Preliminary data on therapeutic effects of Irbesartan in a novel, tubular injury-specific mouse model of diabetic nephropathy.
Suresh, Caroline   (Massachusetts General Hospital)
Mentor: Bonventre, Joseph (Brigham and Womens Hospital)
Diabetes is the most common cause of chronic kidney disease (CKD). To date, diabetic nephropathy has largely been focused on the glomerulus, and as such animal models have focused on the detrimental effects of diabetes on glomerular structure and function. However, recent evidence suggests that the proximal tubule also plays an important role in the initiation and progression of diabetic nephropathy. Angiotensin II receptor blockers (ARBs) have been widely used clinically to treat diabetic nephropathy by lowering intra-glomerular pressure. However, the effect of ARBs on tubular injury is unknown. To this end, we developed a mouse model with diabetes and proximal tubular injury. Briefly, we crossed proximal tubule-specific Six2-Cre mice with transgenic mice expressing Cre-induced diphtheria toxin receptor (iDTR) to generate Six2-Cre+/iDTR mice. We then crossed the progeny with Akita mice carrying the Ins2+/C96Y mutation to generate type 1 diabetic mice that will develop proximal tubule damage after diphtheria toxin injection. Immunostaining for Kim-1 (marker for proximal tubule injury), endomucin (marker for endothelial cells), a-smooth muscle actin (marker for fibrosis) was performed in DTR-induced mice +/- Irbesartan treatment vs. non-induced-DTR mice +/- Irbesartan treatment groups, respectively. Our preliminary data suggests Irbesartan treatment decreased Kim-1 and a-smooth muscle actin (a-SMA) expression, with no change in endomucin levels. Further analysis with more mice per group is required to analyze statistical significance. If these preliminary findings are representative, then the Six2-Cre+/iDTR/Akita mouse shows promise as a model of tubular injury-induced CKD in diabetes.