Top

Published in:

Open Access 01-06-2019 | Diabetic Retinopathy | Article

Pancreatic kallikrein protects against diabetic retinopathy in KK Cg-A^y/J and high-fat diet/streptozotocin-induced mouse models of type 2 diabetes

Authors: Ying Cheng, Xiaochen Yu, Jie Zhang, Yunpeng Chang, Mei Xue, Xiaoyu Li, Yunhong Lu, Ting Li, Ziyu Meng, Long Su, Bei Sun, Liming Chen

Published in: Diabetologia | Issue 6/2019

Abstract

Aims/hypothesis

Many studies have shown that tissue kallikrein has effects on diabetic vascular complications such as nephropathy, cardiomyopathy and neuropathy, but its effects on diabetic retinopathy are not fully understood. Here, we investigated the retinoprotective role of exogenous pancreatic kallikrein and studied potential mechanisms of action.

Methods

We used KK Cg-A^y/J (KKAy) mice (a mouse model of spontaneous type 2 diabetes) and mice with high-fat diet/streptozotocin (STZ)-induced type 2 diabetes as our models. After the onset of diabetes, both types of mice were injected intraperitoneally with either pancreatic kallikrein (KKAy + pancreatic kallikrein and STZ + pancreatic kallikrein groups) or saline (KKAy + saline and STZ + saline groups) for 12 weeks. C57BL/6J mice were used as non-diabetic controls for both models. We analysed pathological changes in the retina; evaluated the effects of pancreatic kallikrein on retinal oxidative stress, inflammation and apoptosis; and measured the levels of bradykinin and B1 and B2 receptors in both models.

Results

In both models, pancreatic kallikrein improved pathological structural features of the retina, increasing the thickness of retinal layers, and attenuated retinal acellular capillary formation and vascular leakage (p < 0.05). Furthermore, pancreatic kallikrein ameliorated retinal oxidative stress, inflammation and apoptosis in both models (p < 0.05). We also found that the levels of bradykinin and B1 and B2 receptors were increased after pancreatic kallikrein in both models (p < 0.05).

Conclusions/interpretation

Pancreatic kallikrein can protect against diabetic retinopathy by activating B1 and B2 receptors and inhibiting oxidative stress, inflammation and apoptosis. Thus, pancreatic kallikrein may represent a new therapeutic agent for diabetic retinopathy.

Available only for authorised users

Beckman JA, Creager MA (2016) Vascular complications of diabetes. Circ Res 118(11):1771–1785. https://doi.org/10.1161/CIRCRESAHA.115.306884 CrossRefPubMed

Antonetti DA, Klein R, Gardner TW (2012) Diabetic retinopathy. N Engl J Med 366(13):1227–1239. https://doi.org/10.1056/NEJMra1005073 CrossRefPubMed

Yau JW, Rogers SL, Kawasaki R et al (2012) Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35(3):556–564. https://doi.org/10.2337/dc11-1909 CrossRefPubMedPubMedCentral

Funatsu H, Noma H, Mimura T, Eguchi S, Hori S (2009) Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmology 116(1):73–79. https://doi.org/10.1016/j.ophtha.2008.09.037 CrossRefPubMed

Kowluru RA, Chan PS (2007) Oxidative stress and diabetic retinopathy. Exp Diabetes Res 2007:43603PubMedPubMedCentral

Tang J, Kern TS (2011) Inflammation in diabetic retinopathy. Prog Retin Eye Res 30(5):343–358. https://doi.org/10.1016/j.preteyeres.2011.05.002 CrossRefPubMedPubMedCentral

Adamiec-Mroczek J, Zajac-Pytrus H, Misiuk-Hojlo M (2015) Caspase-dependent apoptosis of retinal ganglion cells during the development of diabetic retinopathy. Adv Clin Exp Med 24(3):531–535. https://doi.org/10.17219/acem/31805 CrossRefPubMed

King GL (2008) The role of inflammatory cytokines in diabetes and its complications. J Periodontol 79(8s):1527–1534. https://doi.org/10.1902/jop.2008.080246 CrossRefPubMed

Hillmeister P, Persson PB (2012) The kallikrein-kinin system. Acta Physiol 206(4):215–219. https://doi.org/10.1111/apha.12007 CrossRef

10.

