Urinary Angiotensinogen in Patients With Type 1 Diabetes With Microalbuminuria: Gender Differences and Effect of Intensive Insulin Therapy

Jessica Navarro; Alejandro Sanchez; Sheeba H. Ba Aqeel; Minghao Ye; Mohammed Z. Rehman; Jan Wysocki; Alfred Rademaker; Mark E. Molitch; Daniel Batlle

doi:10.1016/j.ekir.2022.09.010

Urinary Angiotensinogen in Patients With Type 1 Diabetes With Microalbuminuria: Gender Differences and Effect of Intensive Insulin Therapy

Jessica Navarro, Alejandro Sanchez, Sheeba H. Ba Aqeel, Minghao Ye, Mohammed Z. Rehman, Jan Wysocki, Alfred Rademaker, Mark E. Molitch, Daniel Batlle^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Introduction: Angiotensinogen (AOG) is the precursor of peptides of the renin angiotensin system (RAS). Because insulin up-regulates transcriptional factors that normally repress kidney AOG synthesis, we evaluated urinary AOG (uAOG) in patients with type 1 diabetes (T1D) and microalbuminuria who are receiving either intensive or conventional insulin therapy. Methods: Urine samples from participants of the Diabetes Control and Complications Trial (DCCT) were used for the following: (i) uAOG/creatinine measurements in 103 patients with microalbuminuria and 103 patients with normoalbuminuria, matched for age, gender, disease duration, and allocation to insulin therapy; and (ii) uAOG/creatinine measurements from patients with microalbuminuria allocated to intensive insulin therapy (n = 58) or conventional insulin therapy (n = 41) after 3 years on each modality. Results: uAOG was higher in patients who started with microalbuminuria than in those with normoalbuminuria (6.65 vs. 4.0 ng/mg creatinine, P < 0.01). uAOG was higher in females than in males with microalbuminuria (11.7 vs. 5.4 ng/mg creatinine, P = 0.015). uAOG was lower in patients with microalbuminuria allocated to intensive insulin therapy than in conventional insulin therapy (3.98 vs. 7.42 ng/mg creatinine, P < 0.01). These differences in uAOG were observed though albumin excretion rate (AER) was not significantly different. Conclusion: In patients with T1D and microalbuminuria, uAOG is increased and varies with gender and the type of insulin therapy independently of AER. This suggests that AOG production is increased in females and it is decreased by intensive insulin therapy. The reduction in uAOG with intensive insulin therapy, by kidney RAS downregulation, may contribute to the known renoprotective action associated with intensive insulin and improved glycemic control.

Original language	English (US)
Pages (from-to)	2657-2667
Number of pages	11
Journal	Kidney International Reports
Volume	7
Issue number	12
DOIs	https://doi.org/10.1016/j.ekir.2022.09.010
State	Published - Dec 2022

Funding

DB and JW are coinventors of patents entitled “Active low molecular weight variants of angiotensin converting enzyme 2 (ACE2),” “Active low molecular weight variants of angiotensin converting enzyme 2 (ACE2) for the treatment of diseases and conditions of the eye,” and “Soluble ACE2 variants and uses therefor.” DB is founder of Angiotensin Therapeutics, Inc. DB received consulting fees from AstraZeneca and Advicenne Inc., all unrelated to this work. During the conduct of these studies, DB received unrelated support from a grant from AstraZeneca and research funding from the Feinberg Foundation. All other authors declare no conflicting interests. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK104785 and by National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant 1R21AI166940-01] as well as by a gift to Northwestern University by the Joseph and Bessie Feinberg Foundation (DB).

Keywords

Type 1 diabetes
albuminuria
angiotensinogen
diabetic kidney disease
renin-angiotensin system

