Frank Brosius

Personal Information
Title Professor
Expertise Nephropathy
Institution University of Arizona
Data Summary
TypeCount
Grants/SubContracts 1
Progress Reports 8
Presentations 8
Publications 36
Protocols 9
Committees 1
Experiments 0
Strains 25
Models 1

Recaptulating transcriptional pathways of human diabetic nephropathy in mice
Grant Number: DK076139

Abstract: Valid murine models of diabetic nephropathy (DN) should replicate the molecular changes and not simply the pathological alterations of patients with DN. Thus, our general hypothesis for development and testing of murine models of diabetic nephropathy is that Current murine models fail to show human-like DN because they fail to replicate glomerular and tubulointerstital gene expression changes that occur in humans with progressive DN. Replication of the critical transcriptomic profiles of patients with progressive DN should induce progressive DN in mice. Our use of data in human DN generated by the European Renal cDNA Bank (ERCB) will be critical in testing and validating the mouse models of the Animal Models of Diabetic Complications Consortium. We have performed initial transcriptomic analyses of humans with DN using the ERCB to identify pathways which are reliably altered in humans but not in murine models. One pathway that is consistently altered in glomeruli and tubulointerstium in diabetes in humans, but not in mice, is the JAK/STAT pathway. Expression of all JAK members was increased when confirmed with real time PCR analysis. We have focused on JAK2 given its key role in mediating responses implicated in DN. Moreover, JAK2 is activated by reactive oxygen species and interacts with PPAR( signaling, both of which are implicated in DN. For our 2 novel models, we propose podocyte and proximal tubular-specific Jak2 transgenic db/m C57BLKS mice. For these and other models in the Consortium we propose to: 1. Determine whether transcriptional changes in humans are reproduced in the glomerular and tubulointersitial compartments of the Jak2//db/db BLKS models, and other AMDCC models; 2. Determine if all the pathologic and pathophysiologic features of human DN are replicated in the Jak2//db/db BLKS models; 3. Determine if JAK2/3 inhibitors prevent development of DN in the Jak2 transgenic models and other good candidate models that replicate human transcriptomic changes; 4. Determine if ROS production drives JAK2 expression in glomerular and/or tubulointerstitial compartments and enhances downstream JAK2 signaling and whether JAK2 expression promotes ROS; 5. Determine if PPAR( agonists prevent J.ak2 downstream effects in glomerular and/or tubulointerstitial compartments. This research is directly relevant to the study and prevention of diabetic kidney disease, the major cause of kidney failure in the U.S. By creating and understanding a mouse model that develops human-like diabetic kidney disease, we can then move rapidly to tests of strategies to prevent and cure this disease.


Institution: University of Arizona
1013 E University Blvd
Tucson, AZ
Fiscal Year:2006
Department:INTERNAL MEDICINE
Project Start: 9/30/2006
Project End: 8/31/2011
ICD: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Progress Reports

No funding program application progress reports found.

Annual Reports

Drag a column header and drop it here to group by that column
Title YearTypeOptions
Brosius, Frank (2004)
2004Annual Report
View
Brosius, Frank (2005)
2005Annual Report
View
Brosius, Frank (2006)
2006Annual Report
View
Brosius, Frank (2007)
2007Annual Report
View
Brosius, Frank (2008)
2008Annual Report
View
Brosius, Frank (2009)
2009Annual Report
View
Brosius, Frank (2010)
2010Annual Report
View
Brosius, Frank (2011)
2011Annual Report
View



 PublicationAltmetricsSubmitted ByPubMed IDStatus

Year: 2017; Items: 2

 
Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease.
Hinder LM, Park M, Rumora AE, Hur J, Eichinger F, Pennathur S, Kretzler M, Brosius FC, Feldman EL
Journal of cellular and molecular medicine, 2017
28272773
Published
 
Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice.
Zhang H, Nair V, Saha J, Atkins KB, Hodgin JB, Saunders TL, Myers MG, Werner T, Kretzler M, Brosius FC
Kidney international, 2017
28554737
Published

Year: 2016; Items: 2

 
JAK inhibition in the treatment of diabetic kidney disease.
Brosius FC, Tuttle KR, Kretzler M
Diabetologia, 2016 (59), 1624 - 7
27333885
Published
 
Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications.
Sas KM, Kayampilly P, Byun J, Nair V, Hinder LM, Hur J, Zhang H, Lin C, Qi NR, Michailidis G, Groop PH, Nelson RG, Darshi M, Sharma K, Schelling JR, Sedor JR, Pop-Busui R, Weinberg JM, Soleimanpour SA, Abcouwer SF, Gardner TW, Burant CF, Feldman EL, Kretzler M, Brosius FC, Pennathur S
JCI insight, 2016 (1), e86976
27699244
Published

Year: 2014; Items: 2

 
Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy.
Guzman J, Jauregui AN, Merscher-Gomez S, Maiguel D, Muresan C, Mitrofanova A, Diez-Sampedro A, Szust J, Yoo TH, Villarreal R, Pedigo C, Molano RD, Johnson K, Kahn B, Hartleben B, Huber TB, Saha J, Burke GW, Abel ED, Brosius FC, Fornoni A
Diabetes, 2014 (63), 701 - 714
24101677
Published
 
MicroRNA-21 in Glomerular Injury.
Lai JY, Luo J, O'Connor C, Jing X, Nair V, Ju W, Randolph A, Ben-Dov IZ, Matar RN, Briskin D, Zavadil J, Nelson RG, Tuschl T, Brosius FC, Kretzler M, Bitzer M
Journal of the American Society of Nephrology : JASN, 2014
25145934
Published

Year: 2013; Items: 4

 
Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli.
Hodgin JB, Nair V, Zhang H, Randolph A, Harris RC, Nelson RG, Weil EJ, Cavalcoli JD, Patel JM, Brosius FC, Kretzler M
Diabetes, 2013 (62), 299 - 308
23139354
Published
 
New targets for treatment of diabetic nephropathy: what we have learned from animal models.
Brosius FC, Alpers CE
Current opinion in nephrology and hypertension, 2013 (22), 17 - 25
23207723
Published
 
How to find a prognostic biomarker for progressive diabetic nephropathy.
Brosius FC, Pennathur S
Kidney international, 2013 (83), 996 - 998
Submitted Externally
23728003
Published
 
AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function.
Dugan LL, You YH, Ali SS, Diamond-Stanic M, Miyamoto S, Decleves AE, Andreyev A, Quach T, Ly S, Shekhtman G, Nguyen W, Chepetan A, Le TP, Wang L, Xu M, Paik KP, Fogo A, Viollet B, Murphy A, Brosius F, Naviaux RK, Sharma K
The Journal of clinical investigation, 2013 (123), 4888 - 4899
24135141
Published

Year: 2012; Items: 2

 
Do we now have a prognostic biomarker for progressive diabetic nephropathy?
Brosius FC, Saran R
Journal of the American Society of Nephrology : JASN, 2012 (23), 376 - 377
22323641
Published
 
Perspectives on systems biology applications in diabetic kidney disease.
Komorowsky CV, Brosius FC, Pennathur S, Kretzler M
Journal of cardiovascular translational research, 2012 (5), 491 - 508
22733404
Published

Year: 2011; Items: 2

 
21067510
Published
 
GLUT1 enhances mTOR activity independently of TSC2 and AMPK.
Buller CL, Heilig CW, Brosius FC
American journal of physiology. Renal physiology, 2011 (301), F588 - F596
21613414
Published

Year: 2010; Items: 8

 
The management of diabetic neuropathy in CKD.
Pop-Busui R, Roberts L, Pennathur S, Kretzler M, Brosius FC, Feldman EL
American journal of kidney diseases : the official journal of the National Kidney Foundation, 2010 (55), 365 - 385
20042258
Published
 
Abnormalities in signaling pathways in diabetic nephropathy.
Brosius FC, Khoury CC, Buller CL, Chen S
Expert review of endocrinology & metabolism, 2010 (5(1)), 51 - 64
20224802
Published
 
Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice.
Zhang H, Schin M, Saha J, Burke K, Holzman LB, Filipiak W, Saunders T, Xiang M, Heilig CW, Brosius FC
American journal of physiology. Renal physiology, 2010 (299), F91 - F98
20375116
Published
 
Transgenic overexpression of GLUT1 in mouse glomeruli produces renal disease resembling diabetic glomerulosclerosis.
Wang Y, Heilig K, Saunders T, Minto A, Deb DK, Chang A, Brosius F, Monteiro C, Heilig CW
American journal of physiology. Renal physiology, 2010 (299), F99 - F111
20375117
Published
 
