15 results on '"Levi, Moshe"'
Search Results
2. Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes
- Author
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Hazra, Sugata, Rasheed, Adil, Bhatwadekar, Ashay, Wang, Xiaoxin, Shaw, Lynn C., Patel, Monika, Caballero, Sergio, Magomedova, Lilia, Solis, Nathaniel, Yan, Yuanqing, Wang, Weidong, Thinschmidt, Jeffrey S., Verma, Amrisha, Li, Qiuhong, Levi, Moshe, Cummins, Carolyn L., and Grant, Maria B.
- Subjects
Diabetic retinopathy -- Risk factors -- Genetic aspects -- Research ,Type 1 diabetes -- Development and progression -- Genetic aspects -- Research ,Cell receptors -- Physiological aspects -- Genetic aspects -- Research ,Health - Abstract
Endothelial progenitor cells (EPCs), critical for mediating vascular repair, are dysfunctional in a hyperglycemic and/or hypercholesterolemic environment. Their dysfunction contributes to the progression of diabetic macro- and microvascular complications. Activation of 'cholesterol-sensing' nuclear receptors, the liver X receptors (LXRα/LXRβ), protects against atherosclerosis by transcriptional regulation of genes important in promoting cholesterol efflux and inhibiting inflammation. We hypothesized that LXR activation with a synthetic ligand would correct diabetes-induced EPC dysfunction and improve diabetic retinopathy. Studies were performed in streptozotocin (STZ)-injected DBA/2J mice fed a high-fat Western diet (DBA/STZ/WD) and treated with the LXR agonist GW3965 and in LXR[α.sup.-/-], LXR[β.sub.-/-], and LXRα/[β.sup.-/-] mice. Retinas were evaluated for number of acellular capillaries and glial fibrillary acidic protein (GFAP) immunoreactivity. Bone marrow EPCs were analyzed for migratory function and gene expression. Compared with vehicle-treated DBA/STZ/WD mice, GW3965 treated mice showed fewer acellular capillaries and reduced GFAP expression. These mice also exhibited enhanced EPC migration and restoration of inflammatory and oxidative stress genes toward nondiabetic levels. LXR[α.sup.-/-], LXR[β.sup.-/-] , and LXRα/[β.sup.-/-] mice developed acellular capillaries and EPC dysfunction similar to the DBA/STZ/WD mice. These studies support a key role for LXR in retinal and bone marrow progenitor dysfunction associated with type 1 diabetes. LXR agonists may represent promising pharmacologic targets for correcting retinopathy and EPC dysfunction., The liver X receptors (LXRs) are widely known for their important roles in modulating whole-body cholesterol homeostasis (1). LXRα (NR1H3) and LXRβ (NR1H2) belong to the nuclear receptor superfamily of [...]
- Published
- 2012
- Full Text
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3. Diabetic nephropathy is accelerated by farnesoid X receptor deficiency and inhibited by farnesoid X receptor activation in a type 1 diabetes model
- Author
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Wang, Xiaoxin X., Jiang, Tao, Shen, Yan, Caldas, Yupanqui, Miyazaki-Anzai, Shinobu, Santamaria, Hannah, Urbanek, Cydney, Solis, Nathaniel, Scherzer, Pnina, Lewis, Linda, Gonzalez, Frank J., Adorini, Luciano, Pruzanski, Mark, Kopp, Jeffrey B., Verlander, Jill W., and Levi, Moshe
- Subjects
Binding proteins -- Physiological aspects -- Genetic aspects -- Research ,Type 1 diabetes -- Complications and side effects ,Mice -- Usage -- Models ,Diabetic nephropathies -- Research -- Risk factors -- Development and progression -- Care and treatment ,Health - Abstract
OBJECTIVE--The pathogenesis of diabetic nephropathy is complex and involves activation of multiple pathways leading to kidney damage. An important role for altered lipid metabolism via sterol regulatory element binding proteins (SREBPs) has been recently recognized in diabetic kidney disease. Our previous studies have shown that the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, modulates renal SREBP-1 expression. The purpose of the present study was then to determine if FXR deficiency accelerates type 1 diabetic nephropathy in part by further stimulation of SREBPs and related pathways, and conversely, if a selective FXR agonist can prevent the development of type 1 diabetic nephropathy. RESEARCH DESIGN AND METHODS--Insulin deficiency and hyperglycemia were induced with streptozotocin (STZ) in C57BL/6 FXR KO mice. Progress of renal injury was compared with nephropathy-resistant wild-type C57BL/6 mice given STZ. DBA/2J mice with STZ-induced hyperglycemia were treated with the selective FXR agonist INT-747 for 12 weeks. To accelerate disease