The Kallikrein/Kinin System in Ocular Function

Abstract

The kallikrein/kinin system uses two distinct serine proteases, plasma kallikrein and tissue kallikrein, to yield bradykinin and Lys-bradykinin (kallidin) from specific substrate kininogens. The kallikrein/kinin system is known to have a role in contact-activated coagulation mechanisms and in inflammatory responses, and recently has been shown to contribute to homeostatic and protective mechanisms in the cardiovascular and renal systems. This article reviews current knowledge of the ocular kallikrein/kinin system within the context of proposed roles for this system in other important organs and tissues. All components of the kallikrein/kinin system are present in the eye and are positioned to participate in key ocular functions. Plasma kallikrein binds to vascular endothelium and generates bradykinin, which may contribute to regulation of ocular blood flow, and, in excess, has been implicated in the pathogenesis of retinal edema in patients with proliferative diabetic retinopathy. Tissue kallikrein is expressed in retina, ciliary muscle, and trabecular meshwork cells and could be a significant factor in the protective mechanism of ischemic preconditioning, and in the modulation of aqueous dynamics. Improved understanding of the role of plasma and tissue kallikreins and kinins in such processes has the potential to identify significant new targets for the therapy of ocular dysfunction.

Introduction

It is well established that the kallikrein/kinin system plays a significant role in surface-activated coagulation, inflammatory responses, pain generation, and vasogenic edema.^1–3 In these events, the activity of the kallikrein/kinin system is generally enhanced by tissue injury, a developing thrombus, or some other pathophysiological stimulus. Much less is understood of the contribution of kallikreins and kinins at tissue and cellular sites in the physiological setting, and, consequently, the importance of the kallikrein/kinin system in regulation of homeostasis in blood vessels or important organs under normal conditions has remained unclear. Significant insights have recently emerged, however, with the development of genetic murine models with selectively modified kallikrein/kinin components, and from the identification of human populations with natural deficiencies in system components. Of particular value has been the recognition of human subjects with a polymorphism in the tissue kallikrein gene, hKLK1, a polymorphism (R53H) that yields a kallikrein enzyme with substantially diminished proteolytic activity.⁴ Studies have now provided convincing evidence of a physiological role of the kallikrein/kinin system in modulation of thrombosis, independently of coagulation, and in the regulation of vascular responses to acutely changing conditions. Interestingly, data from both animal and human studies indicate a critical role for kinin peptides, not in regulation of basal blood pressure, but in the control of flow-dependent vasodilation and in the modulation of adaptive responses to altered shear stress within the arterial vasculature. Participation of the kallikrein/kinin system in physiological regulation of ion transport in the renal tubule has also been clearly demonstrated. The objective of the present article is to discuss current understanding of the kallikrein/kinin system in ocular tissue and the possible contribution of both plasma kallikrein and tissue kallikrein to ocular function and dysfunction.

Kallikrein/Kinin System Components and Regulation

The kallikrein/kinin system consists of two distinctly different proteolytic pathways initiated by the serine proteases, plasma kallikrein (PK) and tissue kallikrein (TK). Activation of either of these enzymes ultimately leads to the production of highly potent kinin peptides with similar biological effects. PK and TK differ substantially, however, in sites of origin and tissue distribution, in substrate specificity, and in the primary mechanisms for regulation of their activities. In view of such differences, it seems likely that the plasma system and tissue system may vary in their physiological and/or pathological roles in different tissues.

