Abstract
BackgroundSeveral studies have shown that activation of the renin-angiotensin system may lead to hypertension, a major risk factor for the development of chronic kidney disease (CKD). The existing hypertension-induced CDK mouse models are quite fast and consequently away from the human pathology. Thus, there is an urgent need for a mouse model that can be used to delineate the pathogenic process leading to progressive renal disease. The objective of this study was dual: to investigate whether mice overexpressing renin could mimic the kinetics and the physiopathological characteristics of hypertension-induced renal disease and to identify cellular and/or molecular events characterizing the different steps of the progression of CKD.Methodology/Principal FindingsWe used a novel transgenic strain, the RenTg mice harboring a genetically clamped renin transgene. At 3 months, heterozygous mice are hypertensive and slightly albuminuric. The expression of adhesion markers such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 are increased in the renal vasculature indicating initiation of endothelial dysfunction. At 5 months, perivascular and periglomerular infiltrations of macrophages are observed. These early renal vascular events are followed at 8 months by leukocyte invasion, decreased expression of nephrin, increased expression of KIM-1, a typical protein of tubular cell stress, and of several pro-fibrotic agents of the TGFβ family. At 12 months, mice display characteristic structural alterations of hypertensive renal disease such as glomerular ischemia, glomerulo- and nephroangio-sclerosis, mesangial expansion and tubular dilation.Conclusions/SignificanceThe RenTg strain develops CKD progressively. In this model, endothelial dysfunction is an early event preceding the structural and fibrotic alterations which ultimately lead to the development of CKD. This model can provide new insights into the mechanisms of chronic renal failure and help to identify new targets for arresting and/or reversing the development of the disease.
Highlights
Several studies estimate that the number of patients affected by chronic kidney disease (CKD) is in sharp rise in western countries [1]
CKD can be promoted by a variety of mechanisms including hypertension which may affect any of the kidney structures by promoting development of chronic inflammation leading to fibrosis and progressive decline of renal function [3]
We found that the decline of renal function, as well as alterations in the expression of proteins involved in the integrity and the function of the kidney, were partially reversible when 13 month old animals were treated by an AT1 receptor antagonist [9]
Summary
Several studies estimate that the number of patients affected by CKD is in sharp rise in western countries [1]. One of the main objectives of our research group over the last years has been the identifications of molecular mechanisms responsible for the development of renal fibrosis For this purpose, we use a multitarget strategy based on experimental models of nephropathies in rodents to study mediators of inflammation, progression, stabilization or regression of renal lesions [4,5,6,7,8]. We use a multitarget strategy based on experimental models of nephropathies in rodents to study mediators of inflammation, progression, stabilization or regression of renal lesions [4,5,6,7,8] Even if these experimental models had provided new insights towards the progression and regression of CKD, a relative limitation would have been the fact that renal disease was induced in young animals for a rather short period of time. The objective of this study was dual: to investigate whether mice overexpressing renin could mimic the kinetics and the physiopathological characteristics of hypertension-induced renal disease and to identify cellular and/or molecular events characterizing the different steps of the progression of CKD
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