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Abstract: FR-PO353

SGLT2 Inhibition Reveals Kidney Reconfiguration and Metabolic Interorgan Communication

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic


  • Billing, Anja M., Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Kim, Young Chul, University of California San Diego, La Jolla, California, United States
  • Vallon, Volker, University of California San Diego, La Jolla, California, United States
  • Rinschen, Markus M., Aarhus Universitet, Aarhus, Midtjylland, Denmark

SGLT2 inhibitors, originally employed for hyperglycemia management, exhibit protective effects against renal and cardiovascular complications, irrespective of diabetes presence. The precise molecular mechanisms underlying these effects remain largely unknown and cannot be solely attributed to their primary function of inhibiting renal glucose re-absorption.


To gain insights into these mechanisms, we employed LC-MS/MS to investigate various aspects, including the proteome, phosphoproteome, gut metaproteome, metabolome, and SGLT2 interactome. For proteomics/phosphoproteomics analysis, we used TMT16-plex labeling or label-free approaches with an Exploris 480 mass spectrometer (Thermo Fisher Scientific) connected to an UltiMate3000 RSLC (Thermo Fisher Scientific) system. For untargeted metabolomics, we utilized a quadrupole time-of-flight Impact II instrument (Bruker) connected to either a Bruker Elute HPLC or an Agilent 1290 infinity HPLC device. Targeted metabolomics was conducted using a 6495C triple-quadrupole coupled to an Agilent 1290 Infinity HPLC.


We performed an extensive analysis of the proteome, phosphoproteome, and metabolome following one week of SGLT2 inhibitor treatment in non-diabetic and early diabetic mice. We integrated data from multiple metabolic organs and body fluids, including the kidney, liver, heart, white adipose tissue, skeletal muscle, plasma, urine, and gut microbiota. The kidney exhibited the strongest and most significant response to SGLT2 inhibitors in terms of metabolic signaling and transporter reconfiguration. Additionally, the gut microbiome displayed a reduction in bacteria taxa capable of fermenting phenylalanine and tryptophan, resulting in lower plasma levels of uremic toxins. Among the most prominently affected metabolites was p-cresol sulfate, a finding confirmed in cohort studies involving diabetic and heart failure patients with reduced ejection fraction.


The metabolic communication facilitated by SGLT2 inhibitors reduced the presence of circulating waste products such as p-cresol sulfate, consequently reducing the need for renal detoxification. This, combined with decreased glucotoxicity in the proximal tubules and a broad downregulation of apical transport activity, provides a metabolic explanation for the kidney and cardiovascular protection observed.


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