PK is a single gene product that is produced primarily in the liver and secreted as the proenzyme prekallikrein. The proenzyme form of PK circulates in the plasma in a complex with high molecular weight kininogen (HMWK). PK, HMWK, and factor XII are key components of the contact-activated intrinsic clotting cascade initiated in vitro by contact with negatively charged surfaces or in vivo at sites of tissue injury. The complex of PK and HMWK readily binds to the plasma membrane of endothelial cells,⁵ as well as that of platelets and granulocytes. Binding of the PK and HMWK complex to the vascular endothelium positions PK to be activated through the action of prolylcarboxypeptidase,⁶ an enzyme constitutively expressed by endothelial cells and localized to the plasma membrane. This process provides a physiological mechanism for PK activation within the vasculature in the absence of factor XII or the clotting cascade.⁷ Once converted to the active form, PK hydrolyzes HMWK to release bradykinin, a peptide with potent vascular effects.

TK is a member of a multigene family consisting of 15 genes. Of these, only the gene KLK1 codes for a TK with catalytic action to yield kinin peptide at local tissue sites. TK is highly expressed in a number of glandular tissues, such as salivary gland, prostate, and pancreas, and is also produced by renal cells, neutrophils, and vascular endothelium. As with PK, TK is secreted as a proenzyme and must be activated proteolytically. Although the precise mechanism for TK activation remains poorly understood, it is clear from studies in models with KLK1 deficiency that TK is active in vivo under physiological conditions and is a primary source of tissue-generated kinin peptides. In humans, TK forms Lys-bradykinin (kallidin) from either HMWK or low molecular weight kininogen (LMWK). Kallidin is similar to bradykinin in biological effects and is readily converted to bradykinin by aminopeptidase activity.

Bradykinin and kallidin have similar biological effects that have been well described at the tissue and cellular levels.¹ They are particularly active in the vasculature where their actions lead to the local production and release of nitric oxide (NO), prostaglandins, and hyperpolarizing factor from endothelial and/or vascular smooth muscle cells, resulting in vasodilation and increased vascular permeability.^1,8 The kinin peptides act through stimulation of B₁ or B₂ kinin receptors. Most kinin actions are mediated by the B₂ receptor,¹ which has high affinity for bradykinin and kallidin and is constitutively expressed in a wide variety of tissues. B₁ receptors are generally expressed in low concentrations under normal conditions but may be rapidly increased in response to tissue injury, inflammation, or other pathophysiological events. The B₁ receptor preferentially responds to the desArg⁹ metabolites of bradykinin and kallidin.^9,10 Kinins have an estimated half-life of less than 30 s in vivo and, consequently, are believed to act in an autocrine/paracrine fashion at sites of production.

The principal enzymes for kinin degradation are carboxypeptidases M and N (kininase 1), which yield the desArg⁹ metabolites of bradykinin and kallidin, angiotensin converting enzyme (kininase 2), and neutral endopeptidase.¹ Endogenous proteins also exist to selectively modulate activities of the kallikrein enzymes. The principal physiological inhibitor of PK is complement 1 inhibitor (C1-Inh) protein,^1,11 whereas TK activity is inhibited by kallikrein-binding protein or kallistatin^1,12 (Fig. 1). Kallistatin has no effect on PK, and C1-Inh does not alter the activity of TK. The existence of specific inhibitory factors for the initiating proteases of the kallikrein/kinin cascade provides an opportunity for selective therapeutic interventions to target either the PK or TK system, selectivity not available with the kinin receptor antagonists, which modify the biological effects of both systems simultaneously.

FIG. 1.

Components of the kallikrein/kinin system. ACE, angiotensin converting enzyme (kininase 2); B₁R, bradykinin 1 receptor; B₂R, bradykinin 2 receptor; C1 Inh, complement 1 inhibitor; desArg⁹-Bk, desArg⁹-bradykinin; desArg⁹-K, desArg⁹-kallidin; HMWK, high molecular weight kininogen; LMWK, low molecular weight kininogen; PK, plasma kallikrein; TK, tissue kallikrein.

