Vicki Thallas-Bonke - Academia.edu (original) (raw)

Papers by Vicki Thallas-Bonke

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy

Diabetologia, Jan 28, 2015

Changes in podocyte morphology and function are associated with albuminuria and progression of di... more Changes in podocyte morphology and function are associated with albuminuria and progression of diabetic nephropathy. NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and Nox4 is upregulated in podocytes in response to high glucose. We assessed the role of NOX4-derived ROS in podocytes in vivo in a model of diabetic nephropathy using a podocyte-specific NOX4-deficient mouse, with a major focus on the development of albuminuria and ultra-glomerular structural damage. Streptozotocin-induced diabetes-associated changes in renal structure and function were studied in male floxedNox4 and podocyte-specific, NOX4 knockout (podNox4KO) mice. We assessed albuminuria, glomerular extracellular matrix accumulation and glomerulosclerosis, and markers of ROS and inflammation, as well as glomerular basement membrane thickness, effacement of podocytes and expression of the podocyte-specific protein nephrin. Podocyte-specific Nox4 deletion in streptozotocin-indu...

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy

Diabetologia, 2015

Changes in podocyte morphology and function are associated with albuminuria and progression of di... more Changes in podocyte morphology and function are associated with albuminuria and progression of diabetic nephropathy. NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and Nox4 is upregulated in podocytes in response to high glucose. We assessed the role of NOX4-derived ROS in podocytes in vivo in a model of diabetic nephropathy using a podocyte-specific NOX4-deficient mouse, with a major focus on the development of albuminuria and ultra-glomerular structural damage. Streptozotocin-induced diabetes-associated changes in renal structure and function were studied in male floxedNox4 and podocyte-specific, NOX4 knockout (podNox4KO) mice. We assessed albuminuria, glomerular extracellular matrix accumulation and glomerulosclerosis, and markers of ROS and inflammation, as well as glomerular basement membrane thickness, effacement of podocytes and expression of the podocyte-specific protein nephrin. Podocyte-specific Nox4 deletion in streptozotocin-induced diabetic mice attenuated albuminuria in association with reduced vascular endothelial growth factor (VEGF) expression and prevention of the diabetes-induced reduction in nephrin expression. In addition, podocyte-specific Nox4 deletion reduced glomerular accumulation of collagen IV and fibronectin, glomerulosclerosis and mesangial expansion, as well as glomerular basement membrane thickness. Furthermore, diabetes-induced increases in renal ROS, glomerular monocyte chemoattractant protein-1 (MCP-1) and protein kinase C alpha (PKC-α) were attenuated in podocyte-specific NOX4-deficient mice. Collectively, this study shows the deleterious effect of Nox4 expression in podocytes by promoting podocytopathy in association with albuminuria and extracellular matrix accumulation in experimental diabetes, emphasising the role of NOX4 as a target for new renoprotective agents.

The authors have nothing to disclose.

DB101033SupplementaryData

Diabetology and Metabolic Syndrome

Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (... more Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs).

AT2R Agonist, Compound 21, Is Reno-Protective Against Type 1 Diabetic Nephropathy

Hypertension, Jan 16, 2015

The hemodynamic and nonhemodynamic effects of angiotensin II on diabetic complications are consid... more The hemodynamic and nonhemodynamic effects of angiotensin II on diabetic complications are considered to be primarily mediated by the angiotensin II type 1 receptor subtype. However, its biological and functional effect mediated through the angiotensin II type 2 receptor subtype is still unclear. Activation of the angiotensin II type 2 receptors has been postulated to oppose angiotensin II type 1 receptor-mediated actions and thus attenuate fibrosis. This study aimed to elucidate the reno-protective role of the novel selective angiotensin II type 2 receptor agonist, Compound 21, in an experimental model of type 1 diabetic nephropathy. Compound 21 treatment significantly attenuated diabetes mellitus-induced elevated levels of cystatin C, albuminuria, mesangial expansion, and glomerulosclerosis in diabetic mice. Moreover, Compound 21 markedly inhibited the expression of various proteins implicated in oxidative stress, inflammation, and fibrosis, in association with decreased extracell...

