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Updated: Apr 16, 2026
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Relaxin-2 does not ameliorate nephropathy in an experimental model of type-1 diabetes
Background/Aims:
In diabetic nephropathy (DN), the current angiotensin-II-blocking pharmacotherapy is frequently failing. For diabetic cardiomyopathy (DC), there is no specific remedy available. Relaxin-2 (Rlx) - an anti-fibrotic, anti-inflammatory, and vasoprotecting peptide – is a candidate drug for both.
Methods:
Low-dose (32 μg/kg/day) and high-dose (320 μg/kg/day) Rlx were tested against vehicle (n = 20 each) and non-diabetic controls (n = 14) for 12 weeks in a model of type-1 diabetes induced in endothelial nitric oxide synthase knock-out (eNOS-KO) mice by intraperitoneal injection of streptozotocin.
Results:
Diabetic animals showed normal plasma creatinine, markedly increased albuminuria and urinary malonyldialdehyde, elevated relative kidney weight, glomerulosclerosis, and increased glomerular size, but no relevant interstitial fibrosis. Neither dose of Rlx affected these changes although the drug was active and targeted plasma levels were achieved. Of note, we found no activation of the renal TGF-β pathway in this model. In the hearts of diabetic animals, no fibrotic alterations indicative of DC could be determined which precluded testing of the initial hypothesis.
Conclusions:
We investigated a model showing early DN without overt tubulointerstitial fibrosis and activation of the TGF-β-Smad-2/3 pathway. In this model, Rlx proved ineffective; however, the same may not apply to other models and types of diabetes.
Insights
Relaxin-2 (Rlx) did not improve early diabetic nephropathy (DN) in mice lacking endothelial nitric oxide synthase. This study suggests Rlx may not be effective for DN without significant fibrosis or specific pathway activation.
Area of Science:
- Nephrology
- Cardiology
- Endocrinology
Background:
- Diabetic nephropathy (DN) and diabetic cardiomyopathy (DC) lack effective treatments.
- Current therapies for DN are often insufficient.
- Relaxin-2 (Rlx) is a potential therapeutic peptide with anti-fibrotic, anti-inflammatory, and vasoprotective properties.
Purpose of the Study:
- To evaluate the efficacy of Relaxin-2 (Rlx) in a mouse model of early diabetic nephropathy (DN) and diabetic cardiomyopathy (DC).
- To assess Rlx's impact on renal and cardiac pathology in a type-1 diabetes model.
Main Methods:
- Type-1 diabetes was induced in endothelial nitric oxide synthase knock-out (eNOS-KO) mice using streptozotocin.
- Mice received low-dose (32 μg/kg/day) or high-dose (320 μg/kg/day) Rlx, vehicle, or served as non-diabetic controls for 12 weeks.
- Renal and cardiac tissues were analyzed for fibrosis, glomerulosclerosis, and other pathological markers. Plasma creatinine, albuminuria, and urinary malonyldialdehyde were measured.
Main Results:
- Diabetic mice exhibited increased albuminuria, urinary malonyldialdehyde, kidney weight, glomerulosclerosis, and glomerular size, but no significant interstitial fibrosis.
- Neither low-dose nor high-dose Rlx treatment altered these diabetic changes.
- No activation of the renal TGF-β pathway was observed in this model. Cardiac tissue showed no fibrotic alterations indicative of DC.
Conclusions:
- Relaxin-2 (Rlx) was ineffective in this model of early DN characterized by minimal fibrosis and absent TGF-β pathway activation.
- The findings suggest Rlx may not be suitable for treating DN in its early stages or in models lacking specific fibrotic pathways.
- Further research is needed to determine Rlx's efficacy in different diabetes models and stages of disease.
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