Hyperglycemia-induced tubular proteinuria in non-obese diabetic mice: A potential role in tubular injury development

Diabetic Kidney Disease (DKD) is a serious public health problem associated with hyperglycemia-induced specific alterations in proximal tubule epithelial cells (PTECs). In this context, there is a strict correlation between PTEC injury and tubular proteinuria in kidney diseases. We aimed to investigate the potential role of PTECs in the development of tubular proteinuria and tubular injury in the early stages of DKD. We used Non-obese Diabetic (NOD) mice, which are susceptible strains for the development of Type 1 diabetes. This model develops type 1 diabetes after reaching 12 weeks of age. To assess the early stages of DKD, we employed NOD mice as well as non-obese diabetes resistant (NOR) mice (approximately 20-22g body weight, n=4/group) at the 3rd week after type 1 diabetes onset (CEUA-UFMG #155/2023). NOR mice were used as controls. It was observed that food and water intakes were significantly higher in the NOD mice when compared with NOR mice (food intake: NOD 7.75±1.37 g vs NOR 3.33±0.33 g; water intake: NOD 22.00±2.82 mL vs NOR 5.33±1.76 mL), which is consistent with the diabetes. In parallel, the results of urinary volume and urinary flow rate were significantly higher (approx. 15 times) in NOD mice when compared with NOR mice. Urinary osmolality was not changed between the experimental groups, spite of the slightly tendency of drop in NOD mice. In relation to renal protein handling, we observed a significant increase in proteinuria and UPCr, markers of renal disease, in NOD mice when compared with NOR mice (proteinuria: NOD 2.97±0.54 mg/24h vs NOR 0.14±0.005 mg/24h; UPCr: NOD 0.81±0.26 vs NOR 0.24±0.094). In addition, we observed that urinary γ-GT levels, specific marker of tubular injury, were significantly higher in the NOD mice when compared to NOR mice (NOD 0.73±0.14 U/L vs NOR 0.18±0.081 U/L). Our preliminary data showed in NOD mice that there is a development of tubular proteinuria associated with tubular injury in the early stages of DKD.