progression, all mice were placed on the Western diet after hyperglycemia development. RESULTS--The present study demonstrates accelerated renal injury in diabetic FXR KO mice. In contrast, treatment with the FXR agonist INT-747 improves renal injury by decreasing proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis, and modulating renal lipid metabolism, macrophage infiltration, and renal expression of SREBPs, profibrotic growth factors, and oxidative stress enzymes in the diabetic DBA/2J strain. CONCLUSIONS--Our findings indicate a critical role for FXR in the development of diabetic nephropathy and show that FXR activation prevents nephropathy in type 1 diabetes. Diabetes 59:2916-2927, 2010, Diabetic nephropathy is the most common renal complication of diabetes and the leading cause of end-stage renal disease (1). The pathogenesis of diabetic nephropathy is complex and involves activation of [...]
- Published
- 2010
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4. Skeletal muscle deoxygenation after the onset of moderate exercise suggests slowed microvascular blood flow kinetics in type 2 diabetes
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Bauer, Timothy A., Reusch, Jane E.B., Levi, Moshe, and Regensteiner, Judith G.
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Exercise -- Physiological aspects -- Health aspects -- Chemical properties ,Blood flow -- Health aspects -- Physiological aspects -- Chemical properties ,Type 2 diabetes -- Physiological aspects -- Health aspects -- Chemical properties ,Muscles -- Chemical properties -- Health aspects -- Physiological aspects ,Health ,Chemical properties ,Physiological aspects ,Health aspects - Abstract
OBJECTIVE--People with type 2 diabetes have impaired exercise responses even in the absence of cardiovascular complications. One key factor associated with the exercise intolerance is abnormally slowed oxygen uptake (V[O.sub.2]) [...]
- Published
- 2007
5. Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy
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Jiang, Tao, Wang, Xiaoxin X., Scherzer, Pnina, Wilson, Paul, Tallman, James, Takahashi, Hideaki, Li, Jinping, Iwahashi, Mieko, Sutherland, Eileen, Arend, Lois, and Levi, Moshe
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Renal manifestations of general diseases -- Evaluation -- Physiological aspects ,Fibrosis -- Evaluation -- Physiological aspects ,Hormone receptors -- Properties -- Physiological aspects ,Diabetic neuropathies -- Evaluation -- Physiological aspects ,Lipid metabolism -- Evaluation -- Physiological aspects ,Health ,Evaluation ,Physiological aspects ,Properties - Abstract
OBJECTIVE--Recent studies indicate an important role for nuclear receptors in regulating lipid and carbohydrate metabolism, fibrosis, and inflammation. Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily. FXR is highly expressed in the liver, intestine, adrenal gland, and kidney. The primary bile acids are the highest affinity endogenous ligands for FXR. The effects of FXR agonists in diabetic kidney disease, the main cause of end-stage renal disease, however, have not been determined. RESEARCH DESIGN AND METHODS--To identify the effect of FXR activation in modulation of diabetic nephropathy, we treated 1) C57BL/6J mice on low-fat diet or high-fat diet with FXR agonists (GW4064 or cholic acid) for 1 week; 2) C57BLKS/ J-db/db mice and their lean mates with GW4064 for 1 week; and 3) C57BL/6J-db/db mice and their lean mates with cholic acid for 12 weeks. RESULTS--We found that FXR agonists modulate renal sterol regulatory element-binding protein-1 (SREBP-1) expression and lipid metabolism and renal expression of profibrotic growth factors, proinflammatory cytokines, and oxidative stress enzymes and decrease glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria. In renal mesangial cells, overexpression of FXR or treatment with GW4064 also inhibited SREBP-1c and other lipogenic genes, transforming growth factor-β, and interleukin-6, suggesting a direct role of FXR in modulating renal lipid metabolism and modulation of fibrosis and inflammation. CONCLUSIONS--These results therefore indicate a new and important role for FXR in the kidney and provide new therapeutic avenues for the treatment of diabetic nephropathy., Since Virchow (1) first suggested the association between lipids and renal disease in 1858, there is now growing evidence that abnormal lipid metabolism and renal accumulation of lipids play a [...]
