Moshe Levi

Personal Information
Title Professor
Expertise Nephropathy
Institution University of Colorado
Data Summary
Grants/SubContracts 4
Progress Reports 8
Presentations 3
Publications 20
Protocols 0
Committees 2
Experiments 0
Strains 3
Models 2

Novel Models of Diabetic Nephropathy
Grant Number: DK076134

Abstract: Background: In a) OVE26 mice with type 1 diabetes, b) C57BI/6 mice with diet induced obesity and insulin resistance, and c) db/db mice with type 2 diabetes mellitus, we have found increased renal expression of the transcriptional factors, i) the sterol regulatory element binding proteins 1 and 2 (SREBP-1 and SREBP-2), and ii) the carbohydrate response element binding protein (ChREBP), which result in increased synthesis and accumulation of triglyceride and cholesterol. The lipid accumulation is associated with development of robust glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria. We have also found that the Farnesoid X Receptor (FXR) is highly expressed in the kidney and the expression of FXR and its target enzymes is decreased in the diabetic kidney. Furthermore we have determined that FXR is an important regulator of SREBP-1 and ChREBP expression as well as oxidative stress, advanced glycation end products (AGEs/RAGE), pro-inflammatory cytokines, and fibrosis inducing growth factors. Hypothesis: Based on these finding we propose that FXR plays an important role on the pathogenesis of diabetic nephropathy. We hypothesize that deletion of FXR will markedly enhance and overexpression of FXR will attenuate diabetic nephropathy in mouse models of type 1 (OVE26) and type 2 (db/db) diabetes. Mouse Model 1: A) We will generate FXR knockout mice, currently on the C57BI/6 genetic background, on Background: In a) OVE26 mice with type 1 diabetes, b) C57BI/6 mice with diet induced obesity and insulin the FVB, and if need be and DBA/2J genetic backgrounds, 2 genetic backgrounds that have been documented to have increased susceptibility to diabetic nephropathy. B) We will then cross breed FXR KO mice on FVB background with i) OVE26 mice (type 1 diabetes) on FVB background or ii) db/db mice (type 2 diabetes) on FVB background to determine if FXR deletion accentuates and accelerates diabetic nephropathy. C) We will generate renal podocyte specific FXR knockout mice on FVB background using the Lox-Cre approach (FXRf/f mice crossed with Nphs2 Cre mice). D) We will then crossbreed podocyte FXR KO mice with i) OVE26 mice or ii) db/db mice. Mouse Model 2: A) We will generate renal podocyte specific conditional and inducible FXR transgenic mice in the FVB Background. B) We will then crossbreed the podocyte specific FXR transgenic mice with OVE26 or db/db mice to determine if increased expression of FXR attenuates or prevents diabetic nephropathy. Phenotyping: In these mice we will determine a) the manifestation of diabetic nephropathy, including glomerular filtration rate, glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria and b) the cellular and biochemical mechanisms that mediate diabetic renal injury including lipid and carbohydrate metabolism, inflammation, fibrosis, oxidative stress, and AGEs/RAGE.

Institution: University of Colorado
Health Sciences Center
4200 E. Ninth Ave.
Denver, CO
Fiscal Year:2006
Project Start: 9/30/2006
Project End: 8/31/2011


How well do plasma cholesterol and triglyceride levels correlate with measurement of organ dysfunction across various AMDCC mouse strains?
The role of lipids in the pathogenesis, progression, and complications of atherosclerosis and neuropathy is well established. However, the potential role of lipids in the pathogenesis and progression of nephropathy is less well established and/or appreciated. We will test the hypothesis that there are significant correlations between plasma cholesterol and/or triglyceride level and diabetic nephropathy. As a positive control we will also determine the correlation between plasma lipids and extent of atherosclerosis. Our specific aims are: 1) To examine the association of plasma total cholesterol level with the development of nephropathy in diabetic mice; 2) To examine the association of plasma triglyceride level with the development of nephropathy in diabetic mice; 3) To examine the association of plasma total cholesterol and triglyceride levels with the development of atherosclerosis in diabetic mice.

