Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease

Maryam Afkarian, Irl B. Hirsch, Katherine R. Tuttle, Carla Greenbaum, Jonathan Himmelfarb, Ian H. De Boer

Research output: Contribution to journalArticle

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Abstract

The renin-angiotensin system (RAS), bone morphogenetic protein (BMP), and WNT pathways are involved in pathogenesis of diabetic kidney disease (DKD). This study characterized assays for urinary angiotensinogen (AGT), gremlin-1, and matrix metalloproteinase 7 (MMP-7), components of the RAS, BMP, and WNT pathways and examined their excretion in DKD. We measured urine AGT, gremlin-1, and MMP-7 in individuals with type 1 diabetes and prevalent DKD (n = 20) or longstanding (n = 61) or new-onset (n = 10) type 1 diabetes without DKD. These urine proteins were also quantified in type 2 DKD (n = 11) before and after treatment with candesartan. The utilized immunoassays had comparable inter-and intra-assay and intraindividual variation to assays used for urine albumin. Median (IQR) urine AGT concentrations were 226.0 (82.1, 550.3) and 13.0 (7.8, 20.0) �g/g creatinine in type 1 diabetes with and without DKD, respectively (P < 0.001). Median (IQR) urine gremlin-1 concentrations were 48.6 (14.2, 254.1) and 3.6 (1.7, 5.5) �g/g, respectively (P < 0.001). Median (IQR) urine MMP-7 concentrations were 6.0 (3.8, 10.5) and 1.0 (0.4, 2.9) �g/g creatinine, respectively (P < 0.001). Treatment with candesartan was associated with a reduction in median (IQR) urine AGT/creatinine from 23.5 (1.6, 105.1) to 2.0 (1.4, 13.7) �g/g, which did not reach statistical significance. Urine gremlin-1 and MMP-7 excretion did not decrease with candesartan. In conclusion, DKD is characterized by markedly elevated urine AGT, MMP-7, and gremlin-1. AGT decreased in response to RAS inhibition, suggesting that this marker reflects therapeutic response. Urinary components of the RAS, BMP, and WNT pathways may identify risk of DKD and aid development of novel therapeutics.

Original languageEnglish (US)
Article numbere12010
JournalPhysiological Reports
Volume2
Issue number5
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Bone Morphogenetic Proteins
Diabetic Nephropathies
Renin-Angiotensin System
Angiotensinogen
Matrix Metalloproteinase 7
Urine
Type 1 Diabetes Mellitus
Creatinine
Immunoassay
Albumins

Keywords

  • BMP pathway
  • Diabetic kidney disease
  • Pathophysiology
  • Renin-angiotensin system
  • WNT pathway

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Afkarian, M., Hirsch, I. B., Tuttle, K. R., Greenbaum, C., Himmelfarb, J., & De Boer, I. H. (2014). Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease. Physiological Reports, 2(5), [e12010]. https://doi.org/10.14814/phy2.12010

Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease. / Afkarian, Maryam; Hirsch, Irl B.; Tuttle, Katherine R.; Greenbaum, Carla; Himmelfarb, Jonathan; De Boer, Ian H.

In: Physiological Reports, Vol. 2, No. 5, e12010, 01.01.2014.

Research output: Contribution to journalArticle

Afkarian, M, Hirsch, IB, Tuttle, KR, Greenbaum, C, Himmelfarb, J & De Boer, IH 2014, 'Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease', Physiological Reports, vol. 2, no. 5, e12010. https://doi.org/10.14814/phy2.12010
Afkarian, Maryam ; Hirsch, Irl B. ; Tuttle, Katherine R. ; Greenbaum, Carla ; Himmelfarb, Jonathan ; De Boer, Ian H. / Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease. In: Physiological Reports. 2014 ; Vol. 2, No. 5.
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abstract = "The renin-angiotensin system (RAS), bone morphogenetic protein (BMP), and WNT pathways are involved in pathogenesis of diabetic kidney disease (DKD). This study characterized assays for urinary angiotensinogen (AGT), gremlin-1, and matrix metalloproteinase 7 (MMP-7), components of the RAS, BMP, and WNT pathways and examined their excretion in DKD. We measured urine AGT, gremlin-1, and MMP-7 in individuals with type 1 diabetes and prevalent DKD (n = 20) or longstanding (n = 61) or new-onset (n = 10) type 1 diabetes without DKD. These urine proteins were also quantified in type 2 DKD (n = 11) before and after treatment with candesartan. The utilized immunoassays had comparable inter-and intra-assay and intraindividual variation to assays used for urine albumin. Median (IQR) urine AGT concentrations were 226.0 (82.1, 550.3) and 13.0 (7.8, 20.0) {\"i}¿½g/g creatinine in type 1 diabetes with and without DKD, respectively (P < 0.001). Median (IQR) urine gremlin-1 concentrations were 48.6 (14.2, 254.1) and 3.6 (1.7, 5.5) {\"i}¿½g/g, respectively (P < 0.001). Median (IQR) urine MMP-7 concentrations were 6.0 (3.8, 10.5) and 1.0 (0.4, 2.9) {\"i}¿½g/g creatinine, respectively (P < 0.001). Treatment with candesartan was associated with a reduction in median (IQR) urine AGT/creatinine from 23.5 (1.6, 105.1) to 2.0 (1.4, 13.7) {\"i}¿½g/g, which did not reach statistical significance. Urine gremlin-1 and MMP-7 excretion did not decrease with candesartan. In conclusion, DKD is characterized by markedly elevated urine AGT, MMP-7, and gremlin-1. AGT decreased in response to RAS inhibition, suggesting that this marker reflects therapeutic response. Urinary components of the RAS, BMP, and WNT pathways may identify risk of DKD and aid development of novel therapeutics.",
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