Montanari D, Yin H, Dobrzynski E et al (2005) Kallikrein gene delivery improves serum glucose and lipid profiles and cardiac function in streptozotocin-induced diabetic rats. Diabetes 54(5):1573–1580. https://doi.org/10.2337/diabetes.54.5.1573 CrossRefPubMed

11.

Liu W, Yang Y, Liu Y et al (2016) Exogenous kallikrein protects against diabetic nephropathy. Kidney Int 90(5):1023–1036. https://doi.org/10.1016/j.kint.2016.06.018 CrossRefPubMed

12.

Zhu D, Zhang L, Cheng L, Ren L, Tang J, Sun D (2016) Pancreatic kininogenase ameliorates renal fibrosis in streptozotocin induced-diabetic nephropathy rat. Kidney Blood Press Res 41(1):9–17. https://doi.org/10.1159/000368542 CrossRefPubMed

13.

Clermont A, Chilcote TJ, Kita T et al (2011) Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats. Diabetes 60(5):1590–1598. https://doi.org/10.2337/db10-1260 CrossRefPubMedPubMedCentral

14.

Kato N, Hou Y, Lu Z et al (2009) Kallidinogenase normalizes retinal vasopermeability in streptozotocin-induced diabetic rats: potential roles of vascular endothelial growth factor and nitric oxide. Eur J Pharmacol 606(1–3):187–190. https://doi.org/10.1016/j.ejphar.2009.01.027 CrossRefPubMed

15.

Iwatsuka H, Shino A, Suzuoki Z (1970) General survey of diabetic features of yellow KK mice. Endocrinol Jpn 17(6):23–35. https://doi.org/10.1507/endocrj1954.17.23 CrossRefPubMed

16.

Zhu SS, Ren Y, Zhang M et al (2011) Wld(S) protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice. Diabetologia 54(9):2440–2450. https://doi.org/10.1007/s00125-011-2226-1 CrossRefPubMed

17.

Chou JC, Rollins SD, Fawzi AA (2013) Trypsin digest protocol to analyze the retinal vasculature of a mouse model. J Vis Exp 76:e50489

18.

Barile GR, Pachydaki SI, Tari SR et al (2005) The RAGE axis in early diabetic retinopathy. Invest Ophthalmol Vis Sci 46(8):2916–2924. https://doi.org/10.1167/iovs.04-1409 CrossRefPubMed

19.

Chang YP, Sun B, Han Z et al (2017) Saxagliptin attenuates albuminuria by inhibiting podocyte epithelial- to-mesenchymal transition via SDF-1α in diabetic nephropathy. Front Pharmacol 8:780. https://doi.org/10.3389/fphar.2017.00780 CrossRefPubMedPubMedCentral

20.

Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW (1998) Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest 102(4):783–791. https://doi.org/10.1172/JCI2425 CrossRefPubMedPubMedCentral

21.

Kannan K, Jain SK (2000) Oxidative stress and apoptosis. Pathophysiology 7(3):153–163. https://doi.org/10.1016/S0928-4680(00)00053-5 CrossRefPubMed

22.

Rubsam A, Parikh S, Fort PE (2018) Role of inflammation in diabetic retinopathy. Int J Mol Sci 19(4):E942CrossRefPubMed

23.

Zhao C, Wang P, Xiao X et al (2003) Gene therapy with human tissue kallikrein reduces hypertension and hyperinsulinemia in fructose-induced hypertensive rats. Hypertension 42(5):1026–1033. https://doi.org/10.1161/01.HYP.0000097603.55404.35 CrossRefPubMed

24.

Wang T, Li H, Zhao C et al (2004) Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries. Gene Ther 11(17):1342–1350. https://doi.org/10.1038/sj.gt.3302294 CrossRefPubMed

25.

Liu J, Feener EP (2013) Plasma kallikrein-kinin system and diabetic retinopathy. Biol Chem 394(3):319–328. https://doi.org/10.1515/hsz-2012-0316 CrossRefPubMedPubMedCentral

26.

