Renal targeting of captopril using captopril-lysozyme conjugate enhances its antiproteinuric effect in adriamycin-induced nephrosis

Willemijn A.K.M. Windt*, Jai Prakash, Robbert Jan Kok, Frits Moolenaar, C. Alex Kluppel, Dick de Zeeuw, Richard P.E. van Dokkum, Robert H. Henning

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    12 Citations (Scopus)

    Abstract

    Introduction: High-sodium intake blunts the renoprotective efficacy of angiotensin-converting enzyme (ACE) inhibitors. We investigated whether targeting the drug to the kidneys may attenuate the inferior response to ACE inhibitor (ACE-I) under high-sodium conditions. The ACE-I, captopril, was coupled to the low molecular weight protein (LMWP) lysozyme, yielding captopril-lysozyme conjugates that accumulate specifically in the proximal tubular cells of the kidneys. We compared the antiproteinuric efficacy of captopril to that of the captopril-lysozyme conjugate in adriamycin-induced proteinuric rats fed with a high-sodium diet. Materials and methods: Rats with adriamycin (single injection 2 mg/kg)-induced proteinuria were put on a high-sodium diet (HS; 3% NaCl). When stable proteinuria developed at 5.5 weeks, animals were assigned to the following subcutaneous treatments: (1) vehicle (n=7); (2) lysozyme (equivalent to the amount in conjugate) (n=7); (3) captopril (5 mg/kg/24 hours) (n=8); (4) captopril-lysozyme conjugate (captopril content equivalent to 1mg captopril/kg/24 hours) (n=7). Blood pressure and proteinuria were monitored. After 10 days of treatment the rats were sacrificed and kidneys and plasma were removed. Results: Results are given as mean ± S.E.M. After injection with adriamycin at t=0, stable proteinuria developed, amounting to 547±79 mg/24 hours at week 5.5. Subsequently, after seven and nine days of treatment, no reduction of proteinuria was observed in the captopril-treated group. In contrast, a significant reduction in proteinuria, amounting to 35±4% (day seven) and 25±2% (day nine), was observed in the captopril-lysozyme conjugate group (p<0.05 compared with the captopril group). In contrast, blood pressure was reduced in the captopril-treated group by 13.9±2.9 mmHg, while in the captopril-lysozyme treated group, an increase of 7.9±3.3 mmHg was found. Renal ACE activity was lowered by 30% in the captopril, as well as in the captopril-lysozyme conjugate treated group, compared with control. Furthermore, the ratio of kidney: plasma levels of captopril almost doubled as a consequence of coupling to lysozyme. Conclusion: In proteinuric rats fed with a high-sodium diet, captopril induced a reduction in blood pressure without an effect on proteinuria. In contrast, renal targeting of a five times lower dose of the ACE-I with the captopril-lysozyme conjugate reduced proteinuria without reducing blood pressure. Therefore, renal targeting of ACE-I may be a promising strategy to optimise the therapeutic response of ACE-I.

    Original languageEnglish
    Pages (from-to)197-202
    Number of pages6
    JournalJRAAS - Journal of the Renin-Angiotensin-Aldosterone System
    Volume5
    Issue number4
    DOIs
    Publication statusPublished - 1 Jan 2004

    Keywords

    • ACE-inhibition
    • Low molecular weight protein
    • Lysozyme
    • Proteinuria
    • Renal targeting

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