- Published
- 2007
6. Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes
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Proctor, Gregory, Jiang, Tao, Iwahashi, Mieko, Wang, Zhuowei, Li, Jinping, and Levi, Moshe
- Subjects
Type 1 diabetes -- Health aspects -- Risk factors ,Lipid metabolism -- Health aspects ,Kidney diseases -- Risk factors ,Health ,Risk factors ,Health aspects - Abstract
In Akita and OVE26 mice, two genetic models of type 1 diabetes, diabetic nephropathy is characterized by mesangial expansion and loss of podocytes, resulting in glomerulosclerosis and proteinuria, and is associated with increased expression of profibrotic growth factors, proinflammatory cytokines, and increased oxidative stress. We have also found significant increases in renal triglyceride and cholesterol content. The increase in renal triglyceride content is associated with 1) increased expression of sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP), which collectively results in increased fatty acid synthesis, 2) decreased expression of peroxisome proliferator-activated receptor (PPAR)-α and -δ, which results in decreased fatty acid oxidation, and 3) decreased expression of farnesoid X receptor (FXR) and small heterodimer partner (SHP). The increase in cholesterol content is associated with 1) increased expression of SREBP-2 and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, which results in increased cholesterol synthesis, and 2) decreased expression of liver X receptor (LXR)-α, LXR-β, and ATP-binding cassette transporter-1, which results in decreased cholesterol efflux. Our results indicate that in type 1 diabetes, there is altered renal lipid metabolism favoring net accumulation of triglycerides and cholesterol, which are driven by increases in SREBP-1, ChREBP, and SREBP-2 and decreases in FXR, LXR-α, and LXR-β which may also play a role in the increased expression of profibrotic growth hormones, proinflammatory cytokines, and oxidative stress., There is growing evidence that abnormal lipid metabolism and renal accumulation of lipids play a role in the pathogenesis of diabetic nephropathy. Virchow (1) first suggested the association between lipids [...]
- Published
- 2006
7. Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FV[B.sup.db/db] mice with type 2 diabetes
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Wang, Zhuowei, Jiang, Tao, Li, Jinping, Proctor, Gregory, McManaman, James L., Lucia, Scott, Chua, Streamson, and Levi, Moshe
- Subjects
Diabetes -- Research ,Lipid metabolism -- Research -- Genetic aspects ,Type 2 diabetes -- Genetic aspects -- Research ,Health ,Genetic aspects ,Research - Abstract
Diabetic kidney disease has been associated with the presence of lipid deposits, but the mechanisms for the lipid accumulation have not been fully determined. In the present study, we found that db/db mice on the FVB genetic background with loss-of-function mutation of the leptin receptor (FVB-[Lepr.sup.db] mice or FV[B.sup.db/db]) develop severe diabetic nephropathy, including glomerulosclerosis, tubulointerstitial fibrosis, increased expression of type IV collagen and fibronectin, and proteinuria, which is associated with increased renal mRNA abundance of transforming growth factor-β, plasminogen activator inhibitor-I, and vascular endothelial growth factor. Electron microscopy demonstrates increases in glomerular basement membrane thickness and foot process (podocyte) length. We found that there is a marked increase in neutral lipid deposits in glomeruli and tubules by oil red O staining and biochemical analysis for cholesterol and triglycerides. We also detected a significant increase in the renal expression of adipocyte differentiation-related protein (adipophilin), a marker of cytoplasmic lipid droplets. We examined the