Nox-4 and progressive kidney disease

Current opinion in nephrology and hypertension, 2015

Nox-4 is a member of the NADPH oxidase (Nox) family of enzymes implicated in reactive oxygen spec... more Nox-4 is a member of the NADPH oxidase (Nox) family of enzymes implicated in reactive oxygen species generation. Nox-4 is distributed in many tissues; however, its physiological functions remain poorly understood. In contrast to other Nox isoforms, it is unique in that it produces large amounts of hydrogen peroxide constitutively and does not require other cytosolic oxidase components for its activation. This review highlights the recent developments in Nox-4 research and progressive kidney disease as well as the potential of new Nox-4 inhibitors to reduce renal damage. Recently, Nox-4 was shown to be implicated in kidney diseases such as diabetic nephropathy. Nox-4 has been identified as playing a role in damage to the kidney induced by hyperglycaemia and other major pathways of renal damage, including advanced glycation end-products, the renin-angiotensin system, TGF-β and protein kinase C. The role of Nox-4 as a target for renoprotection remains controversial, although recent pos...

Atherosclerosis Supplements, 2003

Expression of muscle actins in diffuse mesotheliomas

Human Pathology, 1995

Ultrastructural examinations have shown myofibroblastoid differentiation in sarcomatoid/desmoplas... more Ultrastructural examinations have shown myofibroblastoid differentiation in sarcomatoid/desmoplastic mesotheliomas, but immunohistochemical expression of muscle actins seldom has been documented. We examined 10 sarcomatoid, 12 epithelial, and five biphasic mesotheliomas immunohistochemically for the expression of muscle-specific actin (MSA) and smooth muscle actin (SMA) and compared it with that in 12 specimens of lung cancer. All of the sarcomatoid mesotheliomas were found to be positive for both MSA and SMA. The epithelial cells in nine epithelial and two biphasic mesotheliomas were positive for MSA, but SMA was only positive in one epithelial mesothelioma. Conversely, the lung cancers were negative for both MSA and SMA in the epithelial cells, except for one specimen that was weakly positive for MSA. The stromal cells in both the epithelial mesotheliomas and lung cancers were negative for cytokeratin but were positive for MSA and SMA, whereas the sarcomatoid and biphasic mesothelioma spindle cells were positive for all three antibodies. We concluded that sarcomatoid mesothelioma was positive for MSA and SMA, which is in support of its myofibroblastic differentiation, and that positivity for MSA in some epithelial mesotheliomas might be of diagnostic value in differentiation from lung cancers.

Diabetology & metabolic syndrome, 2014

Background: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angioten... more Background: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs). Methods: Experimental diabetes was induced in 6-week-old male Sprague-Dawley (SD) rats by intravenous injection of STZ. Diabetic rats received ramipril (3 mg/kg body weight/day) or vehicle for 32 weeks. AGE-modified rat serum albumin (AGE-RSA) or RSA was intraperitoneally administrated to 6-week-old male SD rats for 16 weeks. RPTCs were stimulated with 100 μg/ml AGE-modified bovine serum albumin (AGE-BSA) or BSA in the presence or absence of 10 −7 M ramiprilat, an inhibitor of angiotensin-converting enzyme or 100 nM BAY11-7082, an IκB-α phosphorylation inhibitor.

Physiological reports, 2014

Current treatments for diabetic nephropathy (DN) only result in slowing its progression, thus hig... more Current treatments for diabetic nephropathy (DN) only result in slowing its progression, thus highlighting a need to identify novel targets. Increased production of reactive oxygen species (ROS) is considered a key downstream pathway of end-organ injury with increasing data implicating both mitochondrial and cytosolic sources of ROS. The enzyme, NADPH oxidase, generates ROS in the kidney and has been implicated in the activation of protein kinase C (PKC), in the pathogenesis of DN, but the link between PKC and Nox-derived ROS has not been evaluated in detail in vivo. In this study, global deletion of a NADPH-oxidase isoform, Nox4, was examined in mice with streptozotocin-induced diabetes (C57Bl6/J) in order to evaluate the effects of Nox4 deletion, not only on renal structure and function but also on the PKC pathway and downstream events. Nox4 deletion attenuated diabetes-associated increases in albuminuria, glomerulosclerosis, and extracellular matrix accumulation. Lack of Nox4 res...

