Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

Abstract

Recent evidence suggests that higher-than-usual antihypertensive dosages of renin-angiotensin-aldosterone system blockers may provide additional protection from progression of chronic renal disease; however, there have been few long-term studies, and the underlying mechanisms remain uncertain. This study examined the effects of long-term (14 mo) administration of ultrahigh dosages of the angiotensin receptor blocker candesartan on the progression of renal injury in spontaneously hypertensive rats (SHR). Beginning 8 wk after birth, SHR underwent unilateral nephrectomy and were given vehicle (control), or candesartan at a standard 5 mg/kg per d (T5), high 25 mg/kg per d (T25), or ultrahigh 75 mg/kg per d dosage (T75). After 2 wk, BP was reduced in all treated groups; however, it was better controlled in the high-dosage groups (T25 and T75). Urinary protein was significantly reduced in T75 after 2 wk of treatment and was also declined in the other two treatment groups but only after 2 mo. Exogenous angiotensin II test showed that complete angiotensin receptor blockade was achieved only in the high-dosage groups. Renal inflammation and macrophage (ED-1) infiltration were significantly ameliorated in both T25 and T75 but not in T5 rats. This was associated with the changes of tubular expression of monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and the phosphorylated NF-B, a marker for activation. Suppression of ED-1, monocyte chemoattractant protein-1, and RANTES expression and NF-B activation were greater in T75 as compared with T25. These findings suggest that candesartan has dosage-dependent, anti-inflammatory effects that are mediated by suppression of NF-B activation and chemokine expression. Renal protection with high-dosage therapy may depend on these nonhemodynamic effects.

Posttranslational Modification of the AU-Rich Element Binding Protein HuR by Protein Kinase Cδ Elicits Angiotensin II-Induced Stabilization and Nuclear Export of Cyclooxygenase 2 mRNA

“…Prostaglandins generated by the glomerular COX-2 enzyme play an important role in counterbalancing the vasoconstrictory effects of AngII and are, furthermore, implicated in tubuloglomerular feedback mechanism (22). Importantly, in addition to regulation of intrarenal vascular tone and water hemostasis, PGE 2 elicits several growth-promoting and proinflammatory effects initiated by AngII (15,22,63). The AT 1 receptor, which is the primary receptor for AngII in MC, can activate multiple signaling pathways including Ras, the MAPKs, the PI3K, the Akt/PKB kinase, and PKC, respectively (3).…”

Renoprotective effects of angiotensin receptor blocker and stem cells in acute kidney injury: Involvement of inflammatory and apoptotic markers

“…Conceding with our findings, candesartan suppressed the renal MCP-1 and NF-jB in a model of chronic kidney disease. 34 Chen et al 35 showed the anti-inflammatory effects of candesartan through a direct antioxidant action independent of ARB. They postulated that candesartan has the ability to inhibit ROS production and to correct the redox imbalance induced by TNF-a.…”

Role of Intrarenal Angiotensin System Activation, Oxidative Stress, Inflammation, and Impaired Nuclear Factor-Erythroid-2-Related Factor 2 Activity in the Progression of Focal Glomerulosclerosis

“…The salutary effect of rennin-angiotensin system blockade is not only caused by its antihypertensive/hemodynamic actions, but also by its ability to reduce oxidative stress, inflammation, and fibrosis, which are major mediators of progression of renal disease (Esteban et al, 2003;Remuzzi et al, 2005;Hayashi et al, 2010). Several studies have demonstrated activation of the intrarenal angiotensin system marked by concomitant up-regulation of angiotensin II and AT1 receptor expression along with activation/upregulation of oxidative, inflammatory, and fibrogenic pathways in the diseased kidney and their amelioration with angiotensin blockade (Gonçalves et al, 2004;Xu et al, 2005;Vaziri et al, 2007;Yu et al, 2007).…”