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INVITED COMMENTARY
Year : 2017  |  Volume : 19  |  Issue : 1  |  Page : 138-139

Kallikrein-kinin system: is it the fountain of youth?


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Date of Web Publication02-Dec-2016

Correspondence Address:
Fabio Castiglione
St. Peter's Andrology and the Institute of Urology, University College London Hospital, London, UK

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1008-682X.192636

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How to cite this article:
Garaffa G, Castiglione F. Kallikrein-kinin system: is it the fountain of youth?. Asian J Androl 2017;19:138-9

How to cite this URL:
Garaffa G, Castiglione F. Kallikrein-kinin system: is it the fountain of youth?. Asian J Androl [serial online] 2017 [cited 2017 Apr 24];19:138-9. Available from: http://www.ajandrology.com/text.asp?2017/19/1/138/192636 - DOI: 10.4103/1008-682X.192636

Erectile dysfunction (ED) is a common disorder characterized by multifactorial etiology. Cardiovascular disease, diabetes, hormone alterations, and surgical manipulation represent the common causes of ED.[1] Age is also an independent risk factor for ED, with an estimated increase in ED of 4.6% per year between the ages of 60 and 69 years.[2]

The introduction of phosphodiesterase-5 inhibitors (PDE5I), like Viagra, in the market has exponentially improved the therapeutic armamentarium for ED.[3] However, the demand for alternative pharmacotherapeutic options continues to growth as a consequence of the increased percentage of the elderly in the society and increasing acknowledgment that a nearly one-third of ED patients do not respond to PDE5I treatment.

Age-related ED is characterized histologically by the loss of the corpus cavernosum smooth muscle tissue and by its substitution with fibrosis.[4] Fibrosis is defined by the excessive accumulation of extracellular connective tissues such as collagen, elastin, and fibronectin.[5] Progressive cavernous fibrosis can provoke mechanical alterations of the penis, reducing its elasticity and compliance, and it can lead at the end to an irreversible ED.[4]

Reduction of testosterone levels and NO production and an increased concentration of reactive oxygen species in the penis seem to be responsible for the association between aging and ED.[6] However, recently, research has demonstrated the importance of Rho-associated protein kinase (ROCK) signaling in maintaining a flaccid penile state, and inhibition of ROCK signaling potentiates smooth-muscle relaxation. In aged animals, RhoA pathway inhibition via cavernosal injection of Y-27632 decreases ROCK activity and improves erectile function.[7] More important, several studies have suggested the ROCK participation in the pathogenesis of a broad array of fibrotic diseases.[5]

In Asian Journal of Andrology, Cui et al.[8] explored the efficacy and the underlying mechanisms of human Tissue kallikrein 1 (hKLK1) on age-related corpora fibrosis using a rat model of the disease. Tissue kallikrein 1 (KLK1), a member of the serine proteinase superfamily, is responsible for the production of several kinin peptides. Recent studies demonstrated that kallikrein-kinin system (KKS) could be a therapeutic target for cardiovascular diseases and that KLK gene delivery could reduce renal fibrosis, and the transgenic expression of hKLK1 counteracts the progression of cardiac fibrosis in a rat model of diabetic cardiomyopathy.[8],[9]

In the present study,[8] male wild-type Sprague-Dawley rats (WTR) and transgenic rats harboring the hKLK1 gene (TGR) were fed to 4 and 18 months of age, respectively, and divided into three groups: young WTR (yWTR) as the control, aged WTR (18 months, aWTR), and aged TGR (18 months, aTGR). The authors showed that aTGR rats have a better erectile function, less cavernous fibrosis and ROCK system activation than aWTR.

The results of the study are intriguing in that they suggest that hKLK1 might be a new treatment method for age-related ED in animals and human beings. According to these results, overexpression of hKLK1 might counteract the effect of ROCK system and prevent the inevitable age-related fibrosis of the penis. Although the study showed a possible new target of the treatment of ED, the conclusions arising from this experiment are difficult to interpret. In our opinion, the conclusions of this study could have been affected by several limitations.

