Astragaloside IV synergizes with captopril in ameliorating renal fibrosis in uninephrectomized db/db mice

Abstract

Background: Astragaloside IV (AS-IV) is an active ingredient of Astragalus membranaceus, the most frequently prescribed Chinese herbal medicine for diabetic kidney disease (DKD). AS-IV monotherapy has been demonstrated to ameliorate podocyte apoptosis, foot process effacement, mesangial expansion, glomerulosclerosis and interstitial fibrosis. Dual renin-angiotensin system (RAS) blockade has not been recommended for DKD due to a lack of efficacy. Since AS-IV is reported to regulate TGF-beta to ameliorate fibrosis, the prospect of combining AS-IV with renin angiotensin blockade warrants investigation. Methods: Spontaneously diabetic db/db mice and their corresponding non-diabetic db/m littermates were uninephrectomized or sham-operated and received 8 weeks of captopril, AS-IV, combined captopril/AS-IV or vehicle control orally before sacrifice. Urine albumin-to-creatinine ratio (UACR), plasma cystatin C, blood glucose, blood pressure and expression of oxidative stress and fibrosis markers at mRNA and protein levels were determined. Histopathological changes were also examined. Results: Uninephrectomized db/db mice developed progressive albuminuria, glomerulosclerosis, tubulointerstitial fibrosis and tubular atrophy with dilatation with upregulated cortical expression of TGF-beta, alpha-smooth muscle actin, collagen and fibronectin and NOX4. Mice that received either captopril or AS-IV treatment had ameliorated albuminuria and fibrotic lesions versus control. Mice that received combined treatment displayed the lowest glomerular injury index, tubular injury index, UACR and plasma cystatin C. Blood pressure and glucose were comparable between groups. Conclusions: Captopril and AS-IV confer synergistic renal anti-fibrotic and antioxidative effects in uninephrectomized db/db mice. These findings could potentially be translated into clinical practice. Funding support: Hong Kong Society of Nephrology Research Grant