Liver X Receptor in Diabetic Nephropathy and Cardiomyopathy
Despite major advances in the treatment of diabetes, many patients continue to experience diabetes-related pathologies in major organ systems. Diabetic renal and cardiovascular disease remains leading causes of premature mortality in patients with diabetes. In addition, women with diabetes have 40% greater risk for death from all causes, and two times the risk for fatal and nonfatal vascular events, than men with the disease. Therefore, new strategies that target novel pathophysiological causes of microvascular and macrovascular disease in both men and women are urgently needed. We propose to generate pilot data to determine if targeting the Liver X Receptor (LXR) holds therapeutic promise for prevention and treatment of renal and cardiac disease in diabetic male and female mice. Our hypothesis is that in diabetes there is down regulation of LXR expression and activity in the kidney which results in increased cholesterol accumulation, activation of the inflammatory response, and endoplasmic reticulum stress, cellular processes that playa critical role in the pathogenesis of diabetic renal disease. Renal disease by itself induces or accelerates cardiovascular disease. We suggest that downregulation of LXR expression and activity in the cardiac tissue also further mediates cardiac disease. In Specific Aim 1 we will treat male and female a) nondiabetic control db-m mice and b) diabetic db-db mice with an LXR agonist. At the end of a 12 week treatment period with the LXR agonist DMHCA (1-3) we will determine effects of LXR agonist on: 1) renal function including glomerular filtration rate, albuminuria, and renal histopathology, 2) cardiac function including in vivo echo, cardiac histopathology, and markers of fibrosis and hypertrophy; 3) perform high resolution and label-free imaging for lipid accumulation, inflammation, oxidative stress, and fibrosis with CARS-TPE-SHG-FLIM microscopy. We will perform detailed biochemical studies to determine effects of the LXR agonist on i) cholesterol and lipid composition, ii) inflammation, and iii) endoplasmic reticulum stress. In Specific Aim 2 we will perform mechanistic studies in a) human podocytes and b) human cardiac myocytes to determine the effects of 1) LXRa or 2) LXRß overexpression. In cells grown with i) control media, ii) high glucose media, iii) media with fatty acids, and iv) media with high glucose and fatty acids, we will determine effects of LXRa or LXRß overexpression on a) cholesterol and lipid composition, b) inflammation, and c) endoplasmic reticulum stress. We will further check the ability of LXRa or LXRß overexpression in resisting i) cholesterol induced inflammation and ER stress in cells loaded with acetylated LDL in the presence of ACAT inhibitor, ii) thapsigargin induced ER stress, and iii) LPS induced inflammation.

Molecular Mechanisms of Kidney Disease in Diabetes and Obesity
The prevalence of obesity, insulin resistance, and diabetes mellitus is increasing and becoming the leading causes of renal disease. In spite of all the beneficial interventions implemented in patients with diabetes renal disease still progresses in most of these patients. Additional treatment modalities that modulate the pathogenic pathways involved in obesity and diabetic nephropathy are therefore needed to slow the progression of renal disease. In this regard recent studies in rodent models of diabetes indicate that a) nuclear receptors including the farnesoid X receptor (FXR) and liver X receptor (LXR), b) transcriptional factors including the sterol regulatory element binding proteins (SREBPs), and c) G protein coupled receptors including TGR5 have highly beneficial actions to prevent or slow down the progression of renal disease in obesity and diabetes. However it is not known whether these pathways are altered in human kidney disease in obesity and diabetes and whether the expression levels and activity of these pathways correlate with renal histopathology. This pilot grant will therefore address this important question. In Specific Aim 1 we will extract mRNA, miRNA, and protein from fixed and paraffin embedded human kidney biopsy samples from subjects with diabetic nephropathy (DN), obesity related glomerulopathy (ORG), and normal kidneys from samples are obtained from the Department of Pathology, Columbia University, NY, USA, and Department of Pathology, Tel Aviv University, Tel Aviv, Israel. We will analyze pathways related to a) fibrosis, b) oxidative stress, c) inflammation, and d) lipid metabolism, as well as e) nuclear receptors, f) transcription factors, and g) G protein coupled receptors that have been demonstrated to regulate these important pathogenic factors.In Specific Aim 2 we will correlate these molecular and metabolic pathways with estimated GFR, proteinuria, and histopathology for each of the biopsy samples.In Specific Aim 3 we will study the similarities and differences of gene expression secondary to a) type 2 diabetes mellitus and b) obesity without T2DM to study the effect of obesity in the mechanism of diabetic nephropathy.

