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Abstract: PO0668

Contribution of Proximal Tubular ADAM17 in a Pre-Diabetic Mouse Model

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Palau, Vanesa, Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Catalunya, Spain
  • Calle, Sofia Villanueva, Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Catalunya, Spain
  • Jarrín, Javier Josué, Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Catalunya, Spain
  • Márquez, Eva, Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Catalunya, Spain
  • Rodriguez, Eva, Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Catalunya, Spain
  • Crespo, Marta, Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Catalunya, Spain
  • Soler, Maria Jose, Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Catalunya, Spain
  • Pascual, Julio, Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Catalunya, Spain
  • Barrios, Clara, Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Catalunya, Spain
  • Riera, Marta, Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Catalunya, Spain
Background

Both acute and chronic kidney lesions induce an increase in ADAM17 that cleaves several transmembrane proteins, among them molecules related to inflammatory and fibrotic pathways. Our group demonstrated that in experimental type 1 diabetes, inhibition of ADAM17 decreases inflammation and renal fibrosis. Indeed, this protease is proposed as a possible therapeutic tool for the treatment of kidney disease. However, its role in pre-diabetic stages has not been fully analyzed.

Methods

In a knockout mouse model for tubular ADAM17 fed with high-fat diet (HFD), we determined glycemia, glucose tolerance, body weight, hypertrophy and mesangial expansion (PAS staining) and the number of podocytes (immunohistochemistry), after 25 weeks of a follow-up (n = 15 WT, n = 15 KO).

Results

Wild-type (WT) mice on HFD had higher body weight and higher glycaemia with dysregulation of glucose homeostasis compared to mice on standard diet (SD). At the glomerular level, WT mice with HFD had greater glomerular size and mesangial expansion. In contrast, the deletion of ADAM17 in the proximal tubular cell improved glucose tolerance and protected against glomerular injury. The loss of podocytes observed in WT mice with HFD was not observed in HFD-mice with deletion of ADAM17 (see table).

Conclusion

The conditional knockout of ADAM17 at the proximal tubule level improves glucose tolerance and reduces kidney lesions typically observed in diabetes such as glomerular hypertrophy, mesangial expansion and podocytes loss, in a murine model with high-fat diet that mimics pre-diabetes. ADAM17 may therefore have an inducing role in pre-diabetic kidney injury.

 Body Weight (g)3h-fasting blood glucose (mg/dL)Glucose tolerance test (mg/dL)WT-1 staining (podocyte number)Mesangial Area (μm2)Glomerular tuft Area (μm2)
ADAM17WT - SD34,01±0,81191,91±4,12155,75±7,209,74±0,561212,24±83,782653,06±198,82
ADAM17WT - HFD53,18±0,65*236,63±10,04*435,25±36,06*7,25±0,18*1516,18±115,29*3332,01±237,49*
ADAM17KO -SD37,22±1,46199,13±5,94221,71±22,21$10,45±0,631323,22±78,62996,17±187,55
ADAM17KO -HFD54,3±3,01*218,63±13,62241,17±9,74$8,6±0,45*$1403,19±72,363274,29±164,66
       

*p<0,05 HFD vs. SD $p<0,05 KO vs. WT