Combined SGLT2 and DPP4 Inhibition Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Nephropathy in Mice with Type 2 Diabetes

Yochai Birnbaum, Mandeep Bajaj, Hsiu Chiung Yang, Yumei Ye

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Bacground: Sodium–glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors (DPP4I) are used to treat type 2 diabetes (T2DM). DPP4 inhibitors (DPP4) attenuate Nlrp3 inflammasome activation in the kidney. SGLT2 inhibition reduces inflammation and attenuates the progression of diabetic nephropathy (DN). The effects of dapagliflozin (Dapa) on the activation of the Nlrp3 inflammasome and the combined effect of SGLT2 and DPP4 on T2DM-induced inflammasome activation and progression of DN have not been previously studied. We assessed whether Dapa attenuates the inflammasome activation and progression of DN in T2DM mice and whether these effects can be augmented by adding DPP4I saxagliptin (Saxa). Methods and Results: Male BTBR ob/ob and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Serum BUN in the WT mice was 16.9 ± 0.8 mg/dl. It increased to 55.7 ± 2.8 mg/dl in the BTBR mice. Dapa alone reduced BUN to 31.4 ± 1.2 mg/dl. A greater effect was seen in the Dapa+Saxa combination (24.8 ± 0.8 mg/dl). Serum creatinine was 0.16 ± 0.02 and 1.01 ± 0.04 mg/dl in the WT and BTBR mice, respectively. Dapa and Dapa+Saxa attenuated the increase of creatinine to 0.65 ± 0.02 and 0.40 ± 0.03 mg/dl, respectively. Serum cystatin C was elevated in the BTBR mice (3.9 ± 0.1 vs. 0.6 ± 0.2 ng/ml) as compared to WT mice. Dapa (2.4 ± 0.1) and Dapa+Saxa (1.4 ± 0.1) attenuated this increase. Kidney weight was higher in the BTBR than that of WT mice. Dapa reduced the kidney/body weight ratio in the BTBR mice. Dapa+Saxa tended to have greater effect, but the difference was not significant. mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, TNF-α, collagen-1, and collagen-3 significantly increased in the kidneys of the BTBR compared to the WT mice. Dapa alone and to a greater extent, Dapa+Saxa, attenuated the activation of the inflammasome. Yet, the combination did not result in greater attenuation of the collagen-1 and collagen-3 mRNA levels. The P-AMPK/total AMPK ratio was lower in the BTBR mice than in the WT mice. Dapa and Dapa+ Saxa equally increased the ratio. Conclusions: Dapa attenuates T2DM-induced activation of the inflammasome and progression of DN in BTBR ob/ob mice. Adding Saxa to Dapa augmented attenuation of the inflammasome, but had no significant effect on kidney weight or collagen-1 and collagen-3 mRNA levels. Future clinical trials are necessary to study the effect of combined SGLT2 inhibitor and incretin therapy on renal outcomes in patients with T2DM.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalCardiovascular Drugs and Therapy
DOIs
StateAccepted/In press - Mar 5 2018

Fingerprint

Inflammasomes
Diabetic Nephropathies
Type 2 Diabetes Mellitus
Collagen
Kidney
Dipeptidyl-Peptidase IV Inhibitors
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
AMP-Activated Protein Kinases
Blood Urea Nitrogen
Messenger RNA
Creatinine
Serum
Incretins
saxagliptin
Cystatin C
Weights and Measures
Caspase 1