Teufel DP, Bennett G, Harrison H et al (2018) Stable and long-lasting, novel bicyclic peptide plasma kallikrein inhibitors for the treatment of diabetic macular edema. J Med Chem 61(7):2823–2836. https://doi.org/10.1021/acs.jmedchem.7b01625 CrossRefPubMed

27.

Bedoucha M, Atzpodien E, Boelsterli UA (2001) Diabetic KKAy mice exhibit increased hepatic PPARγ1 gene expression and develop hepatic steatosis upon chronic treatment with antidiabetic thiazolidinediones. J Hepatol 35(1):17–23. https://doi.org/10.1016/S0168-8278(01)00066-6 CrossRefPubMed

28.

Okazaki M, Saito Y, Udaka Y et al (2002) Diabetic nephropathy in KK and KK-ay mice. Exp Anim 51(2):191–196. https://doi.org/10.1538/expanim.51.191 CrossRefPubMed

29.

Liu X, Yang G, Fan Q, Wang L (2014) Proteomic profile in glomeruli of type-2 diabetic KKAy mice using 2-dimensional differential gel electrophoresis. Med Sci Monit 20:2705–2713. https://doi.org/10.12659/MSM.893078 CrossRefPubMedPubMedCentral

30.

Ning X, Baoyu Q, Yuzhen L, Shuli S, Reed E, Li QQ (2004) Neuro-optic cell apoptosis and microangiopathy in KKAY mouse retina. Int J Mol Med 13(1):87–92PubMed

31.

Olivares AM, Althoff K, Chen GF et al (2017) Animal models of diabetic retinopathy. Curr Diabetes Rep 17(10):93. https://doi.org/10.1007/s11892-017-0913-0 CrossRef

32.

Lai AK, Lo AC (2013) Animal models of diabetic retinopathy: summary and comparison. J Diabetes Res 2013:106594CrossRefPubMedPubMedCentral

33.

Robinson R, Barathi VA, Chaurasia SS, Wong TY, Kern TS (2012) Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals. Dis Model Mech 5(4):444–456. https://doi.org/10.1242/dmm.009597 CrossRefPubMedPubMedCentral

34.

Kumari S, Panda S, Mangaraj M, Mandal MK, Mahapatra PC (2008) Plasma MDA and antioxidant vitamins in diabetic retinopathy. Indian J Clin Biochem 23(2):158–162. https://doi.org/10.1007/s12291-008-0035-1 CrossRefPubMedPubMedCentral

35.

Kern TS (2007) Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res 2007:95103CrossRefPubMedPubMedCentral

36.

Lim YC, Bhatt MP, Kwon MH et al (2014) Prevention of VEGF-mediated microvascular permeability by C-peptide in diabetic mice. Cardiovasc Res 101(1):155–164. https://doi.org/10.1093/cvr/cvt238 CrossRefPubMed

37.

Lee YJ, Jung SH, Kim SH et al (2016) Essential role of transglutaminase 2 in vascular endothelial growth factor-induced vascular leakage in the retina of diabetic mice. Diabetes 65(8):2414–2428. https://doi.org/10.2337/db15-1594 CrossRefPubMed

38.

Nakamura S, Morimoto N, Tsuruma K et al (2011) Tissue kallikrein inhibits retinal neovascularization via the cleavage of vascular endothelial growth factor-165. Arterioscler Thromb Vasc Biol 31(5):1041–1048. https://doi.org/10.1161/ATVBAHA.111.223594 CrossRefPubMed

39.

Behl Y, Krothapalli P, Desta T, DiPiazza A, Roy S, Graves DT (2008) Diabetes-enhanced tumor necrosis factor-alpha production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy. Am J Pathol 172(5):1411–1418. https://doi.org/10.2353/ajpath.2008.071070 CrossRefPubMedPubMedCentral

40.

Park SW, Yun JH, Kim JH, Kim KW, Cho CH, Kim JH (2014) Angiopoietin 2 induces pericyte apoptosis via α3β1 integrin signaling in diabetic retinopathy. Diabetes 63(9):3057–3068. https://doi.org/10.2337/db13-1942 CrossRefPubMed

41.