Plasma Kallikrein/Kinin System in Ocular Function

The principal components of the plasma kallikrein/kinin system consist of PK, along with factor XII and HMWK. These proteins originate primarily in the liver and are released into the plasma. To date, there is no evidence of the expression of any of these components by ocular tissue. However, as mentioned above, PK and HMWK circulate as a complex that readily binds to the endothelial lining of blood vessels, which then can lead to PK activation and local production of bradykinin.^5,6 It is reasonable to assume that this general mechanism is also operative for the endothelium of ocular blood vessels. Both PK and HMWK have been demonstrated in rat retina,¹³ and bradykinin has been shown to relax isolated retinal arterioles by a NO-dependent mechanism.¹⁴ Furthermore, B₁ and B₂ kinin receptors are found in the inner and outer nuclear layers and ganglion cell layer of the retina.¹⁵ Such observations support the potential for the PK/kinin system to participate in the modulation of retinal blood flow. However, more direct experiments performed in the in vivo setting will be needed to adequately test this possibility.

An interesting development is the recent proposal that the ocular PK/kinin system may contribute to the evolution of retinal edema in certain pathological conditions. Using proteomics in combination with immunoblotting, Feener and associates have identified abundant levels of plasma kallikrein system components in the vitreous fluid of human subjects with proliferative diabetic retinopathy.^16,17 The components present include prekallikrein, factor XII, and HMWK along with significant amounts of the activated forms of both PK and factor XII (XIIa). Factor XIIa, once formed from factor XII, has the potential to activate PK, which then can produce a reciprocal activation of factor XII, creating a positive feedback loop for sustained kallikrein activity and local kinin generation. These proteins likely cross the blood–retinal barrier into the vitreous fluid and, possibly, retinal interstitium as a result of retinal hemorrhage and the enhanced vascular permeability commonly associated with diabetic retinopathy.^18,19 In complementary studies, injection of either purified PK or bradykinin directly into the vitreous fluid of rats was found to increase vascular permeability within the retina,^13,20 an effect that could be attenuated by inhibition of PK activity²⁰ or with the selective B₂ kinin receptor antagonist, Hoe-140.¹³ Furthermore, intravitreal injection of active PK in diabetic rats was observed to induce significant retinal thickening over a 24-h period.²⁰

The combination of these findings suggests that activated PK in the retina and vitreous fluid of patients with proliferative diabetic retinopathy may directly contribute to the interstitial swelling and macular edema that often occurs in these patients. If this proves correct, therapeutic strategies to target the PK/kinin system could be of significant benefit in treatment of these conditions. The potential for such therapy is supported by recent studies employing selective PK inhibitors^21,22 or B₂ kinin receptor antagonist²³ in the acute management of forms of angioedema associated with excessive PK/kinin activity.^24,25

Tissue Kallikrein/Kinin in Ocular Function

In contrast to PK, TK is widely expressed by a variety of tissues, including those of the human eye. Ma and colleagues¹⁵ reported expression of TK, its principal substrate, LMWK, and both B₁ and B₂ kinin receptors in retina and ciliary body. Through hybridization experiments, TK, LMWK, and the kinin receptors were localized to the inner and outer nuclear layers of the retina as well as the ganglion cell layer. Interestingly, whereas PK activity is high in the vitreous fluid of subjects with proliferative diabetic retinopathy,^16,17 TK is reportedly low to nondetectable in the vitreous fluid of such subjects²⁶ and is not likely a factor in this form of ocular pathology.

Components of the TK system are also expressed at multiple tissue sites in the anterior portion of the human eye.²⁷ The presence of mRNA encoding TK and B₁ and B₂ kinin receptors has been demonstrated in nonpigmented epithelial cells and in ciliary muscle and trabecular meshwork cells cultured from human donors. Furthermore, expression of TK and kinin receptor proteins by the epithelial lining of the ciliary body, ciliary muscle, and trabecular meshwork has been verified using immunohistochemistry and immunoblotting. In addition, kininase activity for degradation of bradykinin is present in both ciliary muscle and trabecular meshwork cells. At this time, there is no evidence that expression of LMWK occurs in tissues of the anterior segment. Nonetheless, proteomic analysis of aqueous humor has revealed the presence of kininogen substrate,²⁸ which likely enters through a defined diffusional pathway for the movement of proteins from plasma into the anterior chamber.^29,30 Collectively, the data indicate that all components of the TK system are present throughout the anterior and posterior regions of the eye and are available for the generation of kinins that can then act in an autocrine/paracrine fashion on multiple cell types to influence ocular function.