ASJC Scopus subject areas

Nephrology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ekir.2022.09.010

Cite this

@article{064760565527415d8064b72191c0739e,

title = "Urinary Angiotensinogen in Patients With Type 1 Diabetes With Microalbuminuria: Gender Differences and Effect of Intensive Insulin Therapy",

abstract = "Introduction: Angiotensinogen (AOG) is the precursor of peptides of the renin angiotensin system (RAS). Because insulin up-regulates transcriptional factors that normally repress kidney AOG synthesis, we evaluated urinary AOG (uAOG) in patients with type 1 diabetes (T1D) and microalbuminuria who are receiving either intensive or conventional insulin therapy. Methods: Urine samples from participants of the Diabetes Control and Complications Trial (DCCT) were used for the following: (i) uAOG/creatinine measurements in 103 patients with microalbuminuria and 103 patients with normoalbuminuria, matched for age, gender, disease duration, and allocation to insulin therapy; and (ii) uAOG/creatinine measurements from patients with microalbuminuria allocated to intensive insulin therapy (n = 58) or conventional insulin therapy (n = 41) after 3 years on each modality. Results: uAOG was higher in patients who started with microalbuminuria than in those with normoalbuminuria (6.65 vs. 4.0 ng/mg creatinine, P < 0.01). uAOG was higher in females than in males with microalbuminuria (11.7 vs. 5.4 ng/mg creatinine, P = 0.015). uAOG was lower in patients with microalbuminuria allocated to intensive insulin therapy than in conventional insulin therapy (3.98 vs. 7.42 ng/mg creatinine, P < 0.01). These differences in uAOG were observed though albumin excretion rate (AER) was not significantly different. Conclusion: In patients with T1D and microalbuminuria, uAOG is increased and varies with gender and the type of insulin therapy independently of AER. This suggests that AOG production is increased in females and it is decreased by intensive insulin therapy. The reduction in uAOG with intensive insulin therapy, by kidney RAS downregulation, may contribute to the known renoprotective action associated with intensive insulin and improved glycemic control.",

keywords = "Type 1 diabetes, albuminuria, angiotensinogen, diabetic kidney disease, renin-angiotensin system",

author = "Jessica Navarro and Alejandro Sanchez and {Ba Aqeel}, {Sheeba H.} and Minghao Ye and Rehman, {Mohammed Z.} and Jan Wysocki and Alfred Rademaker and Molitch, {Mark E.} and Daniel Batlle",

note = "Funding Information: DB and JW are coinventors of patents entitled “Active low molecular weight variants of angiotensin converting enzyme 2 (ACE2),” “Active low molecular weight variants of angiotensin converting enzyme 2 (ACE2) for the treatment of diseases and conditions of the eye,” and “Soluble ACE2 variants and uses therefor.” DB is founder of Angiotensin Therapeutics, Inc. DB received consulting fees from AstraZeneca and Advicenne Inc., all unrelated to this work. During the conduct of these studies, DB received unrelated support from a grant from AstraZeneca and research funding from the Feinberg Foundation. All other authors declare no conflicting interests. Funding Information: This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK104785 and by National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant 1R21AI166940-01] as well as by a gift to Northwestern University by the Joseph and Bessie Feinberg Foundation (DB). Publisher Copyright: {\textcopyright} 2022 International Society of Nephrology",

year = "2022",

month = dec,

doi = "10.1016/j.ekir.2022.09.010",

language = "English (US)",

volume = "7",

pages = "2657--2667",

journal = "Kidney International Reports",

issn = "2468-0249",

publisher = "Elsevier Inc.",

number = "12",

}

TY - JOUR

T1 - Urinary Angiotensinogen in Patients With Type 1 Diabetes With Microalbuminuria

T2 - Gender Differences and Effect of Intensive Insulin Therapy

AU - Navarro, Jessica

AU - Sanchez, Alejandro

AU - Ba Aqeel, Sheeba H.

AU - Ye, Minghao

AU - Rehman, Mohammed Z.

AU - Wysocki, Jan

AU - Rademaker, Alfred

AU - Molitch, Mark E.

AU - Batlle, Daniel

N1 - Funding Information: DB and JW are coinventors of patents entitled “Active low molecular weight variants of angiotensin converting enzyme 2 (ACE2),” “Active low molecular weight variants of angiotensin converting enzyme 2 (ACE2) for the treatment of diseases and conditions of the eye,” and “Soluble ACE2 variants and uses therefor.” DB is founder of Angiotensin Therapeutics, Inc. DB received consulting fees from AstraZeneca and Advicenne Inc., all unrelated to this work. During the conduct of these studies, DB received unrelated support from a grant from AstraZeneca and research funding from the Feinberg Foundation. All other authors declare no conflicting interests. Funding Information: This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK104785 and by National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant 1R21AI166940-01] as well as by a gift to Northwestern University by the Joseph and Bessie Feinberg Foundation (DB). Publisher Copyright: © 2022 International Society of Nephrology