Reversible Angiotensin II-Mediated Albuminuria in Rat Kidneys Is Dynamically Associated with Cytoskeletal Organization

Nephron Physiology, 2003

Angiotensin II (ANG II) is intimately involved in normal renal function, and is estimated to exis... more Angiotensin II (ANG II) is intimately involved in normal renal function, and is estimated to exist at a normal physiological range of 6-10 nM within the renal tubules. The potential role that intrarenal ANG II may play in renal disease was assessed by perfusing isolated rat kidneys with or without excess intratubular levels of ANG II, which may mimic changes in the intrarenal RAS under pathological conditions. The effects of increased systemic ANG II were also determined by infusing rats with ANG II by osmotic pump. In isolated perfused kidneys, ANG II significantly and specifically increased the fractional clearance of albumin to clinical levels, as determined by using radiolabelled albumin. This effect was reversible, as removing ANG II from the perfusate caused the albumin fractional clearance to decrease to pre-ANG II exposure levels. The increase in fractional clearance of albumin was not correlated with renal hemodynamic changes, nor glomerular permeability alterations as measured by the fractional clearance of 36 A Ficoll and immunoglobulin G. Immunochemical analysis using anti-alpha-tubulin antibody of perfused kidney sections revealed that ANG II caused a marked disruption of tubular epithelial cytoskeletal components, through disassembly and reorganization of alpha-tubulin. This disruption was reversible. In vivo, osmotic pump delivery of ANG II at less potent dosage caused a proteinuria (Biuret) and an albuminuria (radioimmunoassay) in rats, from as early as 2 days after pump implantation. These results demonstrate that ANG II may reversibly induce clinical levels of albuminuria. These data point to an important role for renal tubules and the intratubular lumen concentrations of ANG II in the renal processing of albumin.

The FASEB Journal, 2003

The aim of this study was to investigate the hypothesis that renal injury in diabetes is partly m... more The aim of this study was to investigate the hypothesis that renal injury in diabetes is partly mediated by AGEs and that the cross-link breaker ALT-711 as a delayed intervention, once early renal injury is evident, is capable of improving renal structure and function. The potential molecular mediators of AGE-induced renal injury were assessed, including TGF-␤, CTGF, as well as expression of collagens.

INTERACTIONS BETWEEN THE RAS, ADVANCED GLYCATION AND NF-kB IN THE DIABETIC KIDNEY: INTERVENTIONAL STUDIES

Nephrology, 2002

Ramipril prevents microtubular changes in proximal tubules from streptozotocin diabetic rats

Nephrology, 2003

This study has investigated the microtubular cytoskeleton in rat glomerular and proximal tubule c... more This study has investigated the microtubular cytoskeleton in rat glomerular and proximal tubule cells in experimental diabetes. The effect of treatment with ramipril on the relationship between microtubule organization and albuminuria in diabetes has also been examined. Diabetes was induced in male Sprague-Dawley rats by administration of streptozotocin (50 mg/kg, i.v.). Rats were treated with or without ramipril in their drinking water for 12 weeks. Diabetes was characterized by an increase in blood glucose level, glomerular filtration rate, and albumin excretion rate. Treatment of diabetic rats with ramipril did not affect glycaemic control, but reduced systolic blood pressure and prevented the rise in albuminuria and glomerular filtration rate. Immunohistochemistry was performed by using the ARK Peroxidase method with alpha-tubulin antibody. The regular, grainy staining pattern of the microtubules present in the renal proximal tubules from control kidneys was altered in diabetic animals, and appeared fragmented and striated. This was prevented by treatment with ramipril. Quantitative morphometric analysis revealed an increase in the percent proportional staining for alpha-tubulin in the proximal tubules of untreated diabetic rats (33.3 +/- 3.3%, n = 8, P < 0.05 vs control) compared with control rats (11.7 +/- 1.7%, n = 6), which was reduced by ramipril treatment (26.7 +/- 2.1%, n = 6, P < 0.05 vs untreated diabetic). Staining for alpha-tubulin in glomerular cells was unchanged in all groups. There was no significant difference in renal alpha-tubulin expression among all groups, as determined by real-time reverse transcription-polymerase chain reaction. These results raise the possibility that diabetes-induced changes in microtubules in the renal proximal tubules may contribute, in part, to the increase in albuminuria observed in diabetes.

