Diabetic Nephropathy is Markedly Enhanced in Mice Lacking the Bradykinin B2 Receptor

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Aug 25

PMID 15326315

Citations 51

Authors

Masao Kakoki

Nobuyuki Takahashi

J Charles Jennette

Oliver Smithies

Affiliations

Soon will be listed here.

Abstract

Type I human diabetics and streptozotocin-induced diabetic mice with higher genetically determined levels of angiotensin-converting enzyme have an increased risk of developing nephropathy. However, previous experiments in mice and computer simulations indicate that modest increases in angiotensin-converting enzyme have minimal effects on blood pressure and angiotensin II levels, although bradykinin decreases significantly, inferring that bradykinin is critical for protecting the kidney in diabetics. Here, we confirm this inference by demonstrating that Akita diabetic mice lacking the bradykinin B2 receptor develop overt albuminuria, excreting the equivalent of >550 mg/day albumin in humans, which contrasts with the microalbuminuria (equivalent to <150 mg/day) seen in their simply diabetic littermates. The overt albuminuria is accompanied by a marked increase in glomerular mesangial sclerosis. The importance of bradykinin demonstrated here bears strongly on how current drugs reduce diabetic nephropathy and suggests that B2 receptor-specific agonists merit consideration in this context.

Citing Articles

Deletion of kinin receptor B2 enhances orthodontic tooth movement and alveolar bone remodeling.

Figueiredo N, Piacsek M, Montalvany-Antonucci C, Santos M, Amaral F, Teixeira M PLoS One. 2025; 20(2):e0318436.

PMID: 40019931 PMC: 11870366. DOI: 10.1371/journal.pone.0318436.

Genetic predisposition to nephropathy and associated cardiovascular disease in people with type 1 diabetes: role of the angiotensinI-converting enzyme (ACE), and beyond; a narrative review.

Mohammedi K, Marre M, Alhenc-Gelas F Cardiovasc Diabetol. 2024; 23(1):453.

PMID: 39709470 PMC: 11662484. DOI: 10.1186/s12933-024-02544-0.

Parallelism and non-parallelism in diabetic nephropathy and diabetic retinopathy.

Tang S, An X, Sun W, Zhang Y, Yang C, Kang X Front Endocrinol (Lausanne). 2024; 15:1336123.

PMID: 38419958 PMC: 10899692. DOI: 10.3389/fendo.2024.1336123.

Rodent models to study type 1 and type 2 diabetes induced human diabetic nephropathy.

Talukdar A, Basumatary M Mol Biol Rep. 2023; 50(9):7759-7782.

PMID: 37458869 DOI: 10.1007/s11033-023-08621-z.

Kinins and Their Receptors as Potential Therapeutic Targets in Retinal Pathologies.

Othman R, Cagnone G, Joyal J, Vaucher E, Couture R Cells. 2021; 10(8).

PMID: 34440682 PMC: 8391508. DOI: 10.3390/cells10081913.

References

Suzuki D, Miyata T, Nangaku M, Takano H, Saotome N, Toyoda M . Expression of megsin mRNA, a novel mesangium-predominant gene, in the renal tissues of various glomerular diseases. J Am Soc Nephrol. 1999; 10(12):2606-13. DOI: 10.1681/ASN.V10122606. View

Wang J, Takeuchi T, Tanaka S, Kubo S, Kayo T, Lu D . A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. J Clin Invest. 1999; 103(1):27-37. PMC: 407861. DOI: 10.1172/JCI4431. View

Duka I, Kintsurashvili E, Gavras I, Johns C, Bresnahan M, Gavras H . Vasoactive potential of the b(1) bradykinin receptor in normotension and hypertension. Circ Res. 2001; 88(3):275-81. DOI: 10.1161/01.res.88.3.275. View

Milia A, Gross V, Plehm R, De Silva Jr J, Bader M, Luft F . Normal blood pressure and renal function in mice lacking the bradykinin B(2) receptor. Hypertension. 2001; 37(6):1473-9. DOI: 10.1161/01.hyp.37.6.1473. View

