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Updated: Oct 7, 2025
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in
Philipp Tauber1, Frederick Sinha1, Raffaela S Berger2
1Institute of Physiology, University of Regensburg, Regensburg, Germany.
Abstract:
Large-scale clinical outcome studies demonstrated the efficacy of SGLT2 inhibitors in patients with type II diabetes. Besides their therapeutic efficacy in diabetes, significant renoprotection was observed in non-diabetic patients with chronic kidney disease (CKD), suggesting the existence of glucose-independent beneficial effects of SGLT2 inhibitors. However, the relevant mechanisms by which SGLT2 inhibition delays the progression of renal injury are still largely unknown and speculative. Previous studies showed that SGLT2 inhibitors reduce diabetic hyperfiltration, which is likely a key element in renoprotection. In line with this hypothesis, this study aimed to investigate the nephroprotective effects of the SGLT2 inhibitor empagliflozin (EMPA) in different mouse models with non-diabetic hyperfiltration and progressing CKD to identify the underlying diabetes-independent cellular mechanisms. Non-diabetic hyperfiltration was induced by unilateral nephrectomy (UNx). Since UNx alone does not result in renal damage, renal disease models with varying degrees of glomerular damage and albuminuria were generated by combining UNx with high NaCl diets ± deoxycorticosterone acetate (DOCA) in different mouse strains with and without genetic predisposition for glomerular injury. Renal parameters (GFR, albuminuria, urine volume) were monitored for 4-6 weeks. Application of EMPA via the drinking water resulted in sufficient EMPA plasma concentration and caused glucosuria, diuresis and in some models renal hypertrophy. EMPA had no effect on GFR in untreated wildtype animals, but significantly reduced hyperfiltration after UNx by 36%. In contrast, EMPA did not reduce UNx induced hyperfiltration in any of our kidney disease models, regardless of their degree of glomerular damage caused by DOCA/salt treatment. Consistent with the lack of reduction in glomerular hyperfiltration, EMPA-treated animals developed albuminuria and renal fibrosis to a similar extent as H2O control animals. Taken together, the data clearly indicate that blockade of SGLT2 has the potential to reduce non-diabetic hyperfiltration in otherwise untreated mice. However, no effects on hyperfiltration or progression of renal injury were observed in hypervolemic kidney disease models, suggesting that high salt intake and extracellular volume might attenuate the protective effects of SGLT2 blockers.
Insights
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced hyperfiltration in mice without diabetes. However, empagliflozin did not protect against kidney disease progression in models with high salt intake, suggesting volume overload may limit SGLT2 inhibitor efficacy.
Area of Science:
- Nephrology
- Pharmacology
- Endocrinology
Background:
- SGLT2 inhibitors show renoprotective effects beyond diabetes management.
- Glucose-independent mechanisms for SGLT2 inhibitor efficacy in chronic kidney disease (CKD) are not fully understood.
- Hyperfiltration is implicated in CKD progression and may be a target for SGLT2 inhibitors.
Purpose of the Study:
- To investigate the nephroprotective effects of empagliflozin (EMPA) in non-diabetic mouse models of hyperfiltration and CKD.
- To identify potential diabetes-independent cellular mechanisms of SGLT2 inhibition.
- To assess the impact of EMPA on hyperfiltration and renal injury progression under varying conditions.
Main Methods:
- Non-diabetic hyperfiltration induced by unilateral nephrectomy (UNx) in mice.
- Renal disease models created by combining UNx with high salt diets ± deoxycorticosterone acetate (DOCA).
- Monitoring of glomerular filtration rate (GFR), albuminuria, and urine volume over 4-6 weeks; EMPA administered via drinking water.
Main Results:
- EMPA significantly reduced hyperfiltration by 36% after UNx in otherwise healthy mice.
- EMPA failed to reduce hyperfiltration in kidney disease models with high salt/DOCA treatment.
- Albuminuria and renal fibrosis progressed similarly in EMPA-treated and control groups in disease models.
Conclusions:
- SGLT2 inhibition can reduce non-diabetic hyperfiltration in the absence of significant renal injury.
- Hypervolemia and high salt intake may attenuate the renoprotective effects of SGLT2 inhibitors.
- Further research is needed to elucidate the role of extracellular volume in mediating SGLT2 inhibitor efficacy in CKD.
