Deletion of LOX-1 attenuates renal injury following angiotensin II infusion.
Angiotensin II upregulates the expression of LOX-1, a recently identified oxidized low-density lipoprotein receptor controlled by redox state which in turn upregulates angiotensin II activity on its activation. To test whether interruption of this positive feedback loop might reduce angiotensin II-induced hypertension and subsequent renal injury, we studied LOX-1 knockout mice. After infusion with angiotensin II for 4 weeks systolic blood pressure gradually increased in the wild-type mice; this rise was significantly attenuated in the LOX-1 knockout mice. Along with the rise in systolic blood pressure, renal function (blood urea nitrogen and creatinine) decreased in the wild-type mice, but the deterioration of function was significantly less in the LOX-1 knockout mice. Glomerulosclerosis, arteriolar sclerosis, tubulointerstitial damage, and renal collagen accumulation were all significantly less in the LOX-1 knockout mice. The reduction in collagen formation was accompanied by a decrease in connective tissue growth factor mRNA, angiotensin type 1 receptor expression, and phosphorylation of p38 and p44/42 mitogen-activated protein kinases. Expression of endothelial nitric oxide synthase was increased in the kidneys of the LOX-1 knockout mice compared to the wild-type mice. Overall, our study suggests that LOX-1 is a key modulator in the development of angiotensin II-induced hypertension and subsequent renal damage.
Hu
Changping
C
Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.
Kang
Bum-Yong
BY
Megyesi
Judit
J
Kaushal
Gur P
GP
Safirstein
Robert L
RL
Mehta
Jawahar L
JL
D000805:Angiotensin III / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005355:Fibrosis; D006973:Hypertension / Q000473:pathology; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D051127:Scavenger Receptors, Class E / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
C526318:CCN2 protein, mouse; C495138:Olr1 protein, mouse; D044140:Receptor, Angiotensin, Type 1; D051127:Scavenger Receptors, Class E; D000805:Angiotensin III; D055513:Connective Tissue Growth Factor; D052250:Nitric Oxide Synthase Type III; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases