Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy.
BACKGROUND
The molecular mechanisms of renal injury in diabetic nephropathy (DN) are not completely understood, although inflammatory cells play a key role. The renin-angiotensin system (RAS) is involved in kidney damage; however, few studies have examined the localization of RAS components in human DN. Our aim was to investigate in renal biopsies the expression of RAS and their correlation with proinflammatory parameters and renal injury.


METHODS
The biopsies from 10 patients with type 2 diabetes mellitus and overt nephropathy were studied for the expression of RAS components by immunohistochemistry (IH). In addition, by Southwestern histochemistry we studied the in situ detection of the activated nuclear factor kappa B (NFkappaB), and by IH and/or in situ hybridization (ISH), the expression of monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T cell expressed and secreted (RANTES), whose genes are regulated by NFkappaB.


RESULTS
Angiotensin-converting enzyme (ACE) immunostaining was elevated in tubular cells and appeared in interstitial cells. Elevated levels of angiotensin II (Ang II) immunostaining were observed in tubular and infiltrating interstitial cells. There was also a down-regulation of AT1 and up-regulation of AT2 receptors. An activation of NFkappaB and a marked up-regulation of NFkappaB-dependent chemokines mainly in tubular cells was observed. Elevated levels of NFkappaB, chemokines, and Ang II in tubules were correlated with proteinuria and interstitial cell infiltration.


CONCLUSIONS
Our results show that in human DN, RAS components are modified in renal compartments, showing elevated local Ang II production, activation of tubular cells, and induction of proinflammatory parameters. These data suggest that Ang II contributes to the renal inflammatory process, and may explain the molecular mechanisms of the beneficial effect of RAS blockade.
Mezzano
Sergio
S
Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile. smezzano@uach.cl
Droguett
Alejandra
A
Burgos
M Eugenia
ME
Ardiles
Leopoldo G
LG
Flores
Claudio A
CA
Aros
Claudio A
CA
Caorsi
Italo
I
Vío
Carlos P
CP
Ruiz-Ortega
Marta
M
Egido
Jesús
J
D018925:Chemokines / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000150:complications* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000209:etiology* / Q000473:pathology; D012084:Renin-Angiotensin System; D015854:Up-Regulation
D018925:Chemokines; D018836:Inflammation Mediators; D016328:NF-kappa B