The chemokine monocyte chemoattractant protein-1 contributes to renal dysfunction in swine renovascular hypertension.
Renal artery stenosis (RAS) causes renovascular hypertension and renal damage, which may result from tissue inflammation. We have previously shown that the kidney in RAS exhibits increased expression of monocyte chemoattractant protein (MCP)-1, but its contribution to renal injury remained unknown. This study tested the hypothesis that MCP-1 contributes to renal injury and dysfunction in the stenotic kidney.


METHODS
Kidney hemodynamics, function, and endothelial function were quantified in pigs after 10 weeks of experimental RAS (n = 7), RAS supplemented with the MCP-1 inhibitor bindarit (RAS + bindarit, 50 mg/kg/day orally, n = 6), and normal controls (n = 8). Renal inflammation was assessed by the immunoreactivity of MCP-1, its receptor chemotactic cytokine receptor 2, and NFkappaB, and oxidative stress by nicotinamide adenine dinucleotide phosphate-oxidase expression and in-situ superoxide production. Renal microvascular density was evaluated by micro-CT and fibrosis by trichrome staining, collagen-I immunostaining, and hydroxyproline content.


RESULTS
After 10 weeks of RAS, blood pressure was similarly elevated in RAS and RAS + bindarit. Compared with normal controls, stenotic RAS kidneys had decreased renal blood flow (5.4 +/- 1.6 vs. 11.4 +/- 1.0 ml/min/kg, P < 0.05) and glomerular filtration rate and impaired endothelial function, which were significantly improved in bindarit-treated RAS pigs (to 8.4 +/- 0.8 ml/min/kg, P < 0.05 vs. RAS). Furthermore, bindarit markedly decreased tubulointerstitial (but not vascular) oxidative stress, inflammation, and fibrosis, and slightly increased renal microvascular density. The impaired renovascular endothelial function, increased oxidative-stress, and fibrosis in the contralateral kidney were also improved by bindarit.


CONCLUSIONS
MCP-1 contributes to functional and structural impairment in the kidney in RAS, mainly in the tubulointerstitial compartment. Its inhibition confers renoprotective effects by blunting renal inflammation and thereby preserving the kidney in chronic RAS.
Zhu
Xiang-Yang
XY
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
Chade
Alejandro R
AR
Krier
James D
JD
Daghini
Elena
E
Lavi
Ronit
R
Guglielmotti
Angelo
A
Lerman
Amir
A
Lerman
Lilach O
LO
D000818:Animals; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis; D006978:Hypertension, Renovascular / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology*; D007191:Indazoles / Q000494:pharmacology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D011422:Propionates / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000378:metabolism; D012078:Renal Artery Obstruction / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology*; D012079:Renal Circulation / Q000502:physiology*; D034421:Sus scrofa; D015854:Up-Regulation / Q000502:physiology; D019459:Urothelium / Q000378:metabolism
D018932:Chemokine CCL2; D007191:Indazoles; D016328:NF-kappa B; D011422:Propionates; D054390:Receptors, CCR2; D019255:NADPH Oxidases; C079489:bindarit