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Kidney Week

Abstract: PO0659

Impact of Mineralocorticoid Receptor Antagonism in a New Model of Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Palacios Ramirez, Roberto, INSERM, Paris, Île-de-France, France
  • Lima Posada, Ixchel Quetzaliztli, INSERM, Paris, Île-de-France, France
  • Bonnard, Benjamin, INSERM, Paris, Île-de-France, France
  • Genty, Marie, INSERM, Paris, Île-de-France, France
  • Hartleib-Geschwindner, Judith, AstraZeneca, Gothenburg, Sweden, Gothenburg, Västergötland and Bohuslän, Sweden
  • Foufelle, Fabienne, INSERM, Paris, Île-de-France, France
  • Bamberg, Krister, AstraZeneca, Gothenburg, Sweden, Gothenburg, Västergötland and Bohuslän, Sweden
  • Jaisser, Frederic, INSERM, Paris, Île-de-France, France
Background

Diabetic kidney disease (DKD ) is the most prevalent form of chronic kidney disease and is associated with cardiovascular diseases. Several studies reported beneficial effects of mineralocorticoid receptor (MR) antagonists in DKD, indicating the importance of aldosterone/MR axis in this pathology.
To study the metabolic and renal alterations in a new model of DKD and explore the effect of the MR antagonist canrenoate.

Methods

Sham or 5/6 nephrectomy was performed in 6 weeks old C57Bl6J mice. After nephrectomy (Nx) mice were randomly assigned to chow diet (Sham), Nx, 60% fat diet (Nx-HFD) and 60% fat diet + 30 mg/kg/day canrenoate (Nx-HFD-CAN). Glycated hemoglobin (HbA1c) and glucose tolerance (ipGTT) were analyzed after 6 weeks. We evaluated plasma levels of leptin and albuminuria and IL-10 mRNA levels. RNA Nanostring analysis was performed in kidney samples. In vitro studies were performed in renal fibroblasts.

Results

HbAc1 was higher in the Nx-HFD group vs Sham or Nx, an effect prevented by canrenoate (see table). The glucose tolerance was impaired in NX-HFD vs Sham or Nx, an effect ameliorated by canrenoate. Kidney fibrosis was increased in Nx HFD group vs Sham or Nx and it was lower in the canrenoate treated group. Nanostring analysis highlighted the impact of canrenoate on inflammation, fibrosis and proliferation pathways. We found high plasma leptin and kidney IL-10 mRNA levels in the Nx-HFD mice which were lower after canrenoate treatment. The profibrotic effect of leptin observed in renal fibroblasts was mediated by IL-10 (Col1 mRNA levels: Ctl: 0.99±0.03, leptin + IgG: 1.19±0.07*#, leptin + anti-IL10 antibody: 0.90±0.05#, n= 6, p<0.05 * vs Ctrl; # vs Leptin+IgG).

Conclusion

MR antagonism improves metabolic and kidney derangements associated with DKD. The upregulation of leptin/IL-10 signalling observed in this DKD model may contribute to the renal fibrosis.

 Sham (n=7)Nx (n=9)Nx-HFD (n=9)Nx-HFD-CAN (n=9)
HbAc1
(%)
4.32±0.154.2±0.194.57±0.06*4.07±0.14+
GTT AUC1556±341476±72*2443±198*1861±75+
Albuminuria
(mg/24h)
15.0±0.723.3±5.034.0±5.5*22.3±2.7*+
Fibrosis
(relative value vs Sham)
1.03±0.280.96±0.153.0±0.68*1.15±0.18+
Plasma leptin
(log(pg/ml))
2.4±0.332.15±0.063.59±0.26#2.89±0.13+
IL10 mRNA levels
(relative expression vs Sham)
1.0±0.101.12±0.114.21±0.35*#1.03±0.05+

p<0.05 * vs Sham; # vs NX; + vs NX HFD

Funding

  • Commercial Support