Establishment and characterization of a mouse model for studying kidney repair in diabetes.

Abstract

The prognosis of acute kidney injury (AKI) is markedly worse in diabetic patients. Diabetes not only exaggerates the severity of AKI but may 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 non-diabetic 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 day 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.