Stimulation of kinin receptors in ocular cells activates multiple signaling pathways. For example, bradykinin stimulation of B₂ kinin receptors on bovine or human trabecular meshwork cells promotes phosphoinositide formation,³¹ elevates intracellular free calcium,^32,33 and stimulates ERK activity.³⁴ B₂ receptor activation in trabecular meshwork cells also promotes synthesis and release of prostaglandins.³⁵ At a more functional level, bradykinin stimulation of B₂ receptors relaxes retinal arterioles¹⁴ and the ciliary artery³⁶ and has been shown to increase outflow facility in perfused bovine anterior segments.³⁷ Although relaxation of arterial blood vessels is a rapid effect, bradykinin's action to enhance outflow facility is slow to develop and requires hours to achieve peak effect. Stimulation of outflow is also dependent on matrix metalloproteinase (MMP) activity, consistent with bradykinin's action to promote acute release of constitutively-expressed MMP-9 from both bovine and human trabecular meshwork cells.^34,37 These results raise the possibility that the TK/kinin system may have a role in the regulation of ocular blood flow and in the control of aqueous dynamics. With regard to the latter point, however, it must be emphasized that animal models of anterior segment exhibit clear differences from that of the human eye, and the potential for TK and kinins to modulate aqueous outflow remains to be examined rigorously in perfused human anterior segments or other appropriate human models of ocular function.

Disruption of the TK gene (KLK1) in mice markedly reduces kinin-forming activity in tissues. In the salivary gland, the major kinin-producing organ, kinin production was found to be decreased by 98% in TK-deficient mice, and kinin levels were virtually absent in all other tissues examined.³⁸ Formation of kinins from kininogen was also lacking in arterial blood vessels in the absence of TK expression.³⁹ Such findings indicate that, at least in mice, TK is the principal kinin-forming enzyme in major tissues and organs. Interestingly, blood pressure remains normal in situations of diminished or absent TK activity. Nonetheless, experiments in TK-deficient mice and also human subjects point to a physiological role for the TK/kinin system in modulation of vascular tone. Studies in TK-deficient mice have revealed a decreased capacity for flow-induced arterial vasodilation,^39,40 indicative of endothelial dysfunction. A related phenomenon has been reported for human subjects partially deficient in TK activity. In these subjects, elevated shear stress actually resulted in a paradoxical narrowing, rather than opening, of the arterial lumen.⁴¹

Thus, while the vascular TK system may have little role in the regulation of basal blood flow and pressure, it could be critical for proper adjustment of vascular tone to acute changes in flow or sheer stress, an important mechanism in maintaining tissue perfusion during periods of dynamic change in blood supply. Indeed, TK production of kinins in mice has been shown to be a significant factor in limiting ischemia-induced injury in both cardiac and renal tissues.^42,43 Moreover, absence of TK in cardiac tissue has been observed to markedly attenuate the tissue protection generally provided by ischemic preconditioning.⁴⁴ It is intriguing to speculate that the TK/kinin system may also be important in the mechanism of ischemic preconditioning that serves to limit ischemia-induced injury in ocular tissues such as retina.^45,46 Furthermore, if the function of TK activity within the vasculature is to modulate responses to changes in flow or stress, it is possible that the contribution of the TK/kinin system to regulation of aqueous dynamics may not be in the control of basal outflow but, instead, may be in the adaptation of aqueous outflow to changes in intraocular pressure or other stresses that may be exerted upon the trabecular meshwork.