Nephrology, 2013

Low-AGE diet does not attenuate experimental diabetic nephropathy.

Kidney International, 2003

situated in the basolateral membrane of proximal tubular ACE inhibition. cells. In the rat kidney... more situated in the basolateral membrane of proximal tubular ACE inhibition. cells. In the rat kidney, organic cation transporters (OCTs) Background. The renal clearance of organic cations is imsituated in the S 1 and S 2 segments (OCT-1) and in S 2 and portant for the homeostasis of a number of exogenous and S 3 segments (OCT-2) of the proximal tubule are responsiendogenous compounds. The organic cation transporters (OCTs) ble for the first step in active cation secretion [1-3]. OCTs situated on the basolateral surface of proximal tubular cells are necessary for the renal clearance of a broad range of mediate active cation excretion. Alterations of cation transport may occur in diabetes, although the role of the OCTs has not

Kidney International, 2011

Obesity is highly prevalent in Western populations and is considered a risk factor for the develo... more Obesity is highly prevalent in Western populations and is considered a risk factor for the development of renal impairment. Interventions that reduce the tissue burden of advanced glycation end-products (AGEs) have shown promise in stemming the progression of chronic disease. Here we tested if treatments that lower tissue AGE burden in patients and mice would improve obesity-related renal dysfunction. Overweight and obese individuals (body mass index (BMI) 26-39 kg/m 2 ) were recruited to a randomized, crossover clinical trial involving 2 weeks each on a low-and a high-AGE-containing diet. Renal function and an inflammatory profile (monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF)) were improved following the low-AGE diet. Mechanisms of advanced glycation-related renal damage were investigated in a mouse model of obesity using the AGE-lowering pharmaceutical, alagebrium, and mice in which the receptor for AGE (RAGE) was deleted. Obesity, resulting from a diet high in both fat and AGE, caused renal impairment; however, treatment of the RAGE knockout mice with alagebrium improved urinary albumin excretion, creatinine clearance, the inflammatory profile, and renal oxidative stress. Alagebrium treatment, however, resulted in decreased weight gain and improved glycemic control compared with wild-type mice on a high-fat Western diet. Thus, targeted reduction of the advanced glycation pathway improved renal function in obesity.

Accelerated Nephropathy in Diabetic Apolipoprotein E-Knockout Mouse: Role of Advanced Glycation End Products

Journal of the American Society of Nephrology, 2004

Hyperlipidemia not only may be relevant to cardiovascular disease in diabetes but may also play a... more Hyperlipidemia not only may be relevant to cardiovascular disease in diabetes but may also play a role in the development and progression of diabetic nephropathy. Furthermore, there is increasing evidence that advanced glycation end products (AGE) play an important role in diabetic renal disease. The objectives of this study were first to characterize renal injury in diabetic apolipoprotein E knockout (apo E-KO) mice and second to explore the role of AGE in the development and progression of renal disease in this model. Diabetes was induced by injection of streptozotocin in 6-wk-old apo E-KO mice. Diabetic animals received no treatment or treatment with the inhibitor of AGE formation aminoguanidine (1 g/kg per d) or the cross-link breaker [4,5-dimethyl-3-(2-oxo2-phenylethyl)-thiazolium chloride] ALT-711, which cleaves preformed AGE (20 mg/kg per d) for 20 wk. Nondiabetic apo E-KO mice as well as nondiabetic and diabetic C57BL/6 mice served as controls. Compared with nondiabetic apo E-KO mice, induction of diabetes in apo E-KO mice resulted in accelerated renal injury characterized by albuminuria and glomerular and tubulointerstitial injury. These abnormalities were associated with increased expression of collagen type I and type IV and transforming growth factor-beta1 (TGF-beta1), increased alpha-smooth muscle actin immunostaining and macrophage infiltration, and increased serum and renal AGE. The two treatments, which attenuated renal AGE accumulation in a disparate manner, were associated with less albuminuria, structural injury, macrophage infiltration, TGF-beta1, and collagen expression. The accelerated renal injury that was observed in diabetic apo E-KO mice was attenuated by approaches that inhibit renal AGE accumulation.

