Transfer of the CYP4A region of chromosome 5 from Lewis to Dahl S rats attenuates renal injury.
This study examined the effect of transfer of overlapping regions of chromosome 5 that includes (4A(+)) or excludes (4A(-)) the cytochrome P-450 4A (CYP4A) genes from the Lewis rat on the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) and the development of hypertension-induced renal disease in congenic strains of Dahl salt-sensitive (Dahl S) rats. The production of 20-HETE was higher in the outer medulla of 4A(+) than in Dahl S or 4A(-) rats. Mean arterial pressure (MAP) rose to 190 +/- 7 and 185 +/- 3 mmHg in Dahl S and 4A(-) rats fed a high-salt (HS) diet for 21 days but only to 150 +/- 5 mmHg in the 4A(+) strain. Protein excretion increased to 423 +/- 40 and 481 +/- 37 mg/day in Dahl S and 4A(-) rats vs. 125 +/- 15 mg/day in the 4A(+) strain. Baseline glomerular capillary pressure (Pgc) was lower in 4A(+) rats (38 +/- 1 mmHg) than in Dahl S rats (42 +/- 1 mmHg). Pgc increased to 50 +/- 1 mmHg in Dahl S rats fed a HS diet, whereas it remained unaltered in 4A(+) rats (39 +/- 1 mmHg). Baseline glomerular permeability to albumin (P(alb)) was lower in 4A(+) rats (0.19 +/- 0.05) than in Dahl S or 4A(-) rats (0.39 +/- 0.02). P(alb) rose to approximately 0.61 +/- 0.03 in 4A(-) and Dahl S rats fed a HS diet for 7 days, but it remained unaltered in the 4A(+) rats. The expression of transforming growth factor-beta2 was higher in glomeruli of Dahl S rats than in 4A(+) rats fed either a low-salt (LS) or HS diet. Chronic administration of a 20-HETE synthesis inhibitor (HET0016; 10 mg.kg(-1).day(-1) sc) reversed the fall in MAP and renoprotection seen in 4A(+) rats. These results indicate that the introgression of the CYP4A genes from Lewis rats into the Dahl S rats increases the renal formation of 20-HETE and attenuates the development of hypertension and renal disease.
Williams
Jan Michael
JM
Kidney Disease Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Sarkis
Albert
A
Hoagland
Kimberly M
KM
Fredrich
Katherine
K
Ryan
Robert P
RP
Moreno
Carol
C
Lopez
Bernardo
B
Lazar
Jozef
J
Fenoy
Francisco J
FJ
Sharma
Mukut
M
Garrett
Michael R
MR
Jacob
Howard J
HJ
Roman
Richard J
RJ
D000818:Animals; D002874:Chromosome Mapping; D042926:Cytochrome P-450 CYP4A / Q000235:genetics*; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006973:Hypertension / Q000517:prevention & control; D007672:Kidney Cortex / Q000201:enzymology; D007679:Kidney Medulla / Q000201:enzymology; D008861:Microsomes / Q000201:enzymology; D051381:Rats; D020303:Rats, Inbred Dahl / Q000235:genetics*; D011917:Rats, Inbred Lew / Q000235:genetics*; D012709:Serum Albumin / Q000378:metabolism; D013045:Species Specificity
D017931:DNA Primers; D006893:Hydroxyeicosatetraenoic Acids; D012709:Serum Albumin; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D042926:Cytochrome P-450 CYP4A