Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus

Kevin M. Wheelock, Jian Cai, Helen C. Looker, Michael L. Merchant, Robert G. Nelson, Gudeta D. Fufaa, E. Jennifer Weil, Harold I. Feldman, Ramachandran S. Vasan, Paul L. Kimmel, Brad H. Rovin, Michael Mauer, Jon B. Klein

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Abstract

Objective To examine the association of bradykinin and related peptides with the development of diabetic nephropathy lesions in 243 participants with type 1 diabetes (T1D) from the Renin-Angiotensin System Study who, at baseline, were normoalbuminuric, normotensive and had normal or increased glomerular filtration rate (GFR). Design Plasma concentrations of bradykinin and related peptides were measured at baseline by quantitative mass spectrometry. All participants were randomly assigned at baseline to receive placebo, enalapril or losartan during the 5 years between kidney biopsies. Kidney morphometric data were available from kidney biopsies at baseline and after 5 years. Relationships of peptides with changes in morphometric variables were assessed using multiple linear regression after adjustment for age, sex, diabetes duration, HbA1c, mean arterial pressure, treatment assignment and, for longitudinal analyses, baseline structure. Results Baseline median albumin excretion rate of study participants was 5.0 µg/min, and mean GFR was 128 mL/min/1.73 m2. After multivariable adjustment, higher plasma concentration of bradykinin (1–8) was associated with greater glomerular volume (partial r = 0.191, P = 0.019) and total filtration surface area (partial r = 0.211, P = 0.010), and higher bradykinin (1–7) and hyp3-bradykinin (1–7) were associated with lower cortical interstitial fractional volume (partial r = -0.189, P = 0.011; partial r = -0.164, P = 0.027 respectively). In longitudinal analyses, higher bradykinin was associated with preservation of surface density of the peripheral glomerular basement membrane (partial r = 0.162, P = 0.013), and for participants randomized to losartan, higher hyp3-bradykinin (1–8) was associated with more limited increase in cortical interstitial fractional volume (partial r = -0.291, P = 0.033). Conclusions Higher plasma bradykinin and related peptide concentrations measured before clinical onset of diabetic nephropathy in persons with T1D were associated with preservation of glomerular structures, suggesting that elevations of these kinin concentrations may reflect adaptive responses to early renal structural changes in diabetic nephropathy.

Original languageEnglish (US)
Article numbere0180964
JournalPloS one
Volume12
Issue number7
DOIs
StatePublished - Jul 1 2017

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diabetic nephropathy
bradykinin
insulin-dependent diabetes mellitus
Diabetic Nephropathies
Bradykinin
Medical problems
Type 1 Diabetes Mellitus
lesions (animal)
Plasmas
kidneys
peptides
Kidney
Peptides
glomerular filtration rate
Losartan
Biopsy
Glomerular Filtration Rate
biopsy
kinins
renin-angiotensin system

Cite this

Wheelock, K. M., Cai, J., Looker, H. C., Merchant, M. L., Nelson, R. G., Fufaa, G. D., ... Klein, J. B. (2017). Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus. PloS one, 12(7), [e0180964]. https://doi.org/10.1371/journal.pone.0180964

Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus. / Wheelock, Kevin M.; Cai, Jian; Looker, Helen C.; Merchant, Michael L.; Nelson, Robert G.; Fufaa, Gudeta D.; Weil, E. Jennifer; Feldman, Harold I.; Vasan, Ramachandran S.; Kimmel, Paul L.; Rovin, Brad H.; Mauer, Michael; Klein, Jon B.

In: PloS one, Vol. 12, No. 7, e0180964, 01.07.2017.

Research output: Contribution to journalArticle

Wheelock, KM, Cai, J, Looker, HC, Merchant, ML, Nelson, RG, Fufaa, GD, Weil, EJ, Feldman, HI, Vasan, RS, Kimmel, PL, Rovin, BH, Mauer, M & Klein, JB 2017, 'Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus', PloS one, vol. 12, no. 7, e0180964. https://doi.org/10.1371/journal.pone.0180964
Wheelock KM, Cai J, Looker HC, Merchant ML, Nelson RG, Fufaa GD et al. Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus. PloS one. 2017 Jul 1;12(7). e0180964. https://doi.org/10.1371/journal.pone.0180964
Wheelock, Kevin M. ; Cai, Jian ; Looker, Helen C. ; Merchant, Michael L. ; Nelson, Robert G. ; Fufaa, Gudeta D. ; Weil, E. Jennifer ; Feldman, Harold I. ; Vasan, Ramachandran S. ; Kimmel, Paul L. ; Rovin, Brad H. ; Mauer, Michael ; Klein, Jon B. / Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus. In: PloS one. 2017 ; Vol. 12, No. 7.
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AU - Weil, E. Jennifer

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N2 - Objective To examine the association of bradykinin and related peptides with the development of diabetic nephropathy lesions in 243 participants with type 1 diabetes (T1D) from the Renin-Angiotensin System Study who, at baseline, were normoalbuminuric, normotensive and had normal or increased glomerular filtration rate (GFR). Design Plasma concentrations of bradykinin and related peptides were measured at baseline by quantitative mass spectrometry. All participants were randomly assigned at baseline to receive placebo, enalapril or losartan during the 5 years between kidney biopsies. Kidney morphometric data were available from kidney biopsies at baseline and after 5 years. Relationships of peptides with changes in morphometric variables were assessed using multiple linear regression after adjustment for age, sex, diabetes duration, HbA1c, mean arterial pressure, treatment assignment and, for longitudinal analyses, baseline structure. Results Baseline median albumin excretion rate of study participants was 5.0 µg/min, and mean GFR was 128 mL/min/1.73 m2. After multivariable adjustment, higher plasma concentration of bradykinin (1–8) was associated with greater glomerular volume (partial r = 0.191, P = 0.019) and total filtration surface area (partial r = 0.211, P = 0.010), and higher bradykinin (1–7) and hyp3-bradykinin (1–7) were associated with lower cortical interstitial fractional volume (partial r = -0.189, P = 0.011; partial r = -0.164, P = 0.027 respectively). In longitudinal analyses, higher bradykinin was associated with preservation of surface density of the peripheral glomerular basement membrane (partial r = 0.162, P = 0.013), and for participants randomized to losartan, higher hyp3-bradykinin (1–8) was associated with more limited increase in cortical interstitial fractional volume (partial r = -0.291, P = 0.033). Conclusions Higher plasma bradykinin and related peptide concentrations measured before clinical onset of diabetic nephropathy in persons with T1D were associated with preservation of glomerular structures, suggesting that elevations of these kinin concentrations may reflect adaptive responses to early renal structural changes in diabetic nephropathy.

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