expression of sterol regulatory element--binding protein (SREBP)-1 and -2, transcriptional factors that play an important role in the regulation of fatty acid, triglyceride, and cholesterol synthesis. We found significant increases in SREBP-1 and -2 protein levels in nuclear extracts from the kidneys of FV[B.sup.db/db] mice, with increases in the mRNA abundance of acetyl-CoA carboxylase, fatty acid synthase, and 3-hydroxy-3-methylglutaryl-CoA reductase, which mediates the increase in renal triglyceride and cholesterol content. Our results indicate that in FV[B.sup.db/db] mice, renal triglyceride and cholesterol accumulation is mediated by increased activity of SREBP-1 and -2. Based on our previous results with transgenic mice overexpressing SREBP-1 in the kidney, we propose that increased expression of SREBPs plays an important role in causing renal lipid accumulation, glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria in mice with type 2 diabetes., There is growing evidence that abnormal lipid metabolism and renal accumulation of lipids play a role in the pathogenesis of diabetic nephropathy (1-4). Since the description by Kimmelstiel and Wilson [...]
- Published
- 2005
8. Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice
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Beli, Eleni, primary, Yan, Yuanqing, additional, Moldovan, Leni, additional, Vieira, Cristiano P., additional, Gao, Ruli, additional, Duan, Yaqian, additional, Prasad, Ram, additional, Bhatwadekar, Ashay, additional, White, Fletcher A., additional, Townsend, Steven D., additional, Chan, Luisa, additional, Ryan, Caitlin N., additional, Morton, Daniel, additional, Moldovan, Emil G., additional, Chu, Fang-I, additional, Oudit, Gavin Y., additional, Derendorf, Hartmut, additional, Adorini, Luciano, additional, Wang, Xiaoxin X., additional, Evans-Molina, Carmella, additional, Mirmira, Raghavendra G., additional, Boulton, Michael E., additional, Yoder, Mervin C., additional, Li, Qiuhong, additional, Levi, Moshe, additional, Busik, Julia V., additional, and Grant, Maria B., additional
- Published
- 2018
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9. SRGAP2a: A New Player That Modulates Podocyte Cytoskeleton and Injury in Diabetes
- Author
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Levi, Moshe, primary, Myakala, Komuraiah, additional, and Wang, Xiaoxin, additional
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- 2018
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10. Troglitazone Prevents the Development of Glomerulosclerosis and TFG-[Beta] Overexpression in Zucker Diabetic Fatty Rats
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HALAIHEL, NABIL, SUN, LIJUN, HUBERT, ZAJICEK, PUTTAPARTHI, KRISHNA, ZHOU, YAN-TING, WILSON, PAUL, ROGERS, THOMAS, and LEVI, MOSHE
- Subjects
Troglitazone -- Physiological aspects ,Glomerulonephritis -- Prevention ,Type 2 diabetes -- Complications ,Health - Abstract
ZDF is a rat model of type 2 diabetes characterized by insulin resistance and renal functional and pathological alterations characterstic of diabetic nephropathy, including glomerulosclerosis and proteinuria. The purpose of [...]
- Published
- 2000
11. Free Fatty Acids Induce Cell Proliferation and Inhibition of TGF-[Beta] Expression in Cultured Mesangial Cells
- Author
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SUN, LIJUN and LEVI, MOSHE
- Subjects
Transforming growth factors -- Physiological aspects ,Type 2 diabetes -- Development and progression ,Insulin resistance -- Physiological aspects ,Hyperglycemia -- Physiological aspects ,Health - Abstract
In addition to hyperglycemia one of the important features of type 2 diabetes and insulin resistance is the increase in plasma concentration of free fatty acids (FFA).The purpose of the [...]
