Abstract
The early detection of diabetic nephropathy (DN) in mice is necessary for the development of drugs and functional foods. The purpose of this study was to identify genes that are significantly upregulated in the early stage of DN progression and develop a novel model to non-invasively monitor disease progression within living animals using in vivo imaging technology. Streptozotocin (STZ) treatment has been widely used as a DN model; however, it also exhibits direct cytotoxicity to the kidneys. As it is important to distinguish between DN-related and STZ-induced nephropathy, in this study, we compared renal responses induced by the diabetic milieu with two types of STZ models: multiple low-dose STZ injections with a high-fat diet and two moderate-dose STZ injections to induce DN. We found 221 genes whose expression was significantly altered during DN development in both models and identified serum amyloid A3 (Saa3) as a candidate gene. Next, we applied the Saa3 promoter-driven luciferase reporter (Saa3-promoter luc mice) to these two STZ models and performed in vivo bioluminescent imaging to monitor the progression of renal pathology. In this study, to further exclude the possibility that the in vivo bioluminescence signal is related to renal cytotoxicity by STZ treatment, we injected insulin into Saa3-promoter luc mice and showed that insulin treatment could downregulate renal inflammatory responses with a decreased signal intensity of in vivo bioluminescence imaging. These results strongly suggest that Saa3 promoter activity is a potent non-invasive indicator that can be used to monitor DN progression and explore therapeutic agents and functional foods.
Highlights
The early detection of diabetic nephropathy (DN) in mice is necessary for the development of drugs and functional foods
To examine the molecular signature that can characterize an early stage of Diabetic nephropathy (DN) in streptozotocin (STZ)-induced DN models, we performed DNA microarray analyses of kidneys from two STZ-induced DN models using C57BL/6 mice
(2 × 125 mg/kg per day STZ) to establish diabetes in C57BL/6 mice. These injections led to a mild resistance to STZ, suggesting that renal damage in this STZ model is not related to the acute tubular cytotoxicity seen in those undergoing continuous insulin administration to prevent renal pathology [16]
Summary
The early detection of diabetic nephropathy (DN) in mice is necessary for the development of drugs and functional foods. To further exclude the possibility that the in vivo bioluminescence signal is related to renal cytotoxicity by STZ treatment, we injected insulin into Saa3-promoter luc mice and showed that insulin treatment could downregulate renal inflammatory responses with a decreased signal intensity of in vivo bioluminescence imaging These results strongly suggest that Saa promoter activity is a potent non-invasive indicator that can be used to monitor DN progression and explore therapeutic agents and functional foods. DN research relies on traditional diagnostic techniques, such as the histological assessment of collagen deposition and quantification of serum/urine biomarkers (e.g., creatinine, blood urea nitrogen (BUN), albumin, and cytokines) to confirm kidney disorders [3] These markers have provided essential insight into DN progression in human patients, there are problems of low sensitivity and missing early injury responses in diabetic kidneys. These traditional serum/urine biomarkers are often affected by other factors such as age, muscle mass, protein diet, and intake of certain drugs [4,5]
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