Keywords

  • AMPK
  • Diabetic nephropathy
  • Inflammasome
  • SGLT2
  • Type 2 diabetes

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

Cite this

@article{4e2fa3a88fa548b9b33c07738e6be4a6,
title = "Combined SGLT2 and DPP4 Inhibition Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Nephropathy in Mice with Type 2 Diabetes",
abstract = "Bacground: Sodium–glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors (DPP4I) are used to treat type 2 diabetes (T2DM). DPP4 inhibitors (DPP4) attenuate Nlrp3 inflammasome activation in the kidney. SGLT2 inhibition reduces inflammation and attenuates the progression of diabetic nephropathy (DN). The effects of dapagliflozin (Dapa) on the activation of the Nlrp3 inflammasome and the combined effect of SGLT2 and DPP4 on T2DM-induced inflammasome activation and progression of DN have not been previously studied. We assessed whether Dapa attenuates the inflammasome activation and progression of DN in T2DM mice and whether these effects can be augmented by adding DPP4I saxagliptin (Saxa). Methods and Results: Male BTBR ob/ob and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Serum BUN in the WT mice was 16.9 ± 0.8 mg/dl. It increased to 55.7 ± 2.8 mg/dl in the BTBR mice. Dapa alone reduced BUN to 31.4 ± 1.2 mg/dl. A greater effect was seen in the Dapa+Saxa combination (24.8 ± 0.8 mg/dl). Serum creatinine was 0.16 ± 0.02 and 1.01 ± 0.04 mg/dl in the WT and BTBR mice, respectively. Dapa and Dapa+Saxa attenuated the increase of creatinine to 0.65 ± 0.02 and 0.40 ± 0.03 mg/dl, respectively. Serum cystatin C was elevated in the BTBR mice (3.9 ± 0.1 vs. 0.6 ± 0.2 ng/ml) as compared to WT mice. Dapa (2.4 ± 0.1) and Dapa+Saxa (1.4 ± 0.1) attenuated this increase. Kidney weight was higher in the BTBR than that of WT mice. Dapa reduced the kidney/body weight ratio in the BTBR mice. Dapa+Saxa tended to have greater effect, but the difference was not significant. mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, TNF-α, collagen-1, and collagen-3 significantly increased in the kidneys of the BTBR compared to the WT mice. Dapa alone and to a greater extent, Dapa+Saxa, attenuated the activation of the inflammasome. Yet, the combination did not result in greater attenuation of the collagen-1 and collagen-3 mRNA levels. The P-AMPK/total AMPK ratio was lower in the BTBR mice than in the WT mice. Dapa and Dapa+ Saxa equally increased the ratio. Conclusions: Dapa attenuates T2DM-induced activation of the inflammasome and progression of DN in BTBR ob/ob mice. Adding Saxa to Dapa augmented attenuation of the inflammasome, but had no significant effect on kidney weight or collagen-1 and collagen-3 mRNA levels. Future clinical trials are necessary to study the effect of combined SGLT2 inhibitor and incretin therapy on renal outcomes in patients with T2DM.",
keywords = "AMPK, Diabetic nephropathy, Inflammasome, SGLT2, Type 2 diabetes",
author = "Yochai Birnbaum and Mandeep Bajaj and Yang, {Hsiu Chiung} and Yumei Ye",
year = "2018",
month = "3",
day = "5",
doi = "10.1007/s10557-018-6778-x",
language = "English (US)",
pages = "1--11",
journal = "Cardiovascular Drugs and Therapy",
issn = "0920-3206",
publisher = "Kluwer Academic Publishers",

}

TY - JOUR

T1 - Combined SGLT2 and DPP4 Inhibition Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Nephropathy in Mice with Type 2 Diabetes

AU - Birnbaum, Yochai

AU - Bajaj, Mandeep

AU - Yang, Hsiu Chiung

AU - Ye, Yumei

PY - 2018/3/5

Y1 - 2018/3/5

N2 - Bacground: Sodium–glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors (DPP4I) are used to treat type 2 diabetes (T2DM). DPP4 inhibitors (DPP4) attenuate Nlrp3 inflammasome activation in the kidney. SGLT2 inhibition reduces inflammation and attenuates the progression of diabetic nephropathy (DN). The effects of dapagliflozin (Dapa) on the activation of the Nlrp3 inflammasome and the combined effect of SGLT2 and DPP4 on T2DM-induced inflammasome activation and progression of DN have not been previously studied. We assessed whether Dapa attenuates the inflammasome activation and progression of DN in T2DM mice and whether these effects can be augmented by adding DPP4I saxagliptin (Saxa). Methods and Results: Male BTBR ob/ob and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Serum BUN in the WT mice was 16.9 ± 0.8 mg/dl. It increased to 55.7 ± 2.8 mg/dl in the BTBR mice. Dapa alone reduced BUN to 31.4 ± 1.2 mg/dl. A greater effect was seen in the Dapa+Saxa combination (24.8 ± 0.8 mg/dl). Serum creatinine was 0.16 ± 0.02 and 1.01 ± 0.04 mg/dl in the WT and BTBR mice, respectively. Dapa and Dapa+Saxa attenuated the increase of creatinine to 0.65 ± 0.02 and 0.40 ± 0.03 mg/dl, respectively. Serum cystatin C was elevated in the BTBR mice (3.9 ± 0.1 vs. 0.6 ± 0.2 ng/ml) as compared to WT mice. Dapa (2.4 ± 0.1) and Dapa+Saxa (1.4 ± 0.1) attenuated this increase. Kidney weight was higher in the BTBR than that of WT mice. Dapa reduced the kidney/body weight ratio in the BTBR mice. Dapa+Saxa tended to have greater effect, but the difference was not significant. mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, TNF-α, collagen-1, and collagen-3 significantly increased in the kidneys of the BTBR compared to the WT mice. Dapa alone and to a greater extent, Dapa+Saxa, attenuated the activation of the inflammasome. Yet, the combination did not result in greater attenuation of the collagen-1 and collagen-3 mRNA levels. The P-AMPK/total AMPK ratio was lower in the BTBR mice than in the WT mice. Dapa and Dapa+ Saxa equally increased the ratio. Conclusions: Dapa attenuates T2DM-induced activation of the inflammasome and progression of DN in BTBR ob/ob mice. Adding Saxa to Dapa augmented attenuation of the inflammasome, but had no significant effect on kidney weight or collagen-1 and collagen-3 mRNA levels. Future clinical trials are necessary to study the effect of combined SGLT2 inhibitor and incretin therapy on renal outcomes in patients with T2DM.

