AbstractSeveral 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).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.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.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.