Prevention of diabetic nephropathy in Ins2(+/)⁻(AkitaJ) mice by the mitochondria-targeted therapy MitoQ.
Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2(+/)⁻(AkitaJ) mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2(+/)⁻(AkitaJ) mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and β-catenin showed a nuclear accumulation in the Ins2(+/)⁻(AkitaJ) mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis.
Chacko
Balu K
BK
Department of Pathology, University of Alabama at Birmingham, 35294, USA.
Reily
Colin
C
Srivastava
Anup
A
Johnson
Michelle S
MS
Ye
Yaozu
Y
Ulasova
Elena
E
Agarwal
Anupam
A
Zinn
Kurt R
KR
Murphy
Michael P
MP
Kalyanaraman
Balaraman
B
Darley-Usmar
Victor
V
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications; D003928:Diabetic Nephropathies / Q000150:complications / Q000235:genetics / Q000517:prevention & control*; D005355:Fibrosis / Q000517:prevention & control; D005920:Glomerular Mesangium / Q000187:drug effects / Q000503:physiopathology; D007150:Immunohistochemistry; D007328:Insulin / Q000172:deficiency* / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D007684:Kidney Tubules / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D014451:Ubiquinone / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051176:beta Catenin; D014451:Ubiquinone
Free Radic Biol Med. 2007 Jun 15;42(12):1766-80
17512456
Am J Nephrol. 2009;30(4):346-53
19609076
Diabetes. 2006 Jan;55(1):225-33
16380497
J Clin Invest. 2006 May;116(5):1302-9
16604193
Free Radic Biol Med. 2006 Oct 15;41(8):1191-6
17015165
Nat Cell Biol. 2006 May;8(5):501-8
16604061
FASEB J. 2005 Jul;19(9):1088-95
15985532
Hypertension. 2009 Aug;54(2):322-8
19581509
J Clin Pathol. 2007 Jan;60(1):18-26
17213346
J Am Soc Nephrol. 2009 Apr;20(4):765-76
19297557
Nephrol Dial Transplant. 2008 Dec;23(12):3880-7
18676351
Exp Biol Med (Maywood). 2008 Jan;233(1):4-11
18156300
Diabetes. 2010 Jul;59(7):1809-16
20299474
J Physiol. 2007 Aug 15;583(Pt 1):9-24
17584843
Biosci Biotechnol Biochem. 2002 Apr;66(4):869-72
12036065
J Nucl Med. 1986 Jan;27(1):111-6
2934521
Cancer Res. 2007 Jul 1;67(13):6392-9
17616699
J Am Soc Nephrol. 2009 Jun;20(6):1303-13
19470681
Diabetes. 2010 Feb;59(2):529-38
19934006
Int Urol Nephrol. 2008;40(4):1059-65
18690545
Am J Physiol Renal Physiol. 2010 Mar;298(3):F788-95
20042456
Diabetes. 2008 Nov;57(11):2924-32
18678617
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):384-9
14691259
Circ Res. 2006 Nov 10;99(10):1067-75
17053193
J Natl Med Assoc. 2004 Nov;96(11):1445-54
15586648
Am J Kidney Dis. 2009 Apr;53(4 Suppl 4):S11-21
19285607
Liver Int. 2010 Aug;30(7):1019-26
20492507
Redox Rep. 2007;12(3):148-62
17623522
Mov Disord. 2010 Aug 15;25(11):1670-4
20568096
J Am Soc Nephrol. 2009 Apr;20(4):742-52
19158353
Acta Diabetol. 2003 Jun;40(2):85-90
12861406
Diabetes. 2004 Feb;53 Suppl 1:S110-8
14749275
Free Radic Biol Med. 2008 Dec 1;45(11):1559-65
18845241
Pol Arch Med Wewn. 2009 Apr;119(4):261-4
19413187
Nature. 2001 Dec 13;414(6865):813-20
11742414
Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10190-5
20479236
J Biol Chem. 2005 Jun 3;280(22):21295-312
15788391
BMC Endocr Disord. 2009 Jan 23;9:2
19166612
Nephrol Dial Transplant. 2010 Jun;25(6):1803-10
20061322
Methods Mol Biol. 2008;447:369-80
18369930
Proc Natl Acad Sci U S A. 2010 May 11;107(19):8788-93
20421486
Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5407-12
12697897
Free Radic Biol Med. 2004 Sep 15;37(6):768-84
15304253
Clin Chim Acta. 2004 Dec;350(1-2):99-106
15530465
Ann N Y Acad Sci. 2006 May;1067:182-90
16803984
Biophys J. 2009 Feb 18;96(4):1388-98
19217856
J Clin Invest. 1999 Jan;103(1):27-37
9884331
J Am Soc Nephrol. 2010 Jan;21(1):124-35
20019166
Diabetes. 2009 Sep;58(9):1986-97
19542201
Am J Physiol Renal Physiol. 2007 Oct;293(4):F1408-12
17634403
J Am Soc Nephrol. 2004 Jan;15(1):1-12
14694152
Annu Rev Pharmacol Toxicol. 2007;47:629-56
17014364
Invest Ophthalmol Vis Sci. 2005 Jun;46(6):2210-8
15914643
Am J Physiol Renal Physiol. 2005 Aug;289(2):F420-30
15814529
Autophagy. 2009 Jan;5(1):19-32
19115482