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Kidney Week

Abstract: PO0719

MAP17 and D-AKAP-2, Two Major Scaffolder Proteins, Are Upregulated in Experimental Diabetic Nephropathy in Response to Empagliflozin on Top of RAS Blockade

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Vergara, Ander, Nephrology and transplantation group. Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
  • Molina Van den Bosch, Mireia, Nephrology and transplantation group. Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
  • Domínguez Báez, Pamela, Nephrology and transplantation group. Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
  • Rettel, Mandy, Proteomics Core Facility. European Molecular Biology Laboratory., Heidelberg, Germany
  • Stein, Frank, Proteomics Core Facility. European Molecular Biology Laboratory., Heidelberg, Germany
  • Benito, Begoña, Cardiology group. Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
  • Bermejo, Sheila, Nephrology and transplantation group. Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
  • Jacobs Cachá, Conxita, Nephrology and transplantation group. Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
  • Soler, Maria Jose, Nephrology and transplantation group. Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
Background

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have proven to delay diabetic nephropathy (DN) progression on top of the standard of care renin-angiotensin system (RAS) blockade. This protection is mostly attributed to improvement in renal hemodynamics although direct effects on the kidney cannot be ruled out. Further, the molecular mechanisms underlying the synergic effect of SGLT2i and RAS blockers is unknown.

Methods

12 weeks old diabetic db/db mice were given empagliflozin (10mg/Kg/day), ramipril (8 mg/Kg/day) or the combination of both drugs during 8 weeks. Vehicle treated db/db and db/m mice were used as controls. Serum glucose, blood pressure, GFR and albuminuria were measured at baseline and at the end of study. At the end of the experiment, mice were euthanized and the kidneys were saved to perform a differential high-throughput proteomic analysis by mass spectrometry using isobaric tandem mass tags (TMT labelling).

Results

Vehicle db/db mice showed increased glycaemia during the whole experiment and empagliflozin normalized blood glucose. Ramipril treatment decreased blood pressure. Diabetic vehicle mice showed incipient DN, mesangial expansion and albuminuria were significantly increased when compared to their non-diabetic littermates. All the treatments reduced mesangial expansion and albuminuria. The differential proteomic analysis revealed 207 proteins differentially expressed in one or more experimental groups (FDR < 0.05 and Log FC>1); among them MAP17 and D-AKAP-2 were upregulated in the kidney of the db/db treated with empagliflozin with ramipril. We validated these findings by western blot.

Conclusion

The combined therapy of empagliflozin with ramipril upregulated both MAP17 and D-AKAP-2 in the kidney of a diabetic mice model. MAP17 and D-AKAP-2 are two major scaffolding proteins found in the proximal tubular cells that place transporters together such as SGLT2 and NHE3 and also regulate the function of protein kinase A (PKA) which in turns inactivates NHE3 by phosphorylation. Our results suggest that SGLT2i on top of RAS blockade may protect the kidney by boosting the inactivation of NHE3 via the upregulation of key scaffolder proteins such as MAP17 and D-AKAP-2.

Funding

  • Commercial Support