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy

Diabetologia, Jan 28, 2015

Changes in podocyte morphology and function are associated with albuminuria and progression of di... more Changes in podocyte morphology and function are associated with albuminuria and progression of diabetic nephropathy. NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and Nox4 is upregulated in podocytes in response to high glucose. We assessed the role of NOX4-derived ROS in podocytes in vivo in a model of diabetic nephropathy using a podocyte-specific NOX4-deficient mouse, with a major focus on the development of albuminuria and ultra-glomerular structural damage. Streptozotocin-induced diabetes-associated changes in renal structure and function were studied in male floxedNox4 and podocyte-specific, NOX4 knockout (podNox4KO) mice. We assessed albuminuria, glomerular extracellular matrix accumulation and glomerulosclerosis, and markers of ROS and inflammation, as well as glomerular basement membrane thickness, effacement of podocytes and expression of the podocyte-specific protein nephrin. Podocyte-specific Nox4 deletion in streptozotocin-indu...

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy

Diabetologia, 2015

Changes in podocyte morphology and function are associated with albuminuria and progression of di... more Changes in podocyte morphology and function are associated with albuminuria and progression of diabetic nephropathy. NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and Nox4 is upregulated in podocytes in response to high glucose. We assessed the role of NOX4-derived ROS in podocytes in vivo in a model of diabetic nephropathy using a podocyte-specific NOX4-deficient mouse, with a major focus on the development of albuminuria and ultra-glomerular structural damage. Streptozotocin-induced diabetes-associated changes in renal structure and function were studied in male floxedNox4 and podocyte-specific, NOX4 knockout (podNox4KO) mice. We assessed albuminuria, glomerular extracellular matrix accumulation and glomerulosclerosis, and markers of ROS and inflammation, as well as glomerular basement membrane thickness, effacement of podocytes and expression of the podocyte-specific protein nephrin. Podocyte-specific Nox4 deletion in streptozotocin-induced diabetic mice attenuated albuminuria in association with reduced vascular endothelial growth factor (VEGF) expression and prevention of the diabetes-induced reduction in nephrin expression. In addition, podocyte-specific Nox4 deletion reduced glomerular accumulation of collagen IV and fibronectin, glomerulosclerosis and mesangial expansion, as well as glomerular basement membrane thickness. Furthermore, diabetes-induced increases in renal ROS, glomerular monocyte chemoattractant protein-1 (MCP-1) and protein kinase C alpha (PKC-α) were attenuated in podocyte-specific NOX4-deficient mice. Collectively, this study shows the deleterious effect of Nox4 expression in podocytes by promoting podocytopathy in association with albuminuria and extracellular matrix accumulation in experimental diabetes, emphasising the role of NOX4 as a target for new renoprotective agents.

The authors have nothing to disclose.

DB101033SupplementaryData

Diabetology and Metabolic Syndrome

Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (... more Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs).

AT2R Agonist, Compound 21, Is Reno-Protective Against Type 1 Diabetic Nephropathy

Hypertension, Jan 16, 2015

The hemodynamic and nonhemodynamic effects of angiotensin II on diabetic complications are consid... more The hemodynamic and nonhemodynamic effects of angiotensin II on diabetic complications are considered to be primarily mediated by the angiotensin II type 1 receptor subtype. However, its biological and functional effect mediated through the angiotensin II type 2 receptor subtype is still unclear. Activation of the angiotensin II type 2 receptors has been postulated to oppose angiotensin II type 1 receptor-mediated actions and thus attenuate fibrosis. This study aimed to elucidate the reno-protective role of the novel selective angiotensin II type 2 receptor agonist, Compound 21, in an experimental model of type 1 diabetic nephropathy. Compound 21 treatment significantly attenuated diabetes mellitus-induced elevated levels of cystatin C, albuminuria, mesangial expansion, and glomerulosclerosis in diabetic mice. Moreover, Compound 21 markedly inhibited the expression of various proteins implicated in oxidative stress, inflammation, and fibrosis, in association with decreased extracell...