- Published
- 2000
12. Troglitazone Modulates Type 2 Renal Na/Pi Cotransport Protein in Zucker Diabetic Fatty Rats
- Author
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HALAIHEL, NABIL, ZAJICEK, HUBERT, SUN, LIJUN, WILSON, PAUL, ZHOU, YAN-TING, and LEVI, MOSHE
- Subjects
Type 2 diabetes -- Physiological aspects ,Troglitazone -- Physiological aspects ,Health - Abstract
The purpose of this study was to determine if renal tubular phosphate transport is impaired in a model of type 2 diabetes mellitus in the rat, the Zucker diabetic fatty [...]
- Published
- 2000
13. Farnesoid X Receptor Modulates Renal Lipid Metabolism, Fibrosis, and Diabetic Nephropathy.
- Author
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Tao Jiang, Wang, Xiaoxin X., Scherzer, Pnina, Wilson, Paul, Tallman, James, Takahashi, Hideaki, Jinping Li, Division of Renal Diseases and Hypertension, Departments of Medicine, Physiology and Biophysics, Denver VA, Iwahashi, Mieko, Sutherland, Eileen, Arend, Lois, and Levi, Moshe
- Subjects
NUCLEAR receptors (Biochemistry) ,HORMONE receptors ,LIPID metabolism ,CARBOHYDRATE metabolism ,FIBROSIS ,DIABETIC nephropathies ,KIDNEY diseases - Abstract
OBJECTIVE--Recent studies indicate an important role for nuclear receptors in regulating lipid and carbohydrate metabolism, fibrosis, and inflammation. Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily. FXR is highly expressed in the liver, intestine, adrenal gland, and kidney. The primary bile acids are the highest affinity endogenous ligands for FXR. The effects of FXR agonists in diabetic kidney disease, the main cause of end-stage renal disease, however, have not been determined. RESEARCH DESIGN AND METHODS--To identify the effect of FXR activation in modulation of diabetic nephropathy, we treated 1) C57BL/6J mice on low-fat diet or high-fat diet with FXR agonists (GW4064 or cholic acid) for 1 week; 2) C57BLKS/J-db/db mice and their lean mates with GW4064 for 1 week; and 3) C57BL/6J-db/db mice and their lean mates with cholic acid for 12 weeks. RESULTS--We found that FXR agonists modulate renal sterol regulatory element-binding protein-1 (SREBP-1) expression and lipid metabolism and renal expression of profibrotic growth factors, proinflammatory cytokines, and oxidative stress enzymes and decrease glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria. In renal mesangial cells, overexpression of FXR or treatment with GW4064 also inhibited SREBP-1c and other lipogenic genes, transforming growth factor-β, and interleukin-6, suggesting a direct role of FXR in modulating renal lipid metabolism and modulation of fibrosis and inflammation. CONCLUSIONS--These results therefore indicate a new and important role for FXR in the kidney and provide new therapeutic avenues for the treatment of diabetic nephropathy. Diabetes 56:2485-2493, 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
14. Regulation of Renal Lipid Metabolism, Lipid Accumulation, and Glomerulosclerosis in FVBdb/db Mice With Type 2 Diabetes.
