls. However, the purinergic response was significantly smaller in diuretic bladder strips compared with controls but not in diabetic rats. A residual NANC of unknown origin increased significantly but differently in diabetics and diuretics compared with controls. In conclusion, neurogenically mediated bladder contraction is altered in the diabetic rat. Diabetic-related changes do not parallel diuretic-induced changes, indicating that the pathogenesis of DBD needs further exploration.

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Peritoneal Accumulation of Advanced Glycosylation End-Products in Diabetic Rats on Dialysis with Icodextrin

Peritoneal Dialysis International ◽

10.1177/089686080002005s08 ◽

2000 ◽

Vol 20 (5_suppl) ◽

pp. 39-47 ◽

Cited By ~ 5

Author(s):

Jeong Ho Lee ◽

Dheerendra K. Reddy ◽

Rajiv Saran ◽

Harold L. Moore ◽

Zbylut J. Twardowski ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Glucose Solution ◽

Diabetic Rats ◽

Diabetic Rat ◽

Peritoneal Membrane ◽

Sprague Dawley ◽

Advanced Glycosylation End Products ◽

Group I ◽

End Products ◽

Advanced Glycosylation

Objective To evaluate and compare the effects of glucose-based solutions to those of icodextrin with respect to peritoneal transport characteristics and formation of advanced glycosylation end-products (AGEs) in the peritoneal membrane in the diabetic rat model of peritoneal dialysis (PD). Study Design Thirty-three male Sprague–Dawley rats weighing between 275 – 300 g were divided into 5 groups: group C ( n = 6), control rats with catheter but not dialyzed; group D ( n = 5), diabetic rats with catheter but not dialyzed; group G ( n = 7), diabetic rats dialyzed with standard 2.5% glucose solution for daytime exchanges and 4.25% glucose solution for the overnight exchange; group H ( n = 8), diabetic rats dialyzed with standard 2.5% glucose solution for daytime exchanges and 7.5% icodextrin solution for overnight exchanges; group I ( n = 7), diabetic rats dialyzed with 7.5% icodextrin solution for all exchanges. Dialysis exchanges were performed three times daily with an instillation volume of 25 mL per exchange for a period of 12 weeks. Tissue sections were stained using a monoclonal anti-AGE antibody. One-hour peritoneal equilibration tests (PET) were performed every 4 weeks for comparison of transport characteristics. Results The level of immunostaining was lowest in group C and highest in group G. Significant differences were seen between group C and groups G, H, and I ( p < 0.001, p = 0.001, and p < 0.05 respectively). Significant differences were also found between group G and groups D and I ( p < 0.05 and p < 0.05 respectively). Over time, glucose concentration at the end of an exchange versus concentration at instillation (D/D0 glucose) decreased and dialysate-to-plasma ratio (D/P) of urea increased. Significant differences were found between groups C and H for D/D0 glucose (0.40 ± 0.01 vs 0.35 ± 0.01, p < 0.05); and between groups C and H for D/P urea (0.87 ± 0.03 vs 0.97 ± 0.02, p < 0.05). Conclusions These results suggest that AGE formation is lower with the use of peritoneal dialysis solution containing icodextrin than with glucose-based solutions. We conclude that the use of icodextrin may be helpful in slowing the deterioration of the peritoneal membrane, prolonging its use for dialysis.

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Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat

AJP Renal Physiology ◽

10.1152/ajprenal.00421.2011 ◽

2012 ◽

Vol 302 (3) ◽

pp. F308-F315 ◽

Cited By ~ 38

Author(s):

Christine Maric-Bilkan ◽

Elizabeth R. Flynn ◽

Alejandro R. Chade

Keyword(s):

Renal Function ◽

Renal Injury ◽

Ex Vivo ◽

Three Dimensional ◽

Microvascular Disease ◽

Renal Tissue ◽

Diabetic Rat ◽

Sprague Dawley ◽

Micro Computed Tomography ◽

Diabetic Kidney

Diabetic nephropathy is a progressive and generalized vasculopathic condition associated with abnormal angiogenesis. We aim to determine whether changes in renal microvascular (MV) density correlate with and play a role in the progressive deterioration of renal function in diabetes. We hypothesize that MV changes represent the early steps of renal injury that worsen as diabetes progresses, initiating a vicious circle that leads to irreversible renal injury. Male nondiabetic (ND) or streptozotocin-induced diabetic (D) Sprague-Dawley rats were followed for 4 or 12 wk. Renal blood flow and glomerular filtration rate (GFR) were measured by PAH and 125I-[iothalamate], respectively. Renal MV density was quantified ex vivo using three-dimensional micro computed tomography and JG-12 immunoreactivity. Vascular endothelial growth factor (VEGF) levels (ELISA) and expression of VEGF receptors and factors involved in MV remodeling were quantified in renal tissue by Western blotting. Finally, renal morphology was investigated by histology. Four weeks of diabetes was associated with increased GFR, accompanied by a 34% reduction in renal MV density and augmented renal VEGF levels. However, at 12 wk, while GFR remained similarly elevated, reduction of MV density was more pronounced (75%) and associated with increased MV remodeling, renal fibrosis, but unchanged renal VEGF compared with ND at 12 wk. The damage, loss, and subsequent remodeling of the renal MV architecture in the diabetic kidney may represent the initiating events of progressive renal injury. This study suggests a novel concept of MV disease as an early instigator of diabetic kidney disease that may precede and likely promote the decline in renal function.

