27-A bradykinin-potentiating peptide (BPP-10c) from Bothrops jararaca induces changes in seminiferous tubules

¹Center for Applied Toxinology (CAT-CEPID), Butantan Institute, São Paulo, São Paulo State, Brazil.

²Laboratory of Immunochemistry, Butantan Institute, São Paulo, São Paulo State, Brazil.

³Department of Celland Developmental Biology, Laboratory of Fish Endocrinology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, São Paulo State, Brazil.

⁴Department of Biochemistry, Chemistry Institute, University of São Paulo (USP), São Paulo, São Paulo State, Brazil.

⁵Natural and Human Sciences Center (CCNH), Federal University of ABC (UFABC), Santo André, São Paulo State, Brazil.

ABSTRACT

Background

The testis-specific isoform of angiotensin-converting enzyme (tACE) is exclusively expressed in germ cells during spermatogenesis. Although the exact role of tACE in male fertility is unknown, it clearly plays a critical function in spermatogenesis. The dipeptidase domain of tACE is identical to the C-terminal catalytic domain of somatic ACE (sACE). Bradykinin potentiating peptides (BPPs) from snake venoms are the first natural sACE inhibitors described and their structure-activity relationship studies were the basis for the development of antihypertensive drugs such as captopril. In recent years, it has been showed that a number of BPPs - including BPP-10c - are able to distinguish between the N- and C-active sites of sACE, what is not applicable to captopril. Considering the similarity between tACE and sACE (and since BPPs are able to distinguish between the two active sites of sACE), the effects of the BPP-10c and captopril on the structure and function of the seminiferous epithelium were characterized in the present study. BPP-10c and captopril were administered in male Swiss mice by intraperitoneal injection (4.7 μmol/kg for 15 days) and histological sections of testes were analyzed. Classification of seminiferous tubules and stage analysis were carried out for quantitative evaluation of germ cells of the seminiferous epithelium. The blood-testis barrier (BTB) permeability and distribution of claudin-1 in the seminiferous epithelium were analyzed by hypertonic fixative method and immunohistochemical analyses of testes, respectively.

Results

The morphology of seminiferous tubules from animals treated with BPP-10c showed an intense disruption of the epithelium, presence of atypical multinucleated cells in the lumen and degenerated germ cells in the adluminal compartment. BPP-10c led to an increase in the number of round spermatids and total support capacity of Sertoli cell in stages I, V, VII/VIII of the seminiferous epithelium cycle, without affecting BTB permeability and the distribution of claudin-1 in the seminiferous epithelium. Interestingly, no morphological or morphometric alterations were observed in animals treated with captopril.

Conclusions

The major finding of the present study was that BPP-10c, and not captopril, modifies spermatogenesis by causing hyperplasia of round spermatids in stages I, V, and VII/VIII of the spermatogenic cycle.

Key words: Bradykinin-potentiating peptide; Snake venom; Angiotensin-converting enzyme; Testis; Seminiferous epithelium

Correspondence: carlos.asilva@ufbac.edu.br

Competing interests The authors declare that there are no competing interests.

Authors' contributions JMG carried out most experiments assisted by other researchers. FCVP, MIB and CL contributed to the design of experiments. ACMC established the conditions for the study. CAS established the conditions for the study, was responsible for drafting the manuscripts, reading it and for the editoria corrections. All authors read and approved the final manuscript.