AB - Bacground: Sodium–glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors (DPP4I) are used to treat type 2 diabetes (T2DM). DPP4 inhibitors (DPP4) attenuate Nlrp3 inflammasome activation in the kidney. SGLT2 inhibition reduces inflammation and attenuates the progression of diabetic nephropathy (DN). The effects of dapagliflozin (Dapa) on the activation of the Nlrp3 inflammasome and the combined effect of SGLT2 and DPP4 on T2DM-induced inflammasome activation and progression of DN have not been previously studied. We assessed whether Dapa attenuates the inflammasome activation and progression of DN in T2DM mice and whether these effects can be augmented by adding DPP4I saxagliptin (Saxa). Methods and Results: Male BTBR ob/ob and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Serum BUN in the WT mice was 16.9 ± 0.8 mg/dl. It increased to 55.7 ± 2.8 mg/dl in the BTBR mice. Dapa alone reduced BUN to 31.4 ± 1.2 mg/dl. A greater effect was seen in the Dapa+Saxa combination (24.8 ± 0.8 mg/dl). Serum creatinine was 0.16 ± 0.02 and 1.01 ± 0.04 mg/dl in the WT and BTBR mice, respectively. Dapa and Dapa+Saxa attenuated the increase of creatinine to 0.65 ± 0.02 and 0.40 ± 0.03 mg/dl, respectively. Serum cystatin C was elevated in the BTBR mice (3.9 ± 0.1 vs. 0.6 ± 0.2 ng/ml) as compared to WT mice. Dapa (2.4 ± 0.1) and Dapa+Saxa (1.4 ± 0.1) attenuated this increase. Kidney weight was higher in the BTBR than that of WT mice. Dapa reduced the kidney/body weight ratio in the BTBR mice. Dapa+Saxa tended to have greater effect, but the difference was not significant. mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, TNF-α, collagen-1, and collagen-3 significantly increased in the kidneys of the BTBR compared to the WT mice. Dapa alone and to a greater extent, Dapa+Saxa, attenuated the activation of the inflammasome. Yet, the combination did not result in greater attenuation of the collagen-1 and collagen-3 mRNA levels. The P-AMPK/total AMPK ratio was lower in the BTBR mice than in the WT mice. Dapa and Dapa+ Saxa equally increased the ratio. Conclusions: Dapa attenuates T2DM-induced activation of the inflammasome and progression of DN in BTBR ob/ob mice. Adding Saxa to Dapa augmented attenuation of the inflammasome, but had no significant effect on kidney weight or collagen-1 and collagen-3 mRNA levels. Future clinical trials are necessary to study the effect of combined SGLT2 inhibitor and incretin therapy on renal outcomes in patients with T2DM.

KW - AMPK

KW - Diabetic nephropathy

KW - Inflammasome

KW - SGLT2

KW - Type 2 diabetes

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DO - 10.1007/s10557-018-6778-x

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JO - Cardiovascular Drugs and Therapy

JF - Cardiovascular Drugs and Therapy

SN - 0920-3206

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