Conclusions

The kallikrein/kinin system has been studied for decades and its role in pathophysiological events is well established; however, recent advances have provided evidence of a much broader participation of kallikreins and kinins at a physiological level. It is now clear that PK and HMWK bind to the vascular endothelium, where PK is then activated to release bradykinin to act locally on blood vessels. TK, in turn, appears to be important for adaptation of blood flow to acute changes in flow or shear stress, and also in the processes for ischemic preconditioning and protection of tissues against ischemic injury. At present, data on the kallikrein/kinin system in the eye are relatively limited. However, PK and HMWK have been demonstrated in retina of the rat, and all components of the TK system are found throughout the human eye in various layers of the retina, ciliary body, ciliary muscle, nonpigmented epithelium, and trabecular meshwork. These components are well positioned to participate in many aspects of ocular function.

B₁ and B₂ receptors are also present on key target tissues and initiate cellular signaling when activated by kinin peptides. Activation of B₂ receptors promotes relaxation of retinal and ciliary arteries and has been shown to increase outflow facility in the perfused bovine anterior segment. Of particular interest is the recent finding of abundant amounts of PK/kinin components in the vitreous fluid of human subjects with proliferative diabetic retinopathy, which has led to the proposal that increased PK activity may contribute to the development of retinal edema in these subjects, similar to the effects of excessive PK activity in patients with hereditary angioedema. These observations, viewed within the context of a new appreciation of potential physiological roles of the kallikrein/kinin system, raise the possibility of a function for kallikreins and kinins in modulation of ocular blood flow, in ischemic preconditioning and protection of ocular tissues against ischemic injury, in adaptation of aqueous outflow to changes in intraocular pressure and stress, and as significant factors in the pathogenesis of advanced diabetic retinopathy. Clearly, significantly more information is needed to determine the merit of such ideas, but answers to these or related questions have the potential to open new targets and avenues of therapy for important forms of ocular dysfunction.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Bhoola

K.D.

, Figueroa

C.D.

, Worthy

Bioregulation of kinins: Kallikreins, kininogens and kininases. Pharmacol. Rev., 44:1–80. 1992.

Joseph

, Kaplan

A.P.

Formation of bradykinin: A major contributor to the innate inflammatory response. Adv. Immunol., 86:159–208. 2005.

Gailani

, Renne

The intrinsic pathway of coagulation: A target for treating thromboembolic disease. J. Thromb. Haemost., 5:1106–1112. 2007.

Slim

, Torremocha

, Moreau

et al. Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. J. Am. Soc. Nephrol., 13:968–976. 2002.

Motta

, Rojkjaer

Hasan, A.A.K., Cines, D.B., and Schmaier, A.H. High molecular weight kininogen regulates prekallikrein assembly and activation on endothelial cells: A novel mechanism for contact activation. Blood, 91:516–528. 1998.

Shariat-Madar

, Mahdi

, Schmaier

A.H.

Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J. Biol. Chem., 277:17962–17969. 2002.

Schmaier

A.H.

, McCrae

K.R.

The plasma kallikrein-kinin system: its evolution from contact activation. J. Thromb. Haemost., 5:2323–2329. 2007.

Leeb-Lundberg

L.M.

, Marceau

, Muller-Esterl

, Pettibone

D.J.

, Zuraw

B.L.

International union of pharmacology. XLV. Classification of the kinin receptor family: From molecular mechanisms to pathophysiological consequences. Pharmacol. Rev., 57:27–77. 2005.

Blais

Jr. , Marceau

, Rouleau

J.-L.

, Adam

. The kallikrein-kininogen-kinin system: lessons from the quantification of endogenous kinins. Peptides, 21:1903–1940. 2000.

10.

Zhang

, Tan

, Zhang

, Skidgel

R.A.

Carboxypeptidase M and kinin B1 receptors interact to facilitate efficient b1 signaling from B2 agonists. J. Biol. Chem., 283:7994–8004. 2008.

