Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models.

Philipp Tauber,Wolfram Gronwald,Michaela Kuhn,Katja Dettmer,Stefan Wagner,Lars S Maier,Frank Schweda,Maximilian Trum,Frederick Sinha,Raffaela S Berger

doi:10.3389/fphar.2021.761855

Philipp Tauber, Wolfram Gronwald + Show 8 more

Open Access

https://doi.org/10.3389/fphar.2021.761855

Copy DOI

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.

Highlights

Over the last years, inhibitors of the renal sodium-glucose transporter SGLT2, a new class of antidiabetic drugs, have demonstrated their beneficial effect on the progression of diabetic nephropathy in several large-scale clinical outcome trials (Zinman et al, 2015; Wanner et al, 2016; Neal et al, 2017; Wiviott et al, 2019)
This effect was blunted in EMPA treated animals, in which hyperfiltration in response to unilateral nephrectomy (UNx) was significantly reduced compared with H2O treated UNx animals (65 vs. 41% glomerular filtration rate (GFR) increase, Figure 2A)
Histological examination of renal slices did not reveal any signs of enhanced fibrosis in response to UNx and EMPA did not have any effect on kidney histology and fibrosis (Figure 2D)

Summary

Introduction

Inhibitors of the renal sodium-glucose transporter SGLT2, a new class of antidiabetic drugs, have demonstrated their beneficial effect on the progression of diabetic nephropathy in several large-scale clinical outcome trials (Zinman et al, 2015; Wanner et al, 2016; Neal et al, 2017; Wiviott et al, 2019). Since these initial clinical trials were conducted exclusively in patients with type II diabetes, it remained unclear whether the nephroprotective effects due to SGLT2 inhibition could be translated to non-diabetic chronic kidney disease (CKD). The immediate reduction in diabetic glomerular hyperfiltration appears to be a common event in patients on SGLT2 inhibitors and is likely critical for longterm maintenance of GFR and prevention of progressive kidney damage (Kohan et al, 2016; Wanner et al, 2016; Perkovic et al, 2018; Perkovic et al, 2019)

Objectives

Methods

Results

Conclusion