Sex dimorphic actions of rosiglitazone in generalised peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient mice.
Duan SZ, Usher MG, Foley EL, Milstone DS, Brosius FC, Mortensen RM
Diabetologia, 2010 (53), 1493 - 1505
20401461
Published
 
A new pair of SOCS for diabetic nephropathy.
Brosius FC, Banes-Berceli A
Journal of the American Society of Nephrology : JASN, 2010 (21), 723 - 724
20413610
Published
 
20706214
Published
 
21044762
Published

Year: 2009; Items: 1

 
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
19729434
Published

Year: 2008; Items: 7

 
From fibrosis to sclerosis: mechanisms of glomerulosclerosis in diabetic nephropathy.
Qian Y, Feldman E, Pennathur S, Kretzler M, Brosius FC
Diabetes, 2008 (57(6)), 1439 - 1445
18511444
Published
 
Rosiglitazone Treatment Reduces Diabetic Neuropathy in STZ treated DBA/2J mice
Timothy D Wiggin, Matthias Kretzler, Subramaniam Pennathur, Kelli A. Sullivan, Frank C Brosius, Eva L Feldman
Endocrinology, 2008 (149(10)), 4928 - 4937
18583417
Published
 
Podocyte specific knock out of selenoproteins does not enhance nephropathy in streptozotocin diabetic C57BL/6 mice.
Blauwkamp MN, Yu J, Schin MA, Burke KA, Berry MJ, Carlson BA, Brosius FC, Koenig RJ
BMC nephrology, 2008 (9), 7
18647412
Published
 
Rosiglitazone reduces renal and plasma markers of oxidative injury and reverses urinary metabolite abnormalities in the amelioration of diabetic nephropathy
Hongyu Zhang, Jharna Saha, MaryLee Schin, Jaeman Byun, Matthias Kretzler, Eva L. Feldman, David A. Weild, Subramaniam Pennathur, Frank C. Brosius III
American journal of physiology. Renal physiology, 2008 (295(4)), F1071 - F1081
18667486
Published
 
New insights into the mechanisms of fibrosis and sclerosis in diabetic nephropathy.
Brosius FC
Reviews in endocrine & metabolic disorders, 2008 (9(4)), 245 - 254
18726161
Published
 
Is the ER stressed out in diabetic kidney disease?
Brosius FC, Kaufman RJ
Journal of the American Society of Nephrology : JASN, 2008 (19), 2040 - 2042
18842986
Published
 
Enhanced Expression of JAK-STAT Pathway Members in Human Diabetic Nephropathy
Celine C. Berthier, PhD., Hongyu Zhang, M.D., MaryLee Schin, B.S., Anna Henger, PhD, Robert G. Nelson, M.D., PhD, Berne Yee, M.D., Anissa Boucherot, PhD., Christin Carter-Su, PhD., Lawrence S. Argetsinger, PhD., Maria Pia Rastaldi, M.D., Frank C. Brosius, M.D., Matthias Kretzler, M.D
Diabetes, 2008 (Epub), 469 - 477
19017763
Published

Year: 2007; Items: 1

 
Mouse models of diabetic neuropathy.
Sullivan KA, Hayes JM, Wiggin TD, Backus C, Su Oh S, Lentz SI, Brosius F, Feldman EL
Neurobiology of disease, 2007 (28(3)), 276 - 285
17804249
Published

Year: 2006; Items: 2

 
Role for GLUT1 in diabetic glomerulosclerosis.
Heilig CW, Brosius FC, Cunningham C
Expert reviews in molecular medicine, 2006 (8(4)), 1
16515729
Published
 
Reduction in Podocyte Density as a Pathologic Feature in Early Diabetic Nephropathy in Rodents: Prevention of by Lipoic Acid Treatment
Brian Siu, Jharna Saha, William E. Smoyer, Kelli A. Sullivan, Frank C. Brosius III
BMC nephrology [electronic resource], 2006 (7), 1 - 11
16539708
Published

Year: 2005; Items: 3

 
Mouse Models of Diabetic Nephropathy
MATTHEW D. BREYER, ERWIN BÖTTINGER, FRANK C. BROSIUS, III, THOMAS M. COFFMAN, RAYMOND C. HARRIS, CHARLES W. HEILIG, AND KUMAR SHARMA (FOR THE AMDCC)
Journal of the American Society of Nephrology : JASN, 2005 (16), 27 - 45
15563560
Published
 
