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Authors
Abstract(s)
A nefropatia diabética é a principal causa de falência renal e, consequentemente,
factor determinante de morbilidade e mortalidade relacionada com a diabetes mellitus
(DM). No estado inicial da DM verifica-se hiperfiltração glomerular. A função glomerular
pode ser estimada pela quantificação da taxa de filtração glomerular (GFR). A adenosina
regula a GFR, modula o sistema renina-angiotensina (RAS) e o mecanismo de
feedback tubuloglomerular. A actividade do RAS renal encontra-se aumentada na
nefropatia diabética e contribui para a lesão progressiva da barreira de filtração glomerular.
O bloqueio do RAS constitui uma abordagem terapêutica fundamental em doentes
diabéticos. O efeito inibitório da adenosina sobre o RAS pode ser importante neste
contexto, podendo a adenosina constituir um importante novo alvo terapêutico no contexto
da nefropatia diabética. Foram objectivos deste trabalho a implementação de
uma metodologia para quantificar a GFR, caracterizar os efeitos da 2-cloroadenosina
(2CADO), um análogo estável da adenosina, sobre a função de renal de ratos com
diabetes experimental induzida por injecção de estreptozotocina, e relacioná-los com a
actividade do RAS renal.
Da implementação da metodologia para quantificar a GFR, foi possível concluir
que o melhor método inclui a injecção intravenosa de inulina radioactiva ou fluorescente
e determinação do time-course do decaimento no plasma. A administração intraperitoneal
de 2CADO aos ratos diabéticos atenuou o não aumento de peso corporal e
o aumento da ingestão de comida e bebida, e da excreção de urina. Além disso, atenuou
a excreção urinária de glicose e de ureia e normalizou a excreção urinária de
proteínas. Os ratos diabéticos apresentaram uma excreção urinária da angiotensinogéneo
superior à dos ratos controlo e a 2CADO não alterou este resultado.
Os resultados com a 2CADO demonstram a sua influência benéfica na nefropatia
diabética. Estes efeitos da 2CADO podem estar relacionados com a capacidade para
baixar a glicemia e melhorar a resistência à insulina mas também com efeitos renais
directos e indirectos. São necessários, no entanto, estudos mais aprofundados para
avaliar se a interacção adenosina/Ang II participa nesta renoprotecção indirecta.
Diabetic nephropathy is the main cause for end-stage renal disease and, consequently, a determinant factor to morbidity and mortality related to diabetes mellitus (DM). Initially, DM is characterized by glomerular hyperfiltration. Glomerular function can be estimated by quantification of glomerular filtration rate (GFR). Adenosine regulates GFR, modulates the renin-angiotensin system (RAS) and the tubuloglomerular feedback. Renal RAS activity is enhanced in diabetic nephropathy and contributes to impairment of glomerular filtration barrier. Pharmacological agents that inhibit RAS have been recommended to diabetic patients. Adenosine inhibitory effect of RAS can be important in this context as a new therapeutical target in diabetic nephropathy. The aims of these study were to implement a new method for GFR quantification and to characterize the effects of 2-chloroadenosin (2CADO), a stable and non-metabolized analogue of adenosine, in renal function of estreptozotocininduced diabetic rats and relate them with renal RAS activity. Our results show that the most accurate way to quantify GFR is to inject radioactive or fluorescent inulin, intravenously, and follow plasma decay time-course. The intraperitoneal administration of 2CADO, to estreptozotocin-induced diabetic rats, attenuates the arrest of body weight, and food and water intake, and urine excretion. Furthermore, it attenuates the urinary excretion of glucose and urea and normalizes protein excretion. Estreptozotocin-induced diabetic rats excreted more angiotensinogen than control rats, and 2CADO administration did not change these result. Taken together, the results express the beneficial effect of 2CADO in diabetic nephropathy. 2CADO effects may be related to the capacity to improve glicemia and insulin resistance, but also with direct and indirect renal effects. Further studies are required to evaluate if the adenosine/angiotensin II interaction participates in these indirect renoprotection.
Diabetic nephropathy is the main cause for end-stage renal disease and, consequently, a determinant factor to morbidity and mortality related to diabetes mellitus (DM). Initially, DM is characterized by glomerular hyperfiltration. Glomerular function can be estimated by quantification of glomerular filtration rate (GFR). Adenosine regulates GFR, modulates the renin-angiotensin system (RAS) and the tubuloglomerular feedback. Renal RAS activity is enhanced in diabetic nephropathy and contributes to impairment of glomerular filtration barrier. Pharmacological agents that inhibit RAS have been recommended to diabetic patients. Adenosine inhibitory effect of RAS can be important in this context as a new therapeutical target in diabetic nephropathy. The aims of these study were to implement a new method for GFR quantification and to characterize the effects of 2-chloroadenosin (2CADO), a stable and non-metabolized analogue of adenosine, in renal function of estreptozotocininduced diabetic rats and relate them with renal RAS activity. Our results show that the most accurate way to quantify GFR is to inject radioactive or fluorescent inulin, intravenously, and follow plasma decay time-course. The intraperitoneal administration of 2CADO, to estreptozotocin-induced diabetic rats, attenuates the arrest of body weight, and food and water intake, and urine excretion. Furthermore, it attenuates the urinary excretion of glucose and urea and normalizes protein excretion. Estreptozotocin-induced diabetic rats excreted more angiotensinogen than control rats, and 2CADO administration did not change these result. Taken together, the results express the beneficial effect of 2CADO in diabetic nephropathy. 2CADO effects may be related to the capacity to improve glicemia and insulin resistance, but also with direct and indirect renal effects. Further studies are required to evaluate if the adenosine/angiotensin II interaction participates in these indirect renoprotection.
Description
Keywords
Nefropatia diabética Adenosina Angiotensina II Angiotensina II - Nefropatia diabética
Citation
Publisher
Universidade do Porto