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Updated: Jan 12, 2026
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Oral L-NAME supplementation accelerates the progression of kidney disease in diabetic mice
Maria Novella Nicese1, Angela Koudijs1, Reshma Lalai1
1Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Background:
Diabetic kidney disease (DKD) represents one of the leading causes of end-stage kidney disease (ESKD) worldwide. Given the global impact of DKD, numerous animal models have been designed and tested over the years in order to better understand and treat this disease. However, many of these DKD models exhibit slow progression, implementation challenges and maintenance issues. For this reason, we aimed to develop an accelerated and reproducible mouse model of DKD.
Methods:
For our experiments we opted for leptin receptor knock-out (C57BLKS/J Lepdb) mice as type 2 diabetes model. To aggravate kidney damage, we administered the endothelial nitric oxide synthase (eNOS) inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) in drinking water at 2 different concentrations (40 mg/kg/day and 80 mg/kg/day) for 6 weeks.
Results:
As early as 3 weeks, L-NAME treatment resulted in increased systolic blood pressure, accompanied by a significant decrease in glomerular filtration rate (GFR) and an increase in albumin-to-creatinine ratio. Periodic acid-Schiff (PAS) staining of kidney sections revealed that mice treated with 80 mg/kg/day of L-NAME developed enlarged glomeruli and mesangial expansion, while Wilms tumor protein (WT1) staining revealed a decrease in podocytes in the glomeruli. Moreover, Sirius red and collagen I stainings showed an increase of fibrotic tissue and collagen deposition in the kidneys.
Conclusions:
Taken together, our results demonstrate that L-NAME accelerates the progression of DKD in C57BLKS/J Lepdb mice, with detectable signs of kidney dysfunction after 3 weeks of treatment. Therefore, this model could be used to assess the therapeutic potential of novel interventions against DKD.
Insights
This study developed an accelerated mouse model for diabetic kidney disease (DKD) using N(ω)-nitro-L-arginine methyl ester (L-NAME) in leptin receptor knock-out mice. The model shows rapid kidney dysfunction, making it useful for testing new DKD therapies.
Area of Science:
- Nephrology
- Pharmacology
- Animal Models
Background:
- Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD).
- Existing DKD animal models often have slow progression and practical challenges.
- There is a need for accelerated and reproducible DKD models.
Purpose of the Study:
- To develop an accelerated and reproducible mouse model for studying diabetic kidney disease (DKD).
Main Methods:
- Leptin receptor knock-out mice (type 2 diabetes model) were treated with N(ω)-nitro-L-arginine methyl ester (L-NAME) at 40 mg/kg/day or 80 mg/kg/day for 6 weeks.
- Kidney function was assessed by measuring systolic blood pressure, glomerular filtration rate (GFR), and albumin-to-creatinine ratio.
- Kidney tissue was analyzed using Periodic acid-Schiff (PAS), Wilms tumor protein 1 (WT1), Sirius red, and collagen I staining.
Main Results:
- L-NAME administration rapidly increased systolic blood pressure and kidney damage markers (decreased GFR, increased albumin-to-creatinine ratio) within 3 weeks.
- Histological analysis revealed enlarged glomeruli, mesangial expansion, podocyte loss, and increased fibrosis and collagen deposition in L-NAME treated mice.
- The 80 mg/kg/day L-NAME dose showed more pronounced pathological changes.
Conclusions:
- N(ω)-nitro-L-arginine methyl ester (L-NAME) effectively accelerates DKD progression in C57BLKS/J Lepdb mice.
- This accelerated model exhibits key DKD pathologies and dysfunction within 3 weeks.
- The developed model is suitable for evaluating the efficacy of potential DKD therapeutic interventions.
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