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Reversal of Renal Tubule Transporter Downregulation during Severe Leptospirosis with Antimicrobial Therapy

Tubular dysfunction is a hallmark of severe leptospirosis. Antimicrobial therapy is thought to interfere on renal involvement. We evaluated the expression of a proximal tubule type-3 Na⁺/H⁺ exchanger (NHE3) and a thick ascending limb Na⁺-K⁺-2Cl^– cotransporter (NKCC2) in controls and treated hamsters. Animals infected by a serovar Copenhageni isolate, were treated or not with ampicillin (AMP) and/or N-acetylcysteine (NAC). Leptospiral antigen(s) and expression of renal transporters were evaluated by immunohistochemistry, and serum thiobarbituric acid (TBARS) was quantified. Infected hamsters had high amounts of detectable leptospiral antigen(s) in target tissues while renal expression of NHE3 and NKCC2 decreased. Ampicillin treatment was associated with minimal or no detection of leptospiral antigens, normal expression of NHE3 and NKCC2 transporters, and reduced levels of TBARS. NAC effect was restricted to lowering TBARS. Early and late AMP treatment rescued tubular defects in severe leptospirosis disease, and there was no evidence of benefit from antioxidant therapy.

Received March 13, 2007. Accepted for publication May 22, 2007.

Financial support: Financial support for this study was provided by the Fundação de Amparo à Pesquisa do Estado de São Paulo, the Conselho Nacional de Desenvolvimento Científico e Tecnológico, the Fundação Faculdade de Medicina USP, and the Laboratório de Investigação Médica USP, and Public Health Service (grants AI052473 and TW00919), the National Institute of Allergy and Infectious Diseases (grants 300861/96-11 and 420067/2005-1), and the Renorbio Program from the Brazilian National Research Council.

^* Address correspondence to Anne Spichler, University of São Paulo, Department of Nephrology, Laboratorio Pesquisa Basica LIM/12, Faculdade de Medicina USP, Av. Dr. Arnaldo, 455 3° Andar, Sala 3310, CEP 01246–903 São Paulo, SP, Brazil. E-mail: annespichler{at}terra.com.br

Authors’ addresses: Anne Spichler and Antonio Seguro, Department of Nephrology, LIM/12, University of São Paulo School of Medicine, and Laboratorio Pesquisa Basica LIM/12, Faculdade de Medicina USP, Av. Dr. Arnaldo, 455, 3rd floor, Room 3310, Mail code 01246–903, São Paulo, Brazil, Telephone: +55 11 306209848, Fax: +55 11 30629848, E-mails: annespichler{at}terra.com.br and trulu{at}usp.br. Albert I. Ko, Everton Fagonde Silva, and Cleiton Silva, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz/MS, Rua Waldemar Falcão, 121, Salvador, Bahia, Mail code 40295–001, Brazil, E-mails: aik2001{at}med.cornell.edu, efagonde{at}hotmail.com, and cleitonsilva{at}hotmail.com. Thales De Brito and Ana Maria Silva, Institute of Tropical Medicine, University of Sao Paulo Medical School, LIM/06, Sao Paulo, Brazil, Telephone: +55–11–30617066, Fax: +55–11–30645132, E-mail: thalesbr{at}usp.br. Daniel Athanazio, Departamento de Biointeração, ICS, UFBA, Av. Reitor Miguel Calmon, s/n^o, Campus do Canela, Mail code 40.110–100, Salvador, Bahia, Brazil, E-mail: dathanazio{at}cpqgm.fiocruz.br.