First, we think that the evaluation of penile fibrosis, which represents the main endpoint of this study, may be not adequate. The authors performed a semiquantitative method, Masson's trichrome, for the evaluation of collagen content in the penis. In our opinion, a quantitative method like Western blot analysis for collagen and elastin content of the corpora cavernosa could be more accurate.[10],[11]s

Second, the author stated in the conclusion that the fibrosis prevention is due to the inhibition of the ROCK pathway without investigating the effect of the hKLK1 on the NO system. NO represents the main actor of the penile erection mechanism and, additionally, it is well known for its antifibrotic properties.[1],[5] More important, data suggest that effectors of the activated NO pathway may inhibit the ROCK pathway. Under this point of view, the activation of NO system may be responsible for the protective effects of hKLK. This aspect represents, in our opinion, the main limit of the study, especially because the same group had already shown, in a recently very similar study, that hKLK1 could play a preventive role in age-related erectile dysfunction by activation of the NO-cGMP pathway and inhibition of the RhoA-ROCK pathway.[12]

Despite its limitations, this study adds valuable data to the literature suggesting that hKLK gene therapy can benefit patients with age-related ED by attenuating the penile fibrotic process. The question of how the activation of kallikrein system is able to prevent the age-related penile fibrosis needs to be addressed.


  Competing Interests Top


Both authors declare no competing interests.

 
  References Top

1.
Dean RC, Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction. Urol Clin North Am 2005; 32: 379-95, v.  Back to cited text no. 1
    
2.
Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, et al. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. J Urol 2000; 163: 460-3.  Back to cited text no. 2
    
3.
Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil study group. N Engl J Med 1998; 338: 1397-404.  Back to cited text no. 3
    
4.
Bakircioglu ME, Sievert KD, Nunes L, Lau A, Lin CS, et al. Decreased trabecular smooth muscle and caveolin-1 expression in the penile tissue of aged rats. J Urol 2001; 166: 734-8.  Back to cited text no. 4
    
5.
Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 2012; 18: 1028-40.  Back to cited text no. 5
    
6.
Jin L, Burnett AL. RhoA/Rho-kinase in erectile tissue: mechanisms of disease and therapeutic insights. Clin Sci (Lond) 2006; 110: 153-65.  Back to cited text no. 6
    
7.
Sopko NA, Hannan JL, Bivalacqua TJ. Understanding and targeting the Rho kinase pathway in erectile dysfunction. Nat Rev Urol 2014; 11: 622-8.  Back to cited text no. 7
    
8.
Cui K, Luan Y, Wang T, Zhuan L, Rao K, et al. Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1. Asian J Androl 2016. doi: 10.4103/1008-682X.189209. [Epub ahead of print].  Back to cited text no. 8
    
9.
Tschope C, Walther T, Koniger J, Spillmann F, Westermann D, et al. Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene. FASEB J 2004; 18: 828-35.  Back to cited text no. 9
    
10.
Castiglione F, Dewulf K, Hakim L, Weyne E, Montorsi F, et al. Adipose-derived stem cells counteract urethral stricture formation in rats. Eur Urol 2016. pii: S0302-2838(16)30132-4. doi: 10.1016/j.eururo.2016.04.022. [Epub ahead of print].  Back to cited text no. 10
    
11.
Castiglione F, Hedlund P, Van der Aa F, Bivalacqua TJ, Rigatti P, et al. Intratunical injection of human adipose tissue-derived stem cells prevents fibrosis and is associated with improved erectile function in a rat model of Peyronie′s disease. Eur Urol 2013; 63: 551-60.  Back to cited text no. 11
    
12.
Luan Y, Ruan Y, Wang T, Zhuan L, Wen Z, et al. Preserved erectile function in the aged transgenic rat harboring human tissue kallikrein 1. J Sex Med 2016; 13: 1311-22.  Back to cited text no. 12
    




 

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