11.

Davis

A.E.

3rd , Mejia

, Lu

Biological activities of C1 inhibitor. Mol. Immunol., 45:4057–4063. 2008.

12.

Zhou

, Chao

Kallistatin: A novel human tissue kallikrein inhibitor. J. Biol. Chem., 267:25873–25880. 1992.

13.

Phipps

J.A.

, Clermont

A.C.

, Sinha

et al. Plasma kallikrein mediates angiotensin II type I receptor-stimulated retinal vascular permeability. Hypertension, 53:175–181. 2009.

14.

Jeppesen

, Aalkjaer

, Bek

Bradykinin relaxation in small porcine retinal arterioles. Invest. Ophthalmol. Vis. Sci., 43:1891–1896. 2002.

15.

J.X.

, Song

, Hatcher

H.C.

et al. Expression and cellular localization of the kallikrein-kinin system in human ocular tissues. Exp. Eye Res., 63:19–26. 1996.

16.

Gao

B.B.

, Clermont

, Rook

et al. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat. Med., 13:181–188. 2007.

17.

Gao

B.B.

, Chen

, Timothy

, Aiello

L.P.

, Feener

E.P.

Characterization of the vitreous proteome in diabetes without diabetic retinopathy and diabetes with proliferative diabetic retinopathy. J. Proteome Res., 7:2516–2525. 2008.

18.

Krogsaa

, Lund-Andersen

, Mehlsen

, Sestoft

, Larsen

The blood-retinal barrier permeability in diabetic patients. Acta Ophthalmol., 59:689–694. 1981.

19.

Frank

R.M.

Diabetic retinopathy. N. Engl. J. Med., 350:48–58. 2004.

20.

Clermont

, Chilcote

T.J.

, Kita

et al. Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats. Diabetes, 60:1590–1598. 2011.

21.

Schneider

, Lumry

, Vegh

, Williams

A.H.

, Schmalbach

. Critical role of kallikrein in hereditary angioedema pathogenesis: A clinical trial of ecallantide, a novel kallikrein inhibitor. J. Allergy Clin. Immunol., 120:416–422. 2007.

22.

Zuraw

, Cicardi

, Levy

R.J.

et al. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J. Allergy Clin. Immunol., 126:821–827. 2010.

23.

Bork

, Frank

, Grundt

et al.

Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant)

J. Allergy Clin. Immunol., 119:1497–1503. 2007.

24.

Nussberger

, Cugno

, Amstutz

et al. Plasma bradykinin in angio-oedema. Lancet, 351:1693–1697. 1998.

25.

Kaplan

A.P.

, Joseph

The bradykinin-forming cascade and its role in hereditary angiodema. Ann. Allergy Asthma Immunol., 104:193–204. 2010.

26.

Pinna

, Emanueli

, Dore

et al. Levels of human tissue kallikrein in the vitreous fluid of patients with severe proliferative diabetic retinopathy. Ophthalmologica, 218:260–263. 2004.

27.

Webb

J.G.

, Yang

, Crosson

C.E.

Expression of the kallikrein/kinin system in human anterior segment. Exp. Eye Res., 89:126–132. 2009.

28.

Chowdhury

U.R.

, Madden

B.J.

, Charlesworth

M.C.

, Fautsch

M.P.

Proteome analysis of human aqueous humor. Invest. Ophthalmol. Vis. Sci., 51:4921–4931. 2010.

29.

Barsotti

M.F.

, Bartels

S.P.

, Freddo

T.F.

, Kamm

R.D.

The source of protein in the aqueous humor of the normal monkey eye. Invest. Ophthalmol. Vis. Sci., 33:581–595. 1992.

30.

Bert

R.J.

, Caruthers

S.D.