Glucose transporters in diabetic nephropathy.
Brosius FC, Heilig CW
Pediatric nephrology (Berlin, Germany), 2005 (20(4)), 447 - 451
15717166
Published
 
Diabetic nephropathy: of mice and men.
Breyer MD, Böttinger E, Brosius FC, Coffman TM, Fogo A, Harris RC, Heilig CW, Sharma K
Advances in chronic kidney disease, 2005 (12(2)), 128 - 145
15822049
Published

Drag a column header and drop it here to group by that column
Title YearTypeOptions
Brosius, Frank (10/17/2005)
2005Presentation
View
Brosius, Frank (10/19/2004)
2004Presentation
View
Brosius, Frank (2006)
2006Presentation
View
Brosius, Frank (2007)
2007Presentation
View
Brosius, Frank (2009)
2009Presentation
View
Brosius, Frank (3/23/2005)
2005Presentation
View
Brosius, Frank (6/2004)
2004Presentation
View
L) Systems Biology Workgroup
2010Presentation
View

No experiments found.

StrainSpeciesDevelopment StatusCreation Method
129S6-Gt(ROSA)26Sortm1(Jak2)Bro/+ [Consortial]M. musculusPhenotyping ongoingknockin
129S6-Gt(ROSA)26Sortm1(Jak2)Bro/+ Tg(Nphs2-Cre) [Consortial]M. musculusPhenotyping ongoingknockin
129S6-Gt(ROSA)26Sortm1(Jak2)Bro [Consortial]M. musculusPhenotyping ongoingknockin
129S6-Gt(ROSA)26Sortm1(Jak2)Bro Tg(Nphs2-Cre) [Consortial]M. musculusPhenotyping ongoingknockin
129S6-Ins2Akita/+ Gt(ROSA)26Sortm1(Jak2)Bro/+ [Consortial]M. musculusPhenotyping ongoingknockin
129S6-Ins2Akita/+ Gt(ROSA)26Sortm1(Jak2)Bro/+ Tg(Nphs2-Cre) [Consortial]M. musculusPhenotyping ongoingknockin
129S6-Ins2Akita/+ Gt(ROSA)26Sortm1(Jak2)Bro [Consortial]M. musculusPhenotyping ongoingknockin
129S6-Ins2Akita/+ Gt(ROSA)26Sortm1(Jak2)Bro Tg(Nphs2-Cre) [Consortial]M. musculusCharacterizing multiple linesknockin
B6-Slc2a4+/+ [Consortial]M. musculusPhenotyping ongoingnot applicable
B6.129S1-Fyntm1Sor [Consortial]M. musculusNot Applicableknockout
B6.129S7-Sod2tm1Leb [Consortial]M. musculusNot Applicableknockout
B6.BKS(D)-Leprdb/J [Consortial]M. musculusNot Applicablespontaneous
B6.Cg(SJL)-Tg(Nes-cre)1Kln/J [Consortial]M. musculusPhenotyping ongoingtransgenic
B6;129S7-Fyntm1Sor/J [Consortial]M. musculusNot Applicableknockout
B6;SJL-TgN(Myl2-Slc2a1)2Mue [Consortial]M. musculusPhenotyping ongoingtransgenic
BKS.Cg-Dock7m +/+ Leprdb [Consortial]M. musculusNot Applicablespontaneous
C57BL/6J-Gclc tm1Neb/+ [Consortial]M. musculusBreeding ongoingknockout
C57BL/6J-Gclctm1Neb/+ Leprdb/+ [Consortial]M. musculusCharacterizing multiple lineschemical induced
C57BL/6j-Gclctm1Neb/+ Leprdb [Consortial]M. musculusBreeding ongoingcongenic
C57BL/6J-Slc2a4tm1Cha [Consortial]M. musculusNot Applicableknockout
C57BL/6J-Tg(SLC2A4) [Consortial]M. musculusPhenotyping ongoingtransgenic
C57BLKS/J-Tg(Nphs2-Slc2a1) Leprdb/db [Consortial]M. musculusPhenotyping ongoingtransgenic
C57BLKS/J-Tg(Nphs2-Slc2a1) Leprdb/m [Consortial]M. musculusPhenotyping ongoingtransgenic
STOCK-Slc2a4lox/lox [Consortial]M. musculusPhenotyping ongoingknockin
STOCK-Tg(Nphs2-Cre) Slc2a4lox/lox [Consortial]M. musculusPhenotyping ongoingcongenic