Abstract
Intrarenal renin-angiotensin system (RAS) activation plays a critical role in the development and progression of renal injury. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by multiple independent mechanisms. Angiotensinogen (AGT) is the only known substrate for renin that is a rate-limiting enzyme of the RAS. Recently, enhanced intrarenal AGT levels have been shown to reflect the intrarenal RAS status in hypertension, chronic glomerular disease and diabetic nephropathy. In this review, we focus on AGT expression of the diseased glomeruli in the progression of glomerular disease. An anti-glomerular basement membrane nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of AGT and Ang II. The addition of Ang II type 1 receptor blocker to CC-chemokine recaptor 2 antagonist markedly attenuated the induction of macrophage infiltration, AGT and Ang II, and reduced glomerular crescent formation. Next, the levels of glomerular AGT expression and marker of reactive oxygen species in Zucker diabetic fatty (ZDF) obese rats were higher than those in ZDF lean rats. Hydrogen peroxide (H(2)O(2)) induced an increase in the AGT expression in primary rat mesangial cells. Furthermore, the H(2)O(2)-induced upregulation of AGT was inhibited by a mitogen-activated protein kinase kinase and a c-Jun N-terminal kinase inhibitor. These data suggest the potential contribution of enhanced AGT expression in glomeruli to the intrarenal RAS activation for the development of glomerular disease.
Highlights
The critical role of the renin-angiotensin system (RAS) in arterial pressure and sodium homeostasis has been widely recognized [1,2]
The addition of angiotensin II (Ang II) type 1 receptor blocker to CC-chemokine recaptor 2 antagonist markedly attenuated the induction of macrophage infiltration, AGT and Ang II, and reduced glomerular crescent formation
The H2O2-induced upregulation of AGT was inhibited by a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor and a c-Jun N-terminal kinase (JNK) inhibitor, but not inhibited by a p-38 MAPK inhibitor. These data suggest that the majority of AGT was induced in mesangial cells in glomeruli under pathological conditions such as diabetic nephropathy, and that AGT expression in mesangial cells was mediated by H2O2 and the subsequent activation of the extracellular-regulated kinase (ERK)/JNK pathway
Summary
The critical role of the renin-angiotensin system (RAS) in arterial pressure and sodium homeostasis has been widely recognized [1,2]. Angiotensin II (Ang II) is the most powerful biologically active product of the RAS [3]. Produced Ang II induces inflammation, cell growth, mitogenesis, apoptosis, migration, and differentiation; regulates the gene expression of bioactive substances; and activates multiple intracellular signaling pathways, all of which might contribute to tissue injury [3]. Intrarenal RAS activity has several pathophysiological functions for in blood pressure regulation and in renal cell growth and production of glomerulosclerosis, which contributes to the development of renal fibrosis [5,6]. Previous studies have shown that angiotensin converting enzyme inhibitor (ACEi) and/or Ang II type 1 (AT1) receptor blocker (ARB) have beneficial effects in rats and humans with various renal diseases, and these effects are often considerably more significant than their suppressive effects on blood pressure [7,8]. This review explores recent findings concerning the expression of angiotensinogen (AGT) in the intrarenal RAS activation in glomerular disease
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