Role of the intrarenal renin–angiotensin system in the progression of renal disease

Abstract

The intrarenal renin-angiotensin system (RAS) has many well-documented pathophysiologic functions in both blood pressure regulation and renal disease development. Angiotensin II (Ang II) is the major bioactive product of the RAS. It induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation. In addition, Ang II regulates the gene expression of bioactive substances and activates multiple intracellular signaling pathways that are involved in renal damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, intracellular formation of reactive oxygen species, cell proliferation, and extracellular matrix synthesis, which in turn facilities renal injury. Involvement of angiotensinogen (AGT) in intrarenal RAS activation and development of renal disease has previously been reported. Moreover, studies have demonstrated that the urinary excretion rates of AGT provide a specific index of the intrarenal RAS status. Enhanced intrarenal AGT levels have been observed in experimental models of renal disease, supporting the concept that AGT plays an important role in the development and progression of renal disease. In this review, we focus on the role of intrarenal RAS activation in the pathophysiology of renal disease. Additionally, we explored the potential of urinary AGT as a novel biomarker of intrarenal RAS status in renal disease.

Angiotensin II Stimulates the NLRP3 Inflammasome to Induce Podocyte Injury and Mitochondrial Dysfunction

“…Ang II, as the strongest effector molecule in the RAS system, was reported to be involved in the pathogenesis of various kidney diseases through inducing renal inflammation [22, 23]. Recent evidence demonstrated that the NLRP3 inflammasome played a detrimental role in kidney diseases [24-26].…”

Intrarenal renin-angiotensin system activation in end-stage renal disease

“…1 Proximal tubular AGT concentrations range from 300–600 n m in anesthetized rats, which greatly exceeds the concentrations of free Ang I and Ang II in tubular fluid. 3 Given the molecular size (50–60 kDa) of AGT, it seems unlikely that significant amounts of plasma AGT filters across the glomerular membrane, further supporting the concept that proximal tubular cells secrete AGT directly into the tubules. 3 To determine whether circulating AGT is a source of urinary AGT, Nakano et al 11 examined the glomerular permeability of AGT by multi-photon imaging, and found an extremely low glomerular permeability of injected exogenous AGT.…”

“…Their efficacy suggests that factors other than angiotensin II (Ang II) are involved in renal disease progression. 3 While evidence suggests that local RAS in various tissues, including the brain, heart and vasculature are regulated independently of the systemic RAS, 1 most current research focuses on analyzing the role of tissue RAS in the kidneys. 4 …”

“…All major components required to generate Ang II are expressed within the kidneys, 1,3 but it is difficult to distinguish the influences of the intrarenal RAS from those of circulating Ang II. 2 There are circumstances in which the intrarenal RAS and circulating Ang II act together, such as during variations in salt intake.…”

“…1 A direct quantitative method of measuring urinary AGT using human AGT enzyme-linked immunosorbent assays has been developed, 8 and clinical studies have indicated that urinary AGT represents a novel biomarker of the activated intrarenal RAS in patients with hypertension, CKD, diabetes, 1 acute kidney injury and organogenesis. 3 Investigation of intrarenal RAS in animal models with end-stage renal disease (ESRD) has proven difficult, however. These animals require dialysis to live, and as such do not excrete urine; it is therefore impossible to evaluate intrarenal RAS activation in dialysis patients using urinary AGT excretion measurements.…”