TY - JOUR
T1 - Endothelial-derived vasoactive mediators in polycystic kidney disease
AU - Al-Nimri, Muna A.
AU - Komers, Radko
AU - Oyama, Terry T.
AU - Subramanya, Arohan R.
AU - Lindsley, Jessie N.
AU - Anderson, Sharon
N1 - Funding Information:
These studies were supported, in part, by grants from the Polycystic Kidney Research Foundation and the NIH (AG 14699). Portions of this work have been published in abstract form (J Am Soc Nephrol 11:612A, 2000). We are grateful to Dr. Scott L. Mader, William E. Schutzer, and John F. Reed for their continuing assistance with the protein analyses, and to Aaron Janowsky, Ph.D., for making his imaging equipment and expertise available to us for these studies.
PY - 2003/5/1
Y1 - 2003/5/1
N2 - Background. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by hypertension and renal vasoconstriction. Mediators of these hemodynamic changes are not well understood, but evidence suggests that endothelial-derived mediators may participate. Methods. Baseline measurements of blood pressure, proteinuria, and urinary nitrite/nitrate excretion were performed in control and cystic male Han:SPRD rats (6 weeks of age). They were then treated with the nitric oxide (NO), nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), or vehicle, for 6 weeks. After repeat systemic measurements, renal function was determined using inulin and para-aminohippurate (PAH) clearances. Levels of renal endothelin-1 (ET-1) and renal endothelial NOS (eNOS) proteins were determined, and immunohistochemistry localized renal eNOS and neuronal NOS (nNOS). Results. Administration of L-NAME aggravated systemic hypertension and renal vasoconstriction in the cystic rats, but did not affect the progression of proteinuria or cystic expansion. Cystic rats demonstrated marked increases in renal ET-1 and eNOS levels. L-NAME reduced eNOS expression in the membrane compartment, but increased eNOS in the cytosol. Localization studies indicated that renal eNOS was abundant in nonvascular compartments, but not in renal vascular and glomerular structures, whereas renal nNOS was diffusely diminished. Conclusion. These alterations of endothelial-derived mediators (up-regulation of ET-1, and dysfunction of the NO system) contribute to vasoconstriction, and thereby are likely to contribute to the progressive loss of renal function in polycystic kidney disease (PKD).
AB - Background. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by hypertension and renal vasoconstriction. Mediators of these hemodynamic changes are not well understood, but evidence suggests that endothelial-derived mediators may participate. Methods. Baseline measurements of blood pressure, proteinuria, and urinary nitrite/nitrate excretion were performed in control and cystic male Han:SPRD rats (6 weeks of age). They were then treated with the nitric oxide (NO), nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), or vehicle, for 6 weeks. After repeat systemic measurements, renal function was determined using inulin and para-aminohippurate (PAH) clearances. Levels of renal endothelin-1 (ET-1) and renal endothelial NOS (eNOS) proteins were determined, and immunohistochemistry localized renal eNOS and neuronal NOS (nNOS). Results. Administration of L-NAME aggravated systemic hypertension and renal vasoconstriction in the cystic rats, but did not affect the progression of proteinuria or cystic expansion. Cystic rats demonstrated marked increases in renal ET-1 and eNOS levels. L-NAME reduced eNOS expression in the membrane compartment, but increased eNOS in the cytosol. Localization studies indicated that renal eNOS was abundant in nonvascular compartments, but not in renal vascular and glomerular structures, whereas renal nNOS was diffusely diminished. Conclusion. These alterations of endothelial-derived mediators (up-regulation of ET-1, and dysfunction of the NO system) contribute to vasoconstriction, and thereby are likely to contribute to the progressive loss of renal function in polycystic kidney disease (PKD).
KW - Cystic disease
KW - Endothelin
KW - Glomerular filtration rate
KW - Nitric oxide
KW - Polycystic kidney
KW - Proteinuria
UR - http://www.scopus.com/inward/record.url?scp=0037407250&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037407250&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.2003.00913.x
DO - 10.1046/j.1523-1755.2003.00913.x
M3 - Article
C2 - 12675853
AN - SCOPUS:0037407250
SN - 0085-2538
VL - 63
SP - 1776
EP - 1784
JO - Kidney International
JF - Kidney International
IS - 5
ER -