Aaltonen P, Luimula P, Astrom E, Palmen T, Gronholm T, Palojoki E . Changes in the expression of nephrin gene and protein in experimental diabetic nephropathy. Lab Invest. 2001; 81(9):1185-90. DOI: 10.1038/labinvest.3780332. View

Huang W, Gallois Y, Bouby N, Bruneval P, Heudes D, Belair M . Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse. Proc Natl Acad Sci U S A. 2001; 98(23):13330-4. PMC: 60870. DOI: 10.1073/pnas.231476798. View

Kim H, Lee G, John S, Maeda N, Smithies O . Molecular phenotyping for analyzing subtle genetic effects in mice: application to an angiotensinogen gene titration. Proc Natl Acad Sci U S A. 2002; 99(7):4602-7. PMC: 123694. DOI: 10.1073/pnas.072083799. View

Duchene J, Schanstra J, Pecher C, Pizard A, Susini C, Esteve J . A novel protein-protein interaction between a G protein-coupled receptor and the phosphatase SHP-2 is involved in bradykinin-induced inhibition of cell proliferation. J Biol Chem. 2002; 277(43):40375-83. DOI: 10.1074/jbc.M202744200. View

Haseyama T, Fujita T, Hirasawa F, Tsukada M, Wakui H, Komatsuda A . Complications of IgA nephropathy in a non-insulin-dependent diabetes model, the Akita mouse. Tohoku J Exp Med. 2003; 198(4):233-44. DOI: 10.1620/tjem.198.233. View

10.

Takahashi N, Hagaman J, Kim H, Smithies O . Minireview: computer simulations of blood pressure regulation by the renin-angiotensin system. Endocrinology. 2003; 144(6):2184-90. DOI: 10.1210/en.2002-221045. View

11.

Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F . An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990; 86(4):1343-6. PMC: 296868. DOI: 10.1172/JCI114844. View

12.

Feldt-Rasmussen B, Hegedus L, Mathiesen E, Deckert T . Kidney volume in type 1 (insulin-dependent) diabetic patients with normal or increased urinary albumin excretion: effect of long-term improved metabolic control. Scand J Clin Lab Invest. 1991; 51(1):31-6. View

13.

Marre M, Bernadet P, Gallois Y, Savagner F, Guyene T, Hallab M . Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes. 1994; 43(3):384-8. DOI: 10.2337/diab.43.3.384. View

14.

Bascands J, Pecher C, Bompart G, Rakotoarivony J, Tack J, Girolami J . Bradykinin-induced in vitro contraction of rat mesangial cells via a B2 receptor type. Am J Physiol. 1994; 267(5 Pt 2):F871-8. DOI: 10.1152/ajprenal.1994.267.5.F871. View

15.

Borkowski J, Ransom R, Seabrook G, Trumbauer M, Chen H, Hill R . Targeted disruption of a B2 bradykinin receptor gene in mice eliminates bradykinin action in smooth muscle and neurons. J Biol Chem. 1995; 270(23):13706-10. DOI: 10.1074/jbc.270.23.13706. View

16.

Krege J, Kim H, Moyer J, Jennette J, Peng L, Hiller S . Angiotensin-converting enzyme gene mutations, blood pressures, and cardiovascular homeostasis. Hypertension. 1997; 29(1 Pt 2):150-7. DOI: 10.1161/01.hyp.29.1.150. View

17.

Yoshioka M, Kayo T, Ikeda T, Koizumi A . A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice. Diabetes. 1997; 46(5):887-94. DOI: 10.2337/diab.46.5.887. View

18.

SMITHIES O, Kim H, Takahashi N, Edgell M . Importance of quantitative genetic variations in the etiology of hypertension. Kidney Int. 2000; 58(6):2265-80. DOI: 10.1046/j.1523-1755.2000.00411.x. View