Combined treatment with atrasentan and losartan significantly increased glomerular podocyte number and reduced proteinuria compared with untreated diabetic controls in a mouse model.
Does combined atrasentan and losartan therapy increase podocyte number and reduce proteinuria in a mouse model of diabetic nephropathy?
Atrasentan combined with losartan restores podocyte number and reduces proteinuria and mesangial matrix in a mouse model of diabetic nephropathy, providing a mechanistic basis for its clinical benefits.
Podocyte loss and proteinuria are both key features of human diabetic nephropathy (DN). The leptin-deficient BTBR mouse strain with the ob/ob mutation develops progressive weight gain, type 2 diabetes, and diabetic nephropathy that has many features of advanced human DN, including increased mesangial matrix, mesangiolysis, podocyte loss, and proteinuria. Selective antagonism of the endothelin-1 type A receptor (ET A R) by atrasentan treatment in combination with renin-angiotensin-aldosterone system inhibition with losartan has been shown to have the therapeutic benefit of lowering proteinuria in patients with DN, but the underlying mechanism for this benefit is not well understood. Using a similar therapeutic approach in diabetic BTBR ob/ob mice, this treatment regimen significantly increased glomerular podocyte number compared with diabetic BTBR ob/ob controls and suggested that parietal epithelial cells were a source for podocyte restoration. Atrasentan treatment alone also increased podocyte number but to a lesser degree. Mice treated with atrasentan demonstrated a reduction in proteinuria, matching the functional improvement reported in humans. This is a first demonstration that treatment with the highly selective ET A R antagonist atrasentan can lead to restoration of the diminished podocyte number characteristic of DN in humans and thereby underlies the reduction in proteinuria in patients with diabetes undergoing similar treatment. The benefit of ET A R antagonism in DN extended to a decrease in mesangial matrix as measured by a reduction in accumulations of collagen type IV in both the atrasentan and atrasentan + losartan-treated groups compared with untreated controls.
Hudkins et al. (Mon,) conducted a other in Diabetic nephropathy. Atrasentan combined with losartan vs. Untreated diabetic BTBR ob/ob controls was evaluated on Glomerular podocyte number and proteinuria. Combined treatment with atrasentan and losartan significantly increased glomerular podocyte number and reduced proteinuria compared with untreated diabetic controls in a mouse model.