, Jara

et al. Demonstration of an anterior diffusional pathway for solutes in the normal human eye with high spatial resolution contrast-enhanced dynamic MR imaging. Invest. Ophthalmol. Vis. Sci., 47:5153–5162. 2006.

31.

Sharif

N.A.

, Xu

S.X.

Pharmacological characterization of bradykinin receptors coupled to phosphoinositide turnover in SV40-immortalized human trabecular meshwork cells. Exp. Eye Res., 63:631–637. 1996.

32.

Llobet

, Gual

, Pales

et al. Bradykinin decreases outflow facility in perfused anterior segments and induces shape changes in passaged BTM cells in vitro. Invest Ophthalmol. Vis. Sci., 40:113–125. 1999.

33.

Webb

J.G.

, Shearer

T.W.

, Yates

P.W.

, Mukhin

Y.V.

, Crosson

C.E.

Bradykinin enhancement of PGE₂ signaling in bovine trabecular meshwork cells. Exp. Eye Res., 76:283–289. 2003.

34.

Webb

J.G.

, Yang

, Crosson

C.E.

Bradykinin activation of extracellular signal-regulated kinases in human trabecular meshwork cells. Exp. Eye Res., 92:495–501. 2011.

35.

Polansky

J.R.

, Kurtz

R.M.

, Alvarado

J.A.

, Weinreb

R.N.

, Mitchell

M.D.

Eicosanoid production and glucocorticoid regulatory mechanisms in cultured human trabecular meshwork cells. Prog. Clin. Biol. Res., 312:113–138. 1989.

36.

Zhu

, Beny

J.L.

, Flammer

, Luscher

T.F.

, Haefliger

I.O.

Relaxation by bradykinin in porcine ciliary artery. Role of nitric oxide and K⁽⁺⁾-channels. Invest. Ophthalmol. Vis. Sci., 38:1761–1767. 1997.

37.

Webb

J.G.

, Husain

, Yates

P.W.

, Crosson

C.E.

Kinin modulation of conventional outflow facility in the bovine eye. J. Ocul. Pharmacol. Ther., 22:310–316. 2006.

38.

Meneton

, Bloch-Faure

, Hagege

A.A.

et al. Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice. Proc. Natl. Acad. Sci. USA, 98:2634–2639. 2001.

39.

Bergaya

, Meneton

, Bloch-Faure

et al. Decreased flow-dependent dilation in carotid arteries of tissue kallikrein-knockout mice. Circ. Res., 88:593–599. 2001.

40.

Bergaya

, Matrougui

, Meneton

, Henrion

, Boulanger

C.M.

Role of tissue kallikrein in response to flow in mouse resistance arteries. J. Hypertens., 22:745–750. 2004.

41.

Azizi

, Boutouyrie

, Bissery

et al. Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans. J. Clin. Invest., 115:780–787. 2005.

42.

Griol-Charhbili

, Messadi-Laribi

, Bascands

J.L.

et al. Role of tissue kallikrein in the cardioprotective effects of ischemic and pharmacological preconditioning in myocardial ischemia. FASEB J., 19:1172–1174. 2005.

43.

Kakoki

, McGarrah

R.W.

, Kim

H.S.

, Smithies

Bradykinin B₁ and B₂ receptors both have protective roles in renal ischemia/reperfusion injury. Proc. Natl. Acad. Sci. USA, 104:7576–7581. 2007.

44.

Messadi-Laribi

, Griol-Charhbili

, Gaies

et al. Cardioprotection and kallikrein-kinin system in acute myocardial ischaemia in mice. Clin. Exp. Pharmacol. Physiol., 35:489–493. 2008.

45.

Roth

, Li

, Rosenbaum

P.S.

et al. Preconditioning provides complete protection against retinal ischemic injury in rats. Invest. Ophthalmol. Vis. Sci., 39:775–785. 1998.

46.

Roth

Endogenous neuroprotection in the retina. Brain Res. Bull., 62:461–466. 2004.