Cacicedo JM, Benjachareowong S, Chou E, Ruderman NB, Ido Y (2005) Palmitate-induced apoptosis in cultured bovine retinal pericytes: roles of NAD(P) H oxidase, oxidant stress, and ceramide. Diabetes 54(6):1838–1845. https://doi.org/10.2337/diabetes.54.6.1838 CrossRefPubMed

42.

Rodriguez AI, Pereira-Flores K, Hernandez-Salinas R, Boric MP, Velarde V (2006) High glucose increases B1-kinin receptor expression and signaling in endothelial cells. Biochem Biophys Res Commun 345(2):652–659. https://doi.org/10.1016/j.bbrc.2006.04.127 CrossRefPubMed

43.

Christopher J, Velarde V, Zhang D, Mayfield D, Mayfield RK, Jaffa AA (2001) Regulation of B(2)-kinin receptors by glucose in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 280(4):H1537–H1546. https://doi.org/10.1152/ajpheart.2001.280.4.H1537 CrossRefPubMed

44.

Abdouh M, Khanjari A, Abdelazziz N, Ongali B, Couture R, Hassessian HM (2003) Early upregulation of kinin B1 receptors in retinal microvessels of the streptozotocin-diabetic rat. Br J Pharmacol 140(1):33–40. https://doi.org/10.1038/sj.bjp.0705210 CrossRefPubMedPubMedCentral

45.

Pouliot M, Talbot S, Senecal J, Dotigny F, Vaucher E, Couture R (2012) Ocular application of the kinin B1 receptor antagonist LF22-0542 inhibits retinal inflammation and oxidative stress in streptozotocin-diabetic rats. PLoS One 7(3):e33864. https://doi.org/10.1371/journal.pone.0033864 CrossRefPubMedPubMedCentral

46.

Catanzaro O, Labal E, Andornino A, Capponi JA, Di Martino I, Sirois P (2012) Blockade of early and late retinal biochemical alterations associated with diabetes development by the selective bradykinin B1 receptor antagonist R-954. Peptides 34(2):349–352. https://doi.org/10.1016/j.peptides.2012.02.008 CrossRefPubMed

47.

Hachana S, Bhat M, Senecal J, Huppe-Gourgues F (2018) Expression, distribution and function of kinin B1 receptor in the rat diabetic retina. Br J Pharmacol 175(6):968–983. https://doi.org/10.1111/bph.14138 CrossRefPubMedPubMedCentral

48.

Igic R (2018) Four decades of ocular renin-angiotensin and kallikrein-kinin systems (1977-2017). Exp Eye Res 166:74–83. https://doi.org/10.1016/j.exer.2017.05.007 CrossRefPubMed

49.

Kakoki M, Sullivan KA, Backus C et al (2010) Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice. Proc Natl Acad Sci U S A 107(22):10190–10195. https://doi.org/10.1073/pnas.1005144107 CrossRefPubMedPubMedCentral

Title: Pancreatic kallikrein protects against diabetic retinopathy in KK Cg-Ay/J and high-fat diet/streptozotocin-induced mouse models of type 2 diabetes
Authors: Ying Cheng
Xiaochen Yu
Jie Zhang
Yunpeng Chang
Mei Xue
Xiaoyu Li
Yunhong Lu
Ting Li
Ziyu Meng
Long Su
Bei Sun
Liming Chen
Publication date: 01-06-2019
Publisher: Springer Berlin Heidelberg
Keywords: Diabetic Retinopathy
Diabetic Retinopathy
Type 2 Diabetes
Published in: Diabetologia / Issue 6/2019
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-019-4838-9

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Pancreatic kallikrein protects against diabetic retinopathy in KK Cg-A^y/J and high-fat diet/streptozotocin-induced mouse models of type 2 diabetes

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Please log in to get access to this content

Other articles of this Issue 6/2019

Imaging mass spectrometry enables molecular profiling of mouse and human pancreatic tissue

Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program

Impaired whole-body heat loss in type 1 diabetes during exercise in the heat: a cause for concern?

Up front

Pregnancy in human IAPP transgenic mice recapitulates beta cell stress in type 2 diabetes

Digital health technology and mobile devices for the management of diabetes mellitus: state of the art

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page