 PublicationAltmetricsSubmitted ByPubMed IDStatus

Year: 2017; Items: 2

The Mechanism of Diabetic Retinopathy Pathogenesis Unifying Key Lipid Regulators, Sirtuin 1 and Liver X Receptor.
Hammer SS, Beli E, Kady N, Wang Q, Wood K, Lydic TA, Malek G, Saban DR, Wang XX, Hazra S, Levi M, Busik JV, Grant MB
EBioMedicine, 2017 (22), 181 - 190
FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity.
Wang XX, Wang D, Luo Y, Myakala K, Dobrinskikh E, Rosenberg AZ, Levi J, Kopp JB, Field A, Hill A, Lucia S, Qiu L, Jiang T, Peng Y, Orlicky D, Garcia G, Herman-Edelstein M, D'Agati V, Henriksen K, Adorini L, Pruzanski M, Xie C, Krausz KW, Gonzalez FJ, Ranjit S, Dvornikov A, Gratton E, Levi M
Journal of the American Society of Nephrology : JASN, 2017

Year: 2015; Items: 1

G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes.
Wang XX, Edelstein MH, Gafter U, Qiu L, Luo Y, Dobrinskikh E, Lucia S, Adorini L, D'Agati VD, Levi J, Rosenberg A, Kopp JB, Gius DR, Saleem MA, Levi M
Journal of the American Society of Nephrology : JASN, 2015

Year: 2014; Items: 1

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice.
Patel M, Wang XX, Magomedova L, John R, Rasheed A, Santamaria H, Wang W, Tsai R, Qiu L, Orellana A, Advani A, Levi M, Cummins CL
Diabetologia, 2014 (57), 435 - 446
Submitted Externally

Year: 2012; Items: 3

Chronic kidney disease: Albuminuria or CKD stage as best marker of CVD in diabetes?
Blaine J, Levi M
Nature reviews. Nephrology, 2012 (8), 376 - 377
Characterization of cholesterol crystals in atherosclerotic plaques using stimulated Raman scattering and second-harmonic generation microscopy.
Suhalim JL, Chung CY, Lilledahl MB, Lim RS, Levi M, Tromberg BJ, Potma EO
Biophysical journal, 2012 (102), 1988 - 1995
Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes.
Hazra S, Rasheed A, Bhatwadekar A, Wang X, Shaw LC, Patel M, Caballero S, Magomedova L, Solis N, Yan Y, Wang W, Thinschmidt JS, Verma A, Li Q, Levi M, Cummins CL, Grant MB
Diabetes, 2012 (61), 3270 - 3279