Nox-4 and progressive kidney disease

Current opinion in nephrology and hypertension, 2015

Nox-4 is a member of the NADPH oxidase (Nox) family of enzymes implicated in reactive oxygen spec... more Nox-4 is a member of the NADPH oxidase (Nox) family of enzymes implicated in reactive oxygen species generation. Nox-4 is distributed in many tissues; however, its physiological functions remain poorly understood. In contrast to other Nox isoforms, it is unique in that it produces large amounts of hydrogen peroxide constitutively and does not require other cytosolic oxidase components for its activation. This review highlights the recent developments in Nox-4 research and progressive kidney disease as well as the potential of new Nox-4 inhibitors to reduce renal damage. Recently, Nox-4 was shown to be implicated in kidney diseases such as diabetic nephropathy. Nox-4 has been identified as playing a role in damage to the kidney induced by hyperglycaemia and other major pathways of renal damage, including advanced glycation end-products, the renin-angiotensin system, TGF-β and protein kinase C. The role of Nox-4 as a target for renoprotection remains controversial, although recent pos...

Atherosclerosis Supplements, 2003

Expression of muscle actins in diffuse mesotheliomas

Human Pathology, 1995

Ultrastructural examinations have shown myofibroblastoid differentiation in sarcomatoid/desmoplas... more Ultrastructural examinations have shown myofibroblastoid differentiation in sarcomatoid/desmoplastic mesotheliomas, but immunohistochemical expression of muscle actins seldom has been documented. We examined 10 sarcomatoid, 12 epithelial, and five biphasic mesotheliomas immunohistochemically for the expression of muscle-specific actin (MSA) and smooth muscle actin (SMA) and compared it with that in 12 specimens of lung cancer. All of the sarcomatoid mesotheliomas were found to be positive for both MSA and SMA. The epithelial cells in nine epithelial and two biphasic mesotheliomas were positive for MSA, but SMA was only positive in one epithelial mesothelioma. Conversely, the lung cancers were negative for both MSA and SMA in the epithelial cells, except for one specimen that was weakly positive for MSA. The stromal cells in both the epithelial mesotheliomas and lung cancers were negative for cytokeratin but were positive for MSA and SMA, whereas the sarcomatoid and biphasic mesothelioma spindle cells were positive for all three antibodies. We concluded that sarcomatoid mesothelioma was positive for MSA and SMA, which is in support of its myofibroblastic differentiation, and that positivity for MSA in some epithelial mesotheliomas might be of diagnostic value in differentiation from lung cancers.

Diabetology & metabolic syndrome, 2014

Background: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angioten... more Background: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs). Methods: Experimental diabetes was induced in 6-week-old male Sprague-Dawley (SD) rats by intravenous injection of STZ. Diabetic rats received ramipril (3 mg/kg body weight/day) or vehicle for 32 weeks. AGE-modified rat serum albumin (AGE-RSA) or RSA was intraperitoneally administrated to 6-week-old male SD rats for 16 weeks. RPTCs were stimulated with 100 μg/ml AGE-modified bovine serum albumin (AGE-BSA) or BSA in the presence or absence of 10 −7 M ramiprilat, an inhibitor of angiotensin-converting enzyme or 100 nM BAY11-7082, an IκB-α phosphorylation inhibitor.

Physiological reports, 2014

Current treatments for diabetic nephropathy (DN) only result in slowing its progression, thus hig... more Current treatments for diabetic nephropathy (DN) only result in slowing its progression, thus highlighting a need to identify novel targets. Increased production of reactive oxygen species (ROS) is considered a key downstream pathway of end-organ injury with increasing data implicating both mitochondrial and cytosolic sources of ROS. The enzyme, NADPH oxidase, generates ROS in the kidney and has been implicated in the activation of protein kinase C (PKC), in the pathogenesis of DN, but the link between PKC and Nox-derived ROS has not been evaluated in detail in vivo. In this study, global deletion of a NADPH-oxidase isoform, Nox4, was examined in mice with streptozotocin-induced diabetes (C57Bl6/J) in order to evaluate the effects of Nox4 deletion, not only on renal structure and function but also on the PKC pathway and downstream events. Nox4 deletion attenuated diabetes-associated increases in albuminuria, glomerulosclerosis, and extracellular matrix accumulation. Lack of Nox4 res...