PY - 2022/12

Y1 - 2022/12

N2 - Introduction: Angiotensinogen (AOG) is the precursor of peptides of the renin angiotensin system (RAS). Because insulin up-regulates transcriptional factors that normally repress kidney AOG synthesis, we evaluated urinary AOG (uAOG) in patients with type 1 diabetes (T1D) and microalbuminuria who are receiving either intensive or conventional insulin therapy. Methods: Urine samples from participants of the Diabetes Control and Complications Trial (DCCT) were used for the following: (i) uAOG/creatinine measurements in 103 patients with microalbuminuria and 103 patients with normoalbuminuria, matched for age, gender, disease duration, and allocation to insulin therapy; and (ii) uAOG/creatinine measurements from patients with microalbuminuria allocated to intensive insulin therapy (n = 58) or conventional insulin therapy (n = 41) after 3 years on each modality. Results: uAOG was higher in patients who started with microalbuminuria than in those with normoalbuminuria (6.65 vs. 4.0 ng/mg creatinine, P < 0.01). uAOG was higher in females than in males with microalbuminuria (11.7 vs. 5.4 ng/mg creatinine, P = 0.015). uAOG was lower in patients with microalbuminuria allocated to intensive insulin therapy than in conventional insulin therapy (3.98 vs. 7.42 ng/mg creatinine, P < 0.01). These differences in uAOG were observed though albumin excretion rate (AER) was not significantly different. Conclusion: In patients with T1D and microalbuminuria, uAOG is increased and varies with gender and the type of insulin therapy independently of AER. This suggests that AOG production is increased in females and it is decreased by intensive insulin therapy. The reduction in uAOG with intensive insulin therapy, by kidney RAS downregulation, may contribute to the known renoprotective action associated with intensive insulin and improved glycemic control.

AB - Introduction: Angiotensinogen (AOG) is the precursor of peptides of the renin angiotensin system (RAS). Because insulin up-regulates transcriptional factors that normally repress kidney AOG synthesis, we evaluated urinary AOG (uAOG) in patients with type 1 diabetes (T1D) and microalbuminuria who are receiving either intensive or conventional insulin therapy. Methods: Urine samples from participants of the Diabetes Control and Complications Trial (DCCT) were used for the following: (i) uAOG/creatinine measurements in 103 patients with microalbuminuria and 103 patients with normoalbuminuria, matched for age, gender, disease duration, and allocation to insulin therapy; and (ii) uAOG/creatinine measurements from patients with microalbuminuria allocated to intensive insulin therapy (n = 58) or conventional insulin therapy (n = 41) after 3 years on each modality. Results: uAOG was higher in patients who started with microalbuminuria than in those with normoalbuminuria (6.65 vs. 4.0 ng/mg creatinine, P < 0.01). uAOG was higher in females than in males with microalbuminuria (11.7 vs. 5.4 ng/mg creatinine, P = 0.015). uAOG was lower in patients with microalbuminuria allocated to intensive insulin therapy than in conventional insulin therapy (3.98 vs. 7.42 ng/mg creatinine, P < 0.01). These differences in uAOG were observed though albumin excretion rate (AER) was not significantly different. Conclusion: In patients with T1D and microalbuminuria, uAOG is increased and varies with gender and the type of insulin therapy independently of AER. This suggests that AOG production is increased in females and it is decreased by intensive insulin therapy. The reduction in uAOG with intensive insulin therapy, by kidney RAS downregulation, may contribute to the known renoprotective action associated with intensive insulin and improved glycemic control.

KW - Type 1 diabetes

KW - albuminuria

KW - angiotensinogen

KW - diabetic kidney disease

KW - renin-angiotensin system

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U2 - 10.1016/j.ekir.2022.09.010

DO - 10.1016/j.ekir.2022.09.010

M3 - Article

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SN - 2468-0249

VL - 7

SP - 2657

EP - 2667

JO - Kidney International Reports

JF - Kidney International Reports

IS - 12

ER -

Urinary Angiotensinogen in Patients With Type 1 Diabetes With Microalbuminuria: Gender Differences and Effect of Intensive Insulin Therapy

Abstract

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ASJC Scopus subject areas

UN SDGs

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