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Mirabegron, A Selective β3-Adrenoceptor Agonist Causes an Improvement in Erectile Dysfunction in Diabetic Rats

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-0869-7493 ◽

2019 ◽

Author(s):

Didem Yilmaz-Oral ◽

Ecem Kaya-Sezginer ◽

Dilan Askin ◽

Yesim Hamurtekin ◽

Serap Gur

Keyword(s):

Erectile Dysfunction ◽

Pde5 Inhibitor ◽

Corpus Cavernosum ◽

Diabetic Rats ◽

Diabetic Rat ◽

Control Group ◽

Sprague Dawley ◽

Intracavernosal Injection ◽

Relaxation Responses

Abstract Aim To investigate the possible beneficial effect of mirabegron [a selective β3-adrenoceptor (AR) agonist] treatment on erectile dysfunction (ED) in streptozotocin-induced diabetic rats. Methods Sprague-Dawley rats (n=20) were divided into two groups: control group and streptozotocin-induced diabetic group. In vivo erectile responses were evaluated after intracavernosal injection of mirabegron (0.4 mg/kg) in rats. The relaxation responses to electrical field stimulation (EFS, 10 Hz), sodium nitroprusside (SNP, 10 nM) and sildenafil (1 μM) of corpus cavernosum (CC) strips were examined after the incubation with mirabegron (10 μM). β3-ARs expression and localization were determined by Western blot and immunohistochemical analyses in CC tissue. Results In vivo erectile responses of diabetic rats [intracavernasal pressure (ICP) / mean arterial pressure, 0.17±0.01] were decreased, which were restored after administration of mirabegron (0.75±0.01, P<0.001). The basal ICP (7.1±0.6 mmHg) in diabetic rats was markedly increased after mirabegron (36.1 ±5.4 mmHg, P<0.01). Mirabegron caused markedly relaxation in diabetic rat CC after phenylephrine precontraction. The relaxation responses to EFS and sildenafil were reduced in diabetic CC, which were increased in the presence of mirabegron. Mirabegron enhanced SNP-induced relaxation response in both groups. The expression and immunoreactivity of β3-ARs localized to CC smooth muscle were observed in control and diabetic rats. Conclusions This is the first study to show that intracavernosal administration of mirabegron improved erectile function and neurogenic relaxation of CC in diabetic rats. These results may be supported by further studies using combinations of mirabegron and phosphodiesterase type 5 (PDE5) inhibitors for the treatment of diabetic ED, especially in patients who do not respond to PDE5 inhibitor therapy.

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Nicotine Exposure Exacerbates Development of Cataracts in a Type 1 Diabetic Rat Model

Experimental Diabetes Research ◽

10.1155/2012/349320 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Nima Tirgan ◽

Gabriela A. Kulp ◽

Praveena Gupta ◽

Adam Boretsky ◽

Tomasz A. Wiraszka ◽

...

Keyword(s):

Rat Model ◽

Serum Levels ◽

Diabetic Rats ◽

Diabetic Rat ◽

Positive Trend ◽

Sprague Dawley ◽

Nicotine Treatment ◽

Sprague Dawley Rats ◽

Diabetic Rat Model

Diabetes and smoking are known risk factors for cataract development. In this study, we evaluated the effect of nicotine on the progression of cataracts in a type 1 diabetic rat model. Diabetes was induced in Sprague-Dawley rats by a single injection of 65 mg/kg streptozotocin. Daily nicotine injections were administered subcutaneously. Forty-five rats were divided into groups of diabetics with and without nicotine treatment and controls with and without nicotine treatment. Progression of lens opacity was monitored using a slit lamp biomicroscope and scores were assigned. To assess whether systemic inflammation played a role in mediating cataractogenesis, we studied serum levels of eotaxin, IL-6, and IL-4. The levels of the measured cytokines increased significantly in nicotine-treated and untreated diabetic animals versus controls and demonstrated a positive trend in the nicotine-treated diabetic rats. Our data suggest the presence of a synergistic relationship between nicotine and diabetes that accelerated cataract formation via inflammatory mediators.

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