Kallikrein gene transfer reduces renal fibrosis, hypertrophy, and proliferation in DOCA-salt hypertensive rats

Abstract

In DOCA-salt hypertension, renal kallikrein levels are increased and may play a protective role in renal injury. We investigated the effect of enhanced kallikrein levels on kidney remodeling of DOCA-salt hypertensive rats by systemic delivery of adenovirus containing human tissue kallikrein gene. Recombinant human kallikrein was detected in the urine and serum of rats after gene delivery. Kallikrein gene transfer significantly decreased DOCA- and salt-induced proteinuria, glomerular sclerosis, tubular dilatation, and luminal protein casts. Sirius red staining showed that kallikrein gene transfer reduced renal fibrosis, which was confirmed by decreased collagen I and fibronectin levels. Furthermore, kallikrein gene delivery diminished myofibroblast accumulation in the interstitium of the cortex and medulla, as well as transforming growth factor (TGF)-beta1 immunostaining in glomeruli. Western blot analysis and ELISA verified the decrease in immunoreactive TGF-beta1 levels. Kallikrein gene transfer also significantly reduced kidney weight, glomerular size, proliferating tubular epithelial cells, and macrophages/monocytes. Reduction of proliferation and hypertrophy was associated with reduced levels of the cyclin-dependent kinase inhibitor p27(Kip1), and the phosphorylation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). The protective effects of kallikrein were accompanied by increased urinary nitrate/nitrite and cGMP levels, and suppression of superoxide formation. These results indicate that kallikrein protects against mineralocorticoid-induced renal fibrosis glomerular hypertrophy, and renal cell proliferation via inhibition of oxidative stress, JNK/ERK activation, and p27(Kip1) and TGF-beta1 expression.

Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling

“…Renal tubulointerstitial lesions, glomerular sclerosis, and enlargement, as well as cardiac hypertrophy and fibrosis, are common features associated with DOCA-salt treatment (13,43) and are accompanied by increased expression of TGF-␤ 1 , a major contributor to tissue remodeling (14,24). As a profibrotic factor, TGF-␤ enhances the expression of extracellular matrix proteins, including collagens I and III, and prevents the degradation of extracellular matrix proteins by inducing the synthesis of TIMPs in renal and cardiac cells (14,24,31).…”

Intermedin ameliorates vascular and renal injury by inhibition of oxidative stress

“…The high blood pressure induced by DOCA-salt treatment leads to damage of the cardiovascular and renal systems, often characterized by endothelial dysfunction, kidney fibrosis, glomerulosclerosis, and renal hypertrophy (4,32). Kidney damage in DOCA-salt rats is accompanied by a significant increase in the production of reactive oxygen species (ROS), proinflammatory cytokines, and profibrotic factors (4,17,18,42). In the present study, we evaluated the protective effect of human IMD gene delivery on DOCA-salt-induced oxidative stress, inflammation, fibrosis, and vascular injury.…”

Bradykinine et néphroprotection

“…Un des premiers travaux rapporte la réduction de certains paramètres du stress oxydant par la BK chez le rat diabétique de type 1 [31]. Une réduction de la formation de radical superoxyde et des concentrations sériques en triglycérides et cholestérol a été démon-trée après transfert du gène de la kallicréine [32][33][34]. Inversement, une aggravation du profil du stress oxydant a été décrite chez les souris n'exprimant pas le RB2 [29].…”

“…Bien que l'idée qu'une stimulation du RB2 de la BK puisse induire des effets thérapeutiques bénéfiques reste encore novatrice, ce concept émerge finalements des travaux de plusieurs groupes indépendants [28,29,[32][33][34]. Plusieurs agonistes non peptidiques sont disponibles et ont été testés dans des modèles différents [38][39][40].…”

“…Le transfert du gène de la kallicréine réduit la glycémie, restaure le profil lipidique et protège la fonction cardiaque chez le rat diabétique de type I [32]. Cette approche montre aussi des effets bénéfiques en améliorant la fibrose rénale chez le rat hypertendu [33,34]. La manipulation pharmacologique du SSK apparaît complexe car elle ne peut obéir à un schéma général directeur mais doit être évaluée en fonction des maladies (hypertension, diabète, inflammation…) et des organes cibles.…”