Reversible Angiotensin II-Mediated Albuminuria in Rat Kidneys Is Dynamically Associated with Cytoskeletal Organization

Nephron Physiology, 2003

Angiotensin II (ANG II) is intimately involved in normal renal function, and is estimated to exis... more Angiotensin II (ANG II) is intimately involved in normal renal function, and is estimated to exist at a normal physiological range of 6-10 nM within the renal tubules. The potential role that intrarenal ANG II may play in renal disease was assessed by perfusing isolated rat kidneys with or without excess intratubular levels of ANG II, which may mimic changes in the intrarenal RAS under pathological conditions. The effects of increased systemic ANG II were also determined by infusing rats with ANG II by osmotic pump. In isolated perfused kidneys, ANG II significantly and specifically increased the fractional clearance of albumin to clinical levels, as determined by using radiolabelled albumin. This effect was reversible, as removing ANG II from the perfusate caused the albumin fractional clearance to decrease to pre-ANG II exposure levels. The increase in fractional clearance of albumin was not correlated with renal hemodynamic changes, nor glomerular permeability alterations as measured by the fractional clearance of 36 A Ficoll and immunoglobulin G. Immunochemical analysis using anti-alpha-tubulin antibody of perfused kidney sections revealed that ANG II caused a marked disruption of tubular epithelial cytoskeletal components, through disassembly and reorganization of alpha-tubulin. This disruption was reversible. In vivo, osmotic pump delivery of ANG II at less potent dosage caused a proteinuria (Biuret) and an albuminuria (radioimmunoassay) in rats, from as early as 2 days after pump implantation. These results demonstrate that ANG II may reversibly induce clinical levels of albuminuria. These data point to an important role for renal tubules and the intratubular lumen concentrations of ANG II in the renal processing of albumin.

The FASEB Journal, 2003

The aim of this study was to investigate the hypothesis that renal injury in diabetes is partly m... more The aim of this study was to investigate the hypothesis that renal injury in diabetes is partly mediated by AGEs and that the cross-link breaker ALT-711 as a delayed intervention, once early renal injury is evident, is capable of improving renal structure and function. The potential molecular mediators of AGE-induced renal injury were assessed, including TGF-␤, CTGF, as well as expression of collagens.

INTERACTIONS BETWEEN THE RAS, ADVANCED GLYCATION AND NF-kB IN THE DIABETIC KIDNEY: INTERVENTIONAL STUDIES

Nephrology, 2002

Ramipril prevents microtubular changes in proximal tubules from streptozotocin diabetic rats

Nephrology, 2003

This study has investigated the microtubular cytoskeleton in rat glomerular and proximal tubule c... more This study has investigated the microtubular cytoskeleton in rat glomerular and proximal tubule cells in experimental diabetes. The effect of treatment with ramipril on the relationship between microtubule organization and albuminuria in diabetes has also been examined. Diabetes was induced in male Sprague-Dawley rats by administration of streptozotocin (50 mg/kg, i.v.). Rats were treated with or without ramipril in their drinking water for 12 weeks. Diabetes was characterized by an increase in blood glucose level, glomerular filtration rate, and albumin excretion rate. Treatment of diabetic rats with ramipril did not affect glycaemic control, but reduced systolic blood pressure and prevented the rise in albuminuria and glomerular filtration rate. Immunohistochemistry was performed by using the ARK Peroxidase method with alpha-tubulin antibody. The regular, grainy staining pattern of the microtubules present in the renal proximal tubules from control kidneys was altered in diabetic animals, and appeared fragmented and striated. This was prevented by treatment with ramipril. Quantitative morphometric analysis revealed an increase in the percent proportional staining for alpha-tubulin in the proximal tubules of untreated diabetic rats (33.3 +/- 3.3%, n = 8, P < 0.05 vs control) compared with control rats (11.7 +/- 1.7%, n = 6), which was reduced by ramipril treatment (26.7 +/- 2.1%, n = 6, P < 0.05 vs untreated diabetic). Staining for alpha-tubulin in glomerular cells was unchanged in all groups. There was no significant difference in renal alpha-tubulin expression among all groups, as determined by real-time reverse transcription-polymerase chain reaction. These results raise the possibility that diabetes-induced changes in microtubules in the renal proximal tubules may contribute, in part, to the increase in albuminuria observed in diabetes.

