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SGLT2 inhibition promotes glomerular repopulation by cells of renin lineage in experimental kidney disease

Loïs A K van der Pluijm1, Angela Koudijs1, Wendy Stam1

  • 1Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Centre, Leiden, the Netherlands.

Acta Physiologica (Oxford, England)
|February 5, 2024
PubMed
Abstract

Insights

Sodium glucose co-transporter-2 (SGLT2) inhibitors promote kidney cell repopulation by juxtaglomerular cells of renin lineage (CoRL). This effect is selective, depending on the type of kidney injury, and may explain SGLT2 inhibitors' renoprotective benefits.

Area of Science:

  • Nephrology
  • Cell Biology
  • Pharmacology

Background:

  • Sodium glucose co-transporter-2 (SGLT2) inhibitors are known for renal protective effects in chronic kidney disease (CKD) and acute kidney injury (AKI).
  • The precise mechanism underlying these renoprotective effects remains incompletely understood.
  • Juxtaglomerular cells of renin lineage (CoRL) are identified as progenitor cells for various glomerular cell types in kidney disease.

Purpose of the Study:

  • To investigate the impact of SGLT2 inhibition on glomerular cell repopulation by CoRL.
  • To examine the phenotypic commitment of CoRL-derived cells under SGLT2 inhibition in different kidney injury models.

Main Methods:

  • Experiments utilized Ren1cre-tdTomato lineage-trace mice subjected to 5/6 nephrectomy (5/6NX) for CKD or bilateral ischemia reperfusion injury (bIRI) for AKI.
  • Mice received daily oral administration of the SGLT2 inhibitor empagliflozin (10 mg/kg) for 14 days.
  • Changes in glomerular cell populations and kidney function were assessed.

Main Results:

  • Both 5/6NX and bIRI increased glomerular CoRL-derived cells. SGLT2 inhibition improved kidney function and reduced glomerulosclerosis in 5/6NX models but not in bIRI models.
  • Empagliflozin increased the number of CoRL-derived glomerular cells in both injury models.
  • SGLT2 inhibition promoted CoRL-derived podocytes in 5/6NX and increased parietal epithelial and mesangial cells in bIRI models.

Conclusions:

  • SGLT2 inhibition via empagliflozin enhances CoRL-mediated glomerular repopulation.
  • The specific cell types repopulated by CoRL are dependent on the nature of the experimental kidney injury.
  • These findings suggest a novel mechanism for the renoprotective action of SGLT2 inhibitors involving selective glomerular cell regeneration.
Keywords:
RAASSGLT2 inhibitioncells of renin lineagekidney repairprogenitorregeneration

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