Genetic deficiency of aldose reductase counteracts the development of diabetic nephropathy in C57BL/6 mice.
OBJECTIVE
The aim of the study was to investigate the effects of genetic deficiency of aldose reductase in mice on the development of key endpoints of diabetic nephropathy.


METHODS
A line of Ar (also known as Akr1b3)-knockout (KO) mice, a line of Ar-bitransgenic mice and control C57BL/6 mice were used in the study. The KO and bitransgenic mice were deficient for Ar in the renal glomeruli and all other tissues, with the exception of, in the bitransgenic mice, a human AR cDNA knockin-transgene that directed collecting-tubule epithelial-cell-specific AR expression. Diabetes was induced in 8-week-old male mice with streptozotocin. Mice were further maintained for 17 weeks then killed. A number of serum and urinary variables were determined for these 25-week-old mice. Periodic acid-Schiff staining, western blots, immunohistochemistry and protein kinase C (PKC) activity assays were performed for histological analyses, and to determine the levels of collagen IV and TGF-β1 and PKC activities in renal cortical tissues.


RESULTS
Diabetes-induced extracellular matrix accumulation and collagen IV overproduction were completely prevented in diabetic Ar-KO and bitransgenic mice. Ar deficiency also completely or partially prevented diabetes-induced activation of renal cortical PKC, TGF-β1 and glomerular hypertrophy. Loss of Ar results in a 43% reduction in urine albumin excretion in the diabetic Ar-KO mice and a 48% reduction in the diabetic bitransgenic mice (p < 0.01).


CONCLUSIONS
Genetic deficiency of Ar significantly ameliorated development of key endpoints linked with early diabetic nephropathy in vivo. Robust and specific inhibition of aldose reductase might be an effective strategy for the prevention and treatment of diabetic nephropathy.
Ministry of Education Key Laboratory for Cell Biology and Tumor Cell Engineering and Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen 361005, People's Republic of China.
H
H
Liu
Y
Y
Luo
T
T
Zhang
Y
Y
Zhang
Q
Q
Wu
L
L
Yuan
S S M
SS
Chung
P J
PJ
Oates
J Y
JY
Yang
D000449:Aldehyde Reductase / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
D000449:Aldehyde Reductase
Mol Cell Biol. 2000 Aug;20(16):5840-6
10913167
Nephron. 1998 Nov;80(3):277-84
9807036
Curr Opin Investig Drugs. 2010 Apr;11(4):402-17
20336588
Diabet Med. 2001 Nov;18(11):906-14
11703436
Diabetes. 1992 Jun;41(6):679-84
1587395
J Clin Endocrinol Metab. 1998 Aug;83(8):2886-91
9709964
Am J Physiol Renal Physiol. 2006 Jul;291(1):F186-95
16449351
Pharmacology. 1996 May;52(5):292-302
8807673
Diabetes. 1984 Jun;33(6):604-7
6427041
Diabetes Care. 2008 Nov;31(11):2148-53
18716049
Diabetes. 1999 Feb;48(2):420-2
10334324
Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):115-23
10708959
Biochemistry. 1995 Sep 5;34(35):11264-75
7669785
Diabetes. 1989 Oct;38(10):1258-70
2507378
Ren Fail. 2001 May-Jul;23(3-4):311-20
11499547
Diabetes. 1997 Feb;46(2):287-91
9000706
Diabet Med. 2000 Feb;17(2):111-8
10746480
Curr Med Chem. 2010;17(34):4256-69
20939814
Kidney Int. 2003 Apr;63(4):1404-16
12631356
J Mol Endocrinol. 2008 May;40(5):243-51
18434430
Kidney Int Suppl. 2007 Aug;(106):S49-53
17653211
Diabetes. 1991 May;40(5):527-31
1902426
Adv Exp Med Biol. 1991;284:139-52
1711272
Semin Nephrol. 2007 Mar;27(2):153-60
17418684
Biochem Cell Biol. 1996;74(3):355-62
8883841
Expert Opin Investig Drugs. 1999 Dec;8(12):2095-2119
11139842
Diabetologia. 1999 Jan;42(1):94-7
10027585
Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1543-52
16356118
Diabetologia. 1995 Mar;38(3):255-61
7758869
Diabetologia. 1991 Oct;34(10):695-701
1959701
Virchows Arch. 2001 Jul;439(1):46-54
11499839
Metabolism. 2001 Dec;50(12):1435-40
11735089
Exp Cell Res. 1990 May;188(1):135-40
2109701
Folia Histochem Cytochem (Krakow). 1979;17(2):137-45
488851
Free Radic Biol Med. 2006 Apr 15;40(8):1454-65
16631535
Diabetologia. 1998 Mar;41(3):362-4
9541179
Diabetes. 1989 Aug;38(8):981-6
2502460
Nephron Exp Nephrol. 2004;98(3):e89-99
15528949
Diabetes. 2008 Jun;57(6):1446-54
18511445
Endocrine. 2002 Jun;18(1):47-56
12166624
Biochem Biophys Res Commun. 2000 Oct 22;277(2):281-6
11032718
J Clin Invest. 1988 Mar;81(3):635-40
3278002
Diabetes Res Clin Pract. 1994 Oct;25(3):147-54
7851268
Mol Cell Biochem. 1993 Aug 11;125(1):27-33
8264569
Metabolism. 1986 Apr;35(4 Suppl 1):55-9
3007926
Curr Drug Targets. 2005 Jun;6(4):475-86
16026266
J Biol Chem. 1998 May 8;273(19):11429-35
9565553
Metabolism. 1997 Jan;46(1):41-7
9005967
Diabetes. 1992 Sep;41(9):1165-71
1499867
J Am Soc Nephrol. 1999 Jun;10(6):1193-203
10361857