- Author
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Wang, Zhuowei, Jiang, Tao, Li, Jinping, Proctor, Gregory, McManaman, James L., Lucia, Scott, Chua, Streamson, and Levi, Moshe
- Subjects
KIDNEY diseases ,DIABETES ,LIPID metabolism ,DIABETES complications ,ENDOCRINE diseases - Abstract
Diabetic kidney disease has been associated with the presence of lipid deposits, but the mechanisms for the lipid accumulation have not been fully determined. In the present study, we found that db/db mice on the FVB genetic background with loss-of-function mutation of the leptin receptor (FVB-Lepr
db mice or FVBdb/db ) develop severe diabetic nephropathy, including glomerulosclerosis, tubulointerstitial fibrosis, increased expression of type IV collagen and fibronectin, and proteinuria, which is associated with increased renal mRNA abundance of transforming growth factor-β, plasminogen activator inhibitor-1, and vascular endothelial growth factor. Electron microscopy demonstrates increases in glomerular basement membrane thickness and foot process (podocyte) length. We found that there is a marked increase in neutral lipid deposits in glomeruli and tubules by oil red O staining and biochemical analysis for cholesterol and triglycerides. We also detected a significant increase in the renal expression of adipocyte differentiation-related protein (adipophilin), a marker of cytoplasmic lipid droplets. We examined the expression of sterol regulatory element-binding protein (SREBP)-1 and -2, transcriptional factors that play an important role in the regulation of fatty acid, triglyceride, and cholesterol synthesis. We found significant increases in SREBP-1 and -2 protein levels in nuclear extracts from the kidneys of FVBdb/db mice, with increases in the mRNA abundance of acetyl-CoA carboxylase, fatty acid synthase, and 3-hydroxy-3-methylglutaryl-CoA reductase, which mediates the increase in renal triglyceride and cholesterol content. Our results indicate that in FVBdb/db mice, renal triglyceride and cholesterol accumulation is mediated by increased activity of SREBP-1 and -2. Based on our previous results with transgenic mice overexpressing SREBP-1 in the kidney, we propose that increased expression of SREBPs plays an important role in causing renal lipid accumulation, glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria in mice with type 2 diabetes. Diabetes 54:2328-2335, 2005 [ABSTRACT FROM AUTHOR]- Published
- 2005
- Full Text
- View/download PDF
15. Renal Cortical Lipid Content and Renal Lesions in Non-Human Primate with Type 2 Diabetes (T2DM).
- Author
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Caramori, M. Luiza, Hansen, Barbara C., Levi, Moshe, Najafian, Behzad, Aslan, Sadaf, Wang, Xiaoxin, Jiang, Tao, and Mauer, Michael
- Subjects
KIDNEY diseases ,LIPID metabolism ,CARDIOVASCULAR diseases ,PEOPLE with diabetes ,LABORATORY monkeys ,DIABETES complications - Abstract
There is a strong concordance in renal and cardiovascular disease in T2DM. Abnormalities in lipid metabolism could be the link between these conditions. Kidney lipid content has been associated with renal injury in DM rodents, but has not been studied in higher species. Sterol regulatory element binding proteins (SERBPs), important regulators of lipid and carbohydrate metabolism, inflammation and fibrosis, and stearoyl-CoA desaturase 1 (SCD1), an SREBP-1 target enzyme critical for triglyceride (TG) synthesis and esterification of free cholesterol (Chol), are highly expressed in the kidney. Spontaneously obese and T2DM rhesus monkeys have glomerular lesions very closely resembling those of human T2DM. We evaluated whether relationships between renal structure and renal lipid content and metabolism were present in this excellent T2DM diabetic nephropathy (DN) model. We studied 7 T2DM, 5 PreDM, and 3 age-matched normal (N) rhesus monkeys that had renal tissues obtained at euthanasia for light microscopy (LM) and lipid studies. Index of mesangial expansion (IME), a semi-quantitative estimate performed on PAS LM slides, is strongly correlated with electron microscopy measured mesangial fractional volume (r=0.86; p<0.0005). Lipid content and SREBP-I, SREBP-2, and SCD1 protein levels were determined on renal cortical tissues. IME and % of sclerosed glomeruli (SG) and tuft to Bowman's capsule adhesions (TBCA) were higher (p<0.05) and % of focal segmental glomerulosclerosis (FSGS) not different in DM vs. N or PreDM monkeys (Table). SREBP- 1 and SREBP-2 were increased in kidneys of DM vs. N monkeys (p<0.05). Renal cortical Chol tended to correlate with %SG (r=0.62; p=0.058). SREBP-1 correlated with IME (r=0.70; p<0.05) and TBCA (r=0.68; p<0.05). SCD-1 also correlated with IME (r=0.65; p<0.01) and TBCA (r=0.58; p=0.023). These are the first direct studies in primates linking lipid metabolism to DN. These "proof of concept" results encourage further studies in this model and in humans, which may uncover the missing linkage between macrovascular and kidney disease in T2DM. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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