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.
Kidney Disease Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Jan Michael
JM
Williams
Albert
A
Sarkis
Kimberly M
KM
Hoagland
Katherine
K
Fredrich
Robert P
RP
Ryan
Carol
C
Moreno
Bernardo
B
Lopez
Jozef
J
Lazar
Francisco J
FJ
Fenoy
Mukut
M
Sharma
Michael R
MR
Garrett
Howard J
HJ
Jacob
Richard J
RJ
Roman
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