Nephrology, 2013

Low-AGE diet does not attenuate experimental diabetic nephropathy.

Kidney International, 2003

situated in the basolateral membrane of proximal tubular ACE inhibition. cells. In the rat kidney... more situated in the basolateral membrane of proximal tubular ACE inhibition. cells. In the rat kidney, organic cation transporters (OCTs) Background. The renal clearance of organic cations is imsituated in the S 1 and S 2 segments (OCT-1) and in S 2 and portant for the homeostasis of a number of exogenous and S 3 segments (OCT-2) of the proximal tubule are responsiendogenous compounds. The organic cation transporters (OCTs) ble for the first step in active cation secretion [1-3]. OCTs situated on the basolateral surface of proximal tubular cells are necessary for the renal clearance of a broad range of mediate active cation excretion. Alterations of cation transport may occur in diabetes, although the role of the OCTs has not

Kidney International, 2011

Obesity is highly prevalent in Western populations and is considered a risk factor for the develo... more Obesity is highly prevalent in Western populations and is considered a risk factor for the development of renal impairment. Interventions that reduce the tissue burden of advanced glycation end-products (AGEs) have shown promise in stemming the progression of chronic disease. Here we tested if treatments that lower tissue AGE burden in patients and mice would improve obesity-related renal dysfunction. Overweight and obese individuals (body mass index (BMI) 26-39 kg/m 2 ) were recruited to a randomized, crossover clinical trial involving 2 weeks each on a low-and a high-AGE-containing diet. Renal function and an inflammatory profile (monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF)) were improved following the low-AGE diet. Mechanisms of advanced glycation-related renal damage were investigated in a mouse model of obesity using the AGE-lowering pharmaceutical, alagebrium, and mice in which the receptor for AGE (RAGE) was deleted. Obesity, resulting from a diet high in both fat and AGE, caused renal impairment; however, treatment of the RAGE knockout mice with alagebrium improved urinary albumin excretion, creatinine clearance, the inflammatory profile, and renal oxidative stress. Alagebrium treatment, however, resulted in decreased weight gain and improved glycemic control compared with wild-type mice on a high-fat Western diet. Thus, targeted reduction of the advanced glycation pathway improved renal function in obesity.

Accelerated Nephropathy in Diabetic Apolipoprotein E-Knockout Mouse: Role of Advanced Glycation End Products

Journal of the American Society of Nephrology, 2004

Hyperlipidemia not only may be relevant to cardiovascular disease in diabetes but may also play a... more Hyperlipidemia not only may be relevant to cardiovascular disease in diabetes but may also play a role in the development and progression of diabetic nephropathy. Furthermore, there is increasing evidence that advanced glycation end products (AGE) play an important role in diabetic renal disease. The objectives of this study were first to characterize renal injury in diabetic apolipoprotein E knockout (apo E-KO) mice and second to explore the role of AGE in the development and progression of renal disease in this model. Diabetes was induced by injection of streptozotocin in 6-wk-old apo E-KO mice. Diabetic animals received no treatment or treatment with the inhibitor of AGE formation aminoguanidine (1 g/kg per d) or the cross-link breaker [4,5-dimethyl-3-(2-oxo2-phenylethyl)-thiazolium chloride] ALT-711, which cleaves preformed AGE (20 mg/kg per d) for 20 wk. Nondiabetic apo E-KO mice as well as nondiabetic and diabetic C57BL/6 mice served as controls. Compared with nondiabetic apo E-KO mice, induction of diabetes in apo E-KO mice resulted in accelerated renal injury characterized by albuminuria and glomerular and tubulointerstitial injury. These abnormalities were associated with increased expression of collagen type I and type IV and transforming growth factor-beta1 (TGF-beta1), increased alpha-smooth muscle actin immunostaining and macrophage infiltration, and increased serum and renal AGE. The two treatments, which attenuated renal AGE accumulation in a disparate manner, were associated with less albuminuria, structural injury, macrophage infiltration, TGF-beta1, and collagen expression. The accelerated renal injury that was observed in diabetic apo E-KO mice was attenuated by approaches that inhibit renal AGE accumulation.