Abstract: FR-PO638

A New Model of Diabetic Nephropathy with Advanced CKD Progression in C57BL/6 Mice

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental


  • Bai, Xiaoyan, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
  • Li, Xiao, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
  • Tian, Jianwei, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
  • Jiao, Wan, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
  • Liu, Youhua, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease in industrialized nations. However, there is a lack of robust mouse models with key features of advanced human DN. Very few options of murine models for studying DN include Akita and OVE26 type 1 diabetic mice, and C57BL/6J db/db, C57BL/KsJ ob/ob, eNOS(-/-) db/db and BT/BR ob/ob type 2 diabetic mice. The limitation of these mice is the requirement for mutation to be superimposed to obtain desired phenotypic characteristics. Most genetically modified mice are on the C57BL/6 background; however, they are notorious for resistance to develop DN. To overcome these conundrums, this study reports a novel DN model by challenging with advanced oxidation protein products (AOPPs) in streptozotocin-induced diabetic C57BL/6 mice.


Uninephrectomized male C57BL/6 mice were divided as follows: 1) non-diabetic; 2) AOPPs-challenged NC; 3) losartan-treated AOPPs-challenged NC; 4) diabetic; 5) AOPPs-challenged diabetic and 6) losartan-treated AOPPs-challenged diabetic mice. After 8, 12 and 24 weeks, biological parameters were evaluated and kidneys harvested for morphology and morphometry.


Glomerular hypertrophy and accumulation of mesangial matrix were present by 8 weeks. By 24 weeks, glomerular lesions similar to those of advanced human DN were present, as demonstrated morphologically by significant mesangial expansion (p<0.001) and sclerosis resembling Kimmelstiel-Wilson nodules, diffuse podocyte foot process effacement (p<0.05), increased glomerular basement membrane width (p<0.001), and worsened tubulointerstitial fibrosis. Immunofluorescence microscopy excluded immune complex diseases for IgG, IgM, and IgA. These morphological changes recapitulate the renal pathology of advanced human DN. AOPPs-challenged diabetic C57BL/6 mice were more sensitive to develop progressive proteinuria beginning at 8 weeks. By 24 weeks, increased albumin excretion rate (p<0.001) was found and losartan treatment alleviated these changes.


AOPPs can accelerate the progression of DN in resistant C57BL/6 mice. This mouse model offers a homogeneous genetic background for studying the pathogenesis of advanced DN that resembles human diabetic kidney disease. It also makes it possible to interrogate the role of specific genetic modifications and to evaluate novel therapeutics in the preclinical setting.


  • Government Support - Non-U.S.