Identification of Novel Targets of Diabetic Nephropathy Using RNA-seq

Diabetic nephropathy (DN) is a major complication of type 1 and type 2 diabetes and may lead to kidney failure. Understanding how diabetes regulates transcriptome dynamics in DN is important for understanding the biology of the disease and for guiding development of new treatments. In this study, we identified a set of unique biomarkers and canonical pathways that may hold the key to understanding mechanisms of DN pathobiology with value for clinical translation. Our data suggest that mitochondrial dysfunction, genotoxicity and oxidative stress are principal events in DN and that P78-PEDF, an active PEDF peptide, holds promise for its management. Overall design: We analyzed the transcriptome of diabetic D2.B6-Ins2Akita/MatbJ mice, a diabetic model of DN, before and after treatment with P78-PEDF. Age-, weight-, and gender-matched diabetic mice and wild-type (wt, DBA/2J background) littermates were treated at 6 wks of age (early treatment) or 12 wks of age (late treatment) for the duration of 6 wks. All animals, including wild-type controls, were implanted with an osmotic mini pump delivering 0.3 ug/g/day P78-PEDF to diabetic groups or vehicle (PBS) to controls (wild-type and diabetic). Four groups of samples were used: 1. Normal mice (wt control), 2. Diabetic mice (diabetic control), 3. Early treatment with P78 (ET), and 4. Late treatment with P78 (LT). For the Diabetic Group, only animals with blood glucose levels > 350 mg/dl were used. Samples were pooled (n=7-13/group) and each group was analyzed using next-generation RNA-seq technology.