The klotho gene, which encodes a single-pass transmembrane protein and a secreted protein, is expressed predominantly by the distal renal tubules and is related to calcium phosphorus metabolism, ion channel regulation, intracellular signaling pathways, and longevity. Klotho deficiency aggravates acute kidney injury and renal fibrosis. Exposure to nicotine also worsens kidney injury. Here, we investigated renal Klotho protein expression in a mouse model of chronic (28-day) nicotine exposure, in which mice received nicotine or vehicle (saccharine) in drinking water, comparing wild-type (WT) mice, klotho-haploinsufficient ( kl/+) mice, and their respective controls, in terms of the effects of that exposure. Nicotine exposure was associated with a significant decline in renal Klotho expression in WT and kl/+ mice as well as a reduction in the glomerular filtration rate in WT mice. Although plasma electrolytes were similar among the groups, fractional excretion of sodium was reduced in both nicotine-exposed groups. The nicotine-WT mice presented augmented baroreflex sensitivity to nitroprusside and augmented sympathetic cardiac modulation. However, nicotine- kl/+ mice presented higher plasma levels of urea and aldosterone together with a higher α-index (spontaneous baroreflex) and higher peripheral sympathetic modulation, as evaluated by spectral analysis. We can conclude that nicotine downregulates Klotho expression as well as that renal and autonomic responses to nicotine exposure are modified in kl/+ mice.

Dedico este trabalho aos dois grandes amores da minha vida: à minha mãe, Carmen, pelo amor incondicional e verdadeiro, e ao meu marido, Igor, meu parceiro da vida e eterno amor. AGRADECIMENTOS A Deus, pela vida e pela benção de viver bem todos os dias. À Profa. Dra. Lúcia da Conceição Andrade, uma profissional brilhante e muito dedicada ao trabalho e às pessoas. Agradeço pela oportunidade de ter sido sua aluna, pelos ensinamentos científicos e pela amizade e carinho que construímos ao longo desta jornada. Ao Prof. Dr. Rildo A. Volpini, um profissional extremamente focado e integrado em tudo o que faz. Obrigado por ter sido meu co-orientador, vou levar sempre comigo os longos dias de bancada, as sugestões e pela amizade e carinho que com certeza foram muito importantes para meu crescimento pessoal e profissional. Ao Prof. Dr. Antonio Carlos Seguro, chefe do Laboratório de Pesquisa Básica-LIM-12, pelas aulas didáticas, por ter autorizado meu afastamento para conclusão do doutorado-sanduíche e pelas sugestões muito bem vindas.