Sodium glucose co-transporter 2 inhibition increases epidermal growth factor expression and improves outcomes in patients with type 2 diabetes

Taha Sen; Wenjun Ju; Viji Nair; Patricia Ladd; Rajasree Menon; Edgar A Otto; Laura Pyle; Tim Vigers; Robert G Nelson; Clare Arnott; Bruce Neal; Michael K Hansen; Matthias Kretzler; Petter Bjornstad; Hiddo J L Heerspink

doi:10.1016/j.kint.2023.07.007

Sodium glucose co-transporter 2 inhibition increases epidermal growth factor expression and improves outcomes in patients with type 2 diabetes

Kidney Int. 2023 Oct;104(4):828-839. doi: 10.1016/j.kint.2023.07.007. Epub 2023 Aug 4.

Authors

Taha Sen¹, Wenjun Ju², Viji Nair³, Patricia Ladd⁴, Rajasree Menon², Edgar A Otto³, Laura Pyle⁵, Tim Vigers⁵, Robert G Nelson⁶, Clare Arnott⁷, Bruce Neal⁸, Michael K Hansen⁹, Matthias Kretzler¹⁰, Petter Bjornstad¹¹, Hiddo J L Heerspink¹²

Affiliations

¹ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
² Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
³ Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁴ Department of Radiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
⁵ Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA; Section of Endocrinology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
⁶ Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA.
⁷ The George Institute for Global Health, University New South Wales (UNSW), Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
⁸ The George Institute for Global Health, University New South Wales (UNSW), Sydney, New South Wales, Australia.
⁹ Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
¹⁰ Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: kretzler@med.umich.edu.
¹¹ Section of Endocrinology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA; Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Electronic address: Petter.M.Bjornstad@cuanschutz.edu.
¹² Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; The George Institute for Global Health, University New South Wales (UNSW), Sydney, New South Wales, Australia. Electronic address: h.j.lambers.heerspink@umcg.nl.

PMID: 37543256
DOI: 10.1016/j.kint.2023.07.007

Abstract

Underlying molecular mechanisms of the kidney protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors are not fully elucidated. Therefore, we studied the association between urinary epidermal growth factor (uEGF), a mitogenic factor involved in kidney repair, and kidney outcomes in patients with type 2 diabetes (T2D). The underlying molecular mechanisms of the SGLT2 inhibitor canagliflozin on EGF using single-cell RNA sequencing from kidney tissue were examined. Urinary EGF-to-creatinine ratio (uEGF/Cr) was measured in 3521 CANagliflozin cardioVascular Assessment Study (CANVAS) participants at baseline and week 52. Associations of uEGF/Cr with kidney outcome were assessed using multivariable-adjusted Cox regression models. Single-cell RNA sequencing was performed using protocol kidney biopsy tissue from ten young patients with T2D on SGLT2i, six patients with T2D on standard care only, and six healthy controls (HCs). In CANVAS, each doubling in baseline uEGF/Cr was associated with a 12% (95% confidence interval 1-22) decreased risk of kidney outcome. uEGF/Cr decreased after 52 weeks with placebo and remained stable with canagliflozin (between-group difference +7.3% (2.0-12.8). In young persons with T2D, EGF mRNA was primarily expressed in the thick ascending loop of Henle. Expression in biopsies from T2D without SGLT2i was significantly lower compared to HCs, whereas treatment with SGLT2i increased EGF levels closer to the healthy state. In young persons with T2D without SGLT2i, endothelin-1 emerged as a key regulator of the EGF co-expression network. SGLT2i treatment was associated with a shift towards normal EGF expression. Thus, decreased uEGF represents increased risk of kidney disease progression in patients with T2D. Canagliflozin increased kidney tissue expression of EGF and was associated with a downstream signaling cascade linked to tubular repair and reversal of tubular injury.

Trial registration: ClinicalTrials.gov NCT01032629.

Keywords: EGF; RNA sequencing; SGTL2; canagliflozin; mRNA; type 2 diabetes.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Canagliflozin / pharmacology
Canagliflozin / therapeutic use
Cardiovascular Diseases* / drug therapy
Diabetes Mellitus, Type 2* / complications
Epidermal Growth Factor / genetics
Glucose
Humans
Sodium / metabolism
Sodium-Glucose Transporter 2 / genetics
Sodium-Glucose Transporter 2 / metabolism
Sodium-Glucose Transporter 2 Inhibitors* / pharmacology
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use

Substances

Canagliflozin
Epidermal Growth Factor
Glucose
Sodium
Sodium-Glucose Transporter 2
Sodium-Glucose Transporter 2 Inhibitors

Associated data

ClinicalTrials.gov/NCT01032629

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding