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Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Establishment and characterization of a mouse model for studying kidney repair in diabetes
Shaoqun Shu1,2, Hui Wang1, Juan Cai1
1Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China.
Abstract:
The prognosis of acute kidney injury (AKI) is markedly worse in patients with diabetes. Diabetes not only exaggerates the severity of AKI but also prevent kidney repair or recovery from AKI. Little is known about the cellular and molecular basis of defective kidney repair in diabetes. One obstacle in studying kidney repair in diabetes is the lack of suitable animal models. Specifically, diabetes increases AKI severity, making it difficult to induce the same level of AKI in diabetic and nondiabetic animals to compare their kidney repair. Here, we have identified a time window of 4 days immediately after the completion of streptozotocin (STZ) treatment in mice when blood glucose has yet to rise. Within this time window, renal ischemia-reperfusion injury (IRI) induced the same level of AKI in STZ-treated mice [127.2 ± 12.82 mg/dL blood urea nitrogen (BUN), 2.275 ± 0.4728 serum creatinine] and vehicle solution-treated mice (128.6 ± 11.83 mg/dL BUN, 2.087 ± 0.4748 mg/dL serum creatinine]. By days 5-6, the post-AKI kidney entered into the phase of kidney repair when diabetic hyperglycemia started in STZ-treated mice, providing the opportunity to study the effect of diabetes on kidney repair without affecting initial AKI. In this model, kidney repair was indeed impaired by diabetes (116.5 ± 8.052 mg/dL BUN and 1.382 ± 0.2732 mg/dL serum creatinine in IR + vehicle group; 136.6 ± 8.740 mg/dL BUN and 1.916 ± 0.3756 mg/dL serum creatinine in IR + STZ group). The impairment was associated with decreased tubular cell proliferation and increased tubular cell senescence, peritubular capillary (PTC) rarefaction, inflammation, and 40.90% more interstitial fibrosis.NEW & NOTEWORTHY Little is known about the cellular and molecular basis of defective kidney repair in diabetes. One obstacle in studying kidney repair in diabetes is the lack of suitable animal models. Here, we report a mouse model to investigate the effect of diabetes on kidney repair without affecting initial injury and found that the repair defect is associated with decreased renal tubular cell proliferation and increased tubular cell senescence, PTC rarefaction, inflammation, and interstitial fibrosis.
Insights
Diabetic mice show impaired acute kidney injury repair due to reduced cell proliferation and increased senescence. This new model allows studying diabetes effects on kidney recovery without altering initial injury severity.
Area of Science:
- Nephrology
- Diabetology
- Regenerative Medicine
Background:
- Diabetes mellitus significantly worsens acute kidney injury (AKI) prognosis and impairs kidney repair.
- The cellular and molecular mechanisms underlying defective kidney repair in diabetes remain poorly understood.
- Existing animal models face challenges in isolating the effects of diabetes on kidney repair from initial AKI severity.
Purpose of the Study:
- To develop and validate a novel mouse model for investigating the impact of diabetes on kidney repair post-AKI.
- To examine the cellular and molecular changes associated with impaired kidney repair in diabetic mice.
Main Methods:
- A 4-day window post-streptozotocin (STZ) treatment was identified where induced AKI severity was comparable between diabetic and non-diabetic mice.
- Renal ischemia-reperfusion injury (IRI) was induced during this window to model AKI.
- Kidney repair markers, tubular cell proliferation/senescence, peritubular capillary (PTC) density, inflammation, and interstitial fibrosis were assessed.
Main Results:
- The developed model successfully separated initial AKI severity from the effects of diabetes on subsequent kidney repair.
- Diabetic mice exhibited impaired kidney repair, evidenced by higher blood urea nitrogen (BUN) and serum creatinine levels compared to controls.
- Impaired repair in diabetic mice was linked to decreased tubular cell proliferation, increased tubular cell senescence, PTC rarefaction, heightened inflammation, and increased interstitial fibrosis.
Conclusions:
- This study presents a valuable mouse model for studying diabetes-specific defects in kidney repair following AKI.
- The findings reveal that diabetes impairs kidney repair through reduced tubular cell regeneration and increased cellular senescence.
- Further research into mitigating tubular senescence, inflammation, and fibrosis is crucial for improving AKI outcomes in diabetic patients.
