Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury.
Acute kidney injury (AKI) is an important risk factor for incident chronic kidney disease (CKD). Clinical studies disclose that ensuing CKD progresses after functional recovery from AKI, but the underlying mechanisms remain illusive. Using a murine model representing AKI-CKD continuum, we show angiotensin II type 1a (AT1a) receptor signaling as one of the underlying mechanisms. Male adult CD-1 mice presented severe AKI with 20% mortality within 2 weeks after right nephrectomy and left renal ischemia-reperfusion injury. Despite functional recovery, focal tubular atrophy, interstitial cell infiltration and fibrosis, upregulation of genes encoding angiotensinogen and AT1a receptor were shown in kidneys 4 weeks after AKI. Thereafter mice manifested increase of blood pressure, albuminuria and azotemia progressively. Drinking water with or without losartan or hydralazine was administered to mice from 4 weeks after AKI. Increase of mortality, blood pressure, albuminuria, azotemia and kidney fibrosis was noted in mice with vehicle administration during the 5-month experimental period. On the contrary, these parameters in mice with losartan administration were reduced to the levels shown in control group. Hydralazine did not provide similar beneficial effect though blood pressure was controlled. These findings demonstrate that losartan can reduce ensuing CKD and mortality after functional recovery from AKI.
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Shun-Yang
SY
Cheng
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
Yu-Hsiang
YH
Chou
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Fang-Ling
FL
Liao
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chi-Chun
CC
Lin
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Renal Division, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
Fan-Chi
FC
Chang
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chia-Hao
CH
Liu
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
Tao-Min
TM
Huang
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Chun-Fu
CF
Lai
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Yu-Feng
YF
Lin
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Vin-Cent
VC
Wu
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Tzong-Shinn
TS
Chu
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Ming-Shiou
MS
Wu
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Shuei-Liong
SL
Lin
Clin J Am Soc Nephrol. 2006 Jan;1(1):43-51
17699189
J Clin Invest. 2005 Jul;115(7):1743-55
16007251
Kidney Int. 2009 Oct;76(8):893-9
19641480
J Am Soc Nephrol. 2004 Jun;15(6):1597-605
15153571
PLoS One. 2013 Dec 18;8(12):e82592
24367525
Proc Natl Acad Sci U S A. 2011 May 31;108(22):9226-31
21576461
J Am Soc Nephrol. 2006 Nov;17(11):2985-91
17035613
Am J Physiol Renal Physiol. 2007 Jul;293(1):F269-78
17507599
J Am Soc Nephrol. 2006 Nov;17(11):3115-23
16988058
J Am Soc Nephrol. 2002 Dec;13(12):2916-29
12444210
Circulation. 2010 May 25;121(20):2211-20
20458011
J Am Heart Assoc. 2014 Jul 15;3(4):
25027018
J Am Soc Nephrol. 2016 Mar;27(3):914-23
26134154
JAMA. 2005 Aug 17;294(7):813-8
16106006
Kidney Int. 2012 Oct;82(8):920-7
22763817
J Clin Invest. 2016 Feb;126(2):721-31
26731474
Cell Stem Cell. 2008 Mar 6;2(3):284-91
18371453
Arch Intern Med. 2008 Mar 24;168(6):609-16
18362253
Crit Care. 2011;15(3):R134
21645350
J Am Soc Nephrol. 2014 Jul;25(7):1496-507
24511135
Arch Intern Med. 2011 Feb 14;171(3):226-33
21325112
JAMA. 2009 Sep 16;302(11):1179-85
19755696
Kidney Int. 2009 Nov;76(10):1089-97
19741590
Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290
15114537
J Am Soc Nephrol. 2007 Apr;18(4):1292-8
17314324
Kidney Int. 2016 Feb;89(2):363-73
26509589
Clin J Am Soc Nephrol. 2009 May;4(5):891-8
19406959
Am J Kidney Dis. 2016 May;67(5):742-52
26690912
J Am Soc Nephrol. 2014 Mar;25(3):595-605
24503241
J Am Soc Nephrol. 2015 Dec;26(12):2905-16
26538634
Kidney Int. 2003 Jul;64(1):350-5
12787428
Hypertension. 2007 Dec;50(6):1134-41
17938382
J Am Soc Nephrol. 2005 Nov;16(11):3365-70
16177006
J Am Soc Nephrol. 2014 Jun;25(6):1198-209
24511140
J Am Soc Nephrol. 2011 Jan;22(1):156-63
21115618
Crit Care Med. 2008 Apr;36(4):1129-37
18379238
Kidney Int. 2011 Jun;79(12):1361-9
21430640
Am J Kidney Dis. 2007 Nov;50(5):703-11
17954283
J Am Soc Nephrol. 2013 Jan;24(1):37-42
23222124
Contrib Nephrol. 2011;174:149-155
21921619
Kidney Int. 2012 Sep;82(5):516-24
22673882
Nat Med. 2010 May;16(5):535-43, 1p following 143
20436483
Crit Care. 2009;13(5):R171
19878554
Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4194-9
20160075
Am J Pathol. 2013 Jan;182(1):118-31
23142380
J Am Soc Nephrol. 2016 Aug;27(8):2257-64
26744488
Crit Care. 2012 Jul 12;16(4):R123
22789111
Nephron Clin Pract. 2008;109(3):c109-18
18663322
Am J Physiol Renal Physiol. 2010 Jun;298(6):F1472-83
20181666
J Pathol. 2015 Jun;236(2):251-63
25664690
J Am Soc Nephrol. 2011 Feb;22(2):317-26
21289217
J Am Soc Nephrol. 2009 Jan;20(1):223-8
19020007
PLoS One. 2012;7(8):e42952
22952623