Endothelin-1 Overexpression Improves Renal Function in eNOS Knockout Mice.
OBJECTIVE
To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+), endothelial nitric oxide synthase knockout (eNOS-/-) and ET+/+eNOS-/- mice.


METHODS
We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics.


RESULTS
eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpine1, TIMP1, Col1a1, CCL2) were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice.


CONCLUSIONS
eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET-1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in β-oxidation of fatty acids) and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels).
Oleg
O
Tsuprykov
Lyubov
L
Chaykovska
Axel
A
Kretschmer
Johannes-Peter
JP
Stasch
Thiemo
T
Pfab
Katharina
K
Krause-Relle
Christoph
C
Reichetzeder
Philipp
P
Kalk
Jerzy
J
Adamski
Berthold
B
Hocher
D000418:Albumins / Q000032:analysis; D000818:Animals; D001794:Blood Pressure; D002331:Carnitine / Q000097:blood; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D055316:Cystatin C / Q000097:blood; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000097:blood / Q000652:urine; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics*; D053495:Osteopontin / Q000097:blood / Q000652:urine; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
D000418:Albumins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D055316:Cystatin C; D019332:Endothelin-1; C493409:Fabp3 protein, mouse; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D053495:Osteopontin; D055513:Connective Tissue Growth Factor; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D002331:Carnitine