Year: 2011; Items: 5

The Vitamin D Receptor Agonist Doxercalciferol Modulates Dietary Fat Induced Renal Disease and Renal Lipid Metabolism
Wang XX, Jiang T, Shen Y, Santamaria H, Solis N, Arbeeny CM, Levi M
American journal of physiology. Renal physiology, 2011
Nuclear receptors in renal disease.
Levi M
Biochimica et biophysica acta, 2011 (1812), 1061 - 1067
Nuclear hormone receptors as therapeutic targets.
Levi M, Wang X, Choudhury D
Contributions to nephrology, 2011 (170), 209 - 216
Urinary matrix metalloproteinase activities: biomarkers for plaque angiogenesis and nephropathy in diabetes.
McKittrick IB, Bogaert Y, Nadeau K, Snell-Bergeon J, Hull A, Jiang T, Wang X, Levi M, Moulton KS
American journal of physiology. Renal physiology, 2011 (301), F1326 - F1333
Identification of cholesterol crystals in plaques of atherosclerotic mice using hyperspectral CARS imaging.
Lim RS, Suhalim JL, Miyazaki-Anzai S, Miyazaki M, Levi M, Potma EO, Tromberg BJ
Journal of lipid research, 2011 (52), 2177 - 2186

Year: 2010; Items: 5

Multimodal CARS microscopy determination of the impact of diet on macrophage infiltration and lipid accumulation on plaque formation in ApoE-deficient mice.
Lim RS, Kratzer A, Barry NP, Miyazaki-Anzai S, Miyazaki M, Mantulin WW, Levi M, Potma EO, Tromberg BJ
Journal of lipid research, 2010 (51), 1729 - 1737
Nuclear hormone receptors in diabetic nephropathy.
Wang XX, Jiang T, Levi M
Nature reviews. Nephrology, 2010 (6), 342 - 351
Farnesoid X Receptor Activation Prevents the Development of Vascular Calcification in ApoE–/– Mice With Chronic Kidney Disease
Shinobu Miyazaki-Anzai, Moshe Levi, Adelheid Kratzer, Tabitha C. Ting, Linda B. Lewis, and Makoto Miyazaki
Circulation research, 2010 (106), 1807 - 1817
Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist.
Rizzo G, Passeri D, De Franco F, Ciaccioli G, Donadio L, Rizzo G, Orlandi S, Sadeghpour B, Wang XX, Jiang T, Levi M, Pruzanski M, Adorini L
Molecular pharmacology, 2010 (78), 617 - 630
Diabetic nephropathy is accelerated by farnesoid X receptor deficiency and inhibited by farnesoid X receptor activation in a type 1 diabetes model.
Wang XX, Jiang T, Shen Y, Caldas Y, Miyazaki-Anzai S, Santamaria H, Urbanek C, Solis N, Scherzer P, Lewis L, Gonzalez FJ, Adorini L, Pruzanski M, Kopp JB, Verlander JW, Levi M
Diabetes, 2010 (59), 2916 - 2927

Year: 2009; Items: 2

Mouse Models of Diabetic Nephropathy: A Midstream Analysis from the Diabetic Complications Consortium
Frank C. Brosius IIIa, Charles E. Alpersb, Erwin P. Bottingerc, Matthew D. Breyerd, ThomasM. Coffmane, Susan B. Gurleye, Raymond C. Harrisf, Masao Kakokig, Matthias Kretzler, Edward H. Leiterh, Moshe Levii, Richard A. McIndoej, Kumar Sharmak, Oliver Smithiesg, Katalin Susztakl, Nobuyuki Takahashig, Takamune Takahashif
Journal of the American Society of Nephrology : JASN, 2009 (20(12)), 2503 - 2512
The farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria.
Wang XX, Jiang T, Shen Y, Adorini L, Pruzanski M, Gonzalez FJ, Scherzer P, Lewis L, Miyazaki-Anzai S, Levi M
American journal of physiology. Renal physiology, 2009 (297(6)), F1587 - F1596

Year: 2007; Items: 1

Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy.
Jiang T, Wang XX, Scherzer P, Wilson P, Tallman J, Takahashi H, Li J, Iwahashi M, Sutherland E, Arend L, Levi M
Diabetes, 2007 (56), 2485 - 2493

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Title YearTypeOptions
I) Regeneration and Repair Workgroup
Levi, Moshe (2007)
Levi, Moshe (2009)

No protocols found.

No experiments found.