Reduced tubular proteinuria in hypertensive rats treated with losartan is associated with higher renal cortical megalin expression.
BACKGROUND
Several clinical studies have demonstrated that angiotensin II antagonists exert renoprotective effects beyond blood pressure control in hypertensive patients. The present work aimed to test the hypothesis that the antiproteinuric effects of losartan are associated with upregulation of the multi-ligand endocytic receptors megalin and cubilin in the proximal tubule of spontaneously hypertensive rats (SHR).


METHODS
Fourteen-week-old SHRs were orally treated for 7 weeks with losartan (50 mg/kg, SHR-L), hydralazine (30 mg/kg, SHR-H), or vehicle (SHR-V). Blood pressure and renal function were determined prior to and following drug treatment. Expression of renal cortical proteins was determined by immunoblotting.


RESULTS
Losartan and hydralazine reduced systolic blood pressure from pretreatment levels in SHRs to a similar extent. However, SHR-L displayed a much greater reduction in proteinuria than SHR-H (44±3% vs. 15±1%, p<0.01) relative to pretreatment urinary protein excretion levels. In SHRs treated with vehicle, proteinuria increased from 87±5 to 153±15 mg/(day kg BW). Reduced tubular proteinuria in SHRs treated with losartan was accompanied by a higher expression of megalin (125±28%) relative to either SHR-V or SHR-H. Neither losartan nor hydralazine significantly altered the renal cortical expression of cubilin in SHRs.


CONCLUSIONS
Collectively, our data demonstrate that the additional renoprotective effects of angiotensin II blockade by losartan are associated with upregulation of megalin in the renal proximal tubule of SHRs. Moreover, it strengthens the view that tubular dysfunction may represent an important contributing mechanism underlying proteinuria in hypertension.
Daniel F
DF
Arruda-Junior
Stephannie G
SG
Virgulino
Adriana C C
AC
Girardi
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D060730:Glomerular Filtration Barrier / Q000378:metabolism; D006830:Hydralazine / Q000494:pharmacology / Q000627:therapeutic use; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D008297:Male; D011507:Proteinuria / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011918:Rats, Inbred SHR; D011956:Receptors, Cell Surface / Q000378:metabolism
D000959:Antihypertensive Agents; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor; D006830:Hydralazine; D019808:Losartan