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The proximal tubular renin–angiotensin system during albuminuria

Nakano, Daisuke; Nishiyama, Akira

doi: 10.1097/HJH.0b013e328348f031
Editorial commentaries

Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan

Correspondence to Akira Nishiyama, MD, PhD, Department of Pharmacology, Kagawa University Medical School, 1750–1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761–0793, Japan Tel: +81 87 891 2125; fax: +81 87 891 2126; e-mail:

The kidneys possess a well controlled barrier that prevents the leakage of albumin from the plasma into urine. Thus, the first sign of renal injury is the appearance of albuminuria. It has been suggested that final concentration of urinary albumin is the difference between albumin leakage at the glomerular filtration barrier and proximal tubular albumin reabsorption. The uptake of filtered albumin in the proximal tubule is a major physiological role of proximal tubular cells (PTCs). Receptor-mediated endocytotic proteins, such as megalin and cubilin, are reported to be responsible for albumin uptake by the PTCs [1,2]. Albumin binds to both megalin and cubilin located on the apical side of PTC membrane and get internalized into the cytosol. Thereafter, albumin gets stored into lysosomes and degraded into small fragments and/or amino acids [3]. A small portion of albumin may also undergo transcytosis from the apical to basolateral membrane [4–6]. It is still unclear whether an increase in glomerular filtration or a decrease in proximal tubule reuptake of albumin contributes to albuminuria [7,8]. However, it is now clear that glomerular filtration of albumin is significantly increased in pathological conditions and, as a result, PTCs may be exposed to greater concentrations of albumin. Previous studies have shown that an increase in albumin exposure may induce PTC stress, leading to PTC apoptosis [9,10] and/or inflammation [11,12], all of which further exacerbate renal injury.

In the current issue of the Journal of Hypertension, Cao et al. [13] demonstrated that increased concentrations of albumin on the apical side of PTCs augment renin–angiotensin system (RAS) expression via the megalin/cubilin/protein kinase C/NADPH oxidase-dependent pathway. These findings are in agreement with those of previous reports in which an increase in albuminuria was found to be associated with an augmentation of the intrarenal RAS and tubulointerstitial fibrosis [14–19]. Taken together, these findings may help in our understanding of the potential role of albumin-induced PTC stress in the progression of renal injury. One may be curious as to how much albumin is required to stimulate intraproximal tubular RAS in vivo. Cao et al. [13] examined the effect of 5 mg/ml of rat serum albumin on the expression of RAS components in PTCs. The concentration used was more than 10% of serum albumin concentration (∼35 mg/ml). This suggests that 10% of the total serum albumin needs to pass the glomerular filtration barrier in order to augment intraproximal tubular RAS. A glomerular sieving coefficient of 0.1 is much greater than that of a normal functioning kidney [20,21]. During an overt albuminuric phase, however, the glomerular sieving coefficient of albumin could be greater than 0.1 (based on our unpublished data analyzed with two-photon laser microscopy). Additionally, as discussed by Cao et al. [13], in-vitro short-term experiments may need a greater concentration of albumin to induce the phenomenon that occurs under in-vivo conditions. Nevertheless, it is possible that albumin leakage from the glomerular filtration barrier stimulates the intraproximal tubular RAS at an early stage of nephropathy. There is also the possibility that increases in albumin concentrations (0.1–10 mg/ml) on the apical side may decrease the albumin binding site on proximal tubules and could limit the detection of the actual amount of albumin uptake [22]. However, Cao et al. [13] found that there was an albumin dose-dependent increase in the RAS expression in PTCs. These data suggest that proximal tubules reuptake albumin and upregulate the RAS even under the nephritic level of albumin.

Another important question is whether the intraproximal tubular RAS is influenced by albumin under pathological conditions. Albumin can be modified via several mechanisms, such as oxidation [23], glycation [24] and binding to advanced glycation end products (AGEs) [25] and free fatty acids [26,27]. Thomas et al. [28] demonstrated that an infusion of AGE-modified rat serum albumin upregulates various components of the intrarenal RAS, including angiotensinogen, renin, angiotensin-converting enzyme (ACE) and AT1 receptor. Furthermore, an AGE inhibitor, pyridoxamine, prevents these changes, suggesting that the pathological modification of albumin may further augment the albumin-induced increase in intraproximal tubular RAS activity.

In-vitro studies have demonstrated that AT1 receptor stimulation suppresses the cellular uptake of albumin, and the subsequent degradation process [29]. These data suggest that the augmented proximal tubular RAS during albuminuria worsens albumin uptake in the proximal tubule, leading to a further increase in albuminuria. The potential role of proximal tubular RAS in the control of blood pressure has also been indicated. Kobori et al. [30] found that proximal tubule-specific overexpression of human angiotensinogen with a systemic overexpression of human renin elevates blood pressure with significant increases in kidney angiotensin II levels in mice. Furthermore, renal tubule-specific overexpression of ACE elevates blood pressure and kidney angiotensin II levels, even in systemic ACE knockout mice [31]. It has also been shown that mice overexpressing proximal tubule-specific angiotensinogen develop hypertension, tubular apoptosis, tubulointerstitial fibrosis and albuminuria, all of which are diminished by catalase overexpression [32]. Cao et al. [13] also demonstrated that 5.0 g/kg per day of albumin induces intraproximal tubular RAS activation and elevates blood pressure in rats, all of which were suppressed by treatment with the antioxidant apocynin. These data support the hypothesis, which was based on the findings of clinical studies [33], that augmentation of intraproximal tubular RAS impairs renal function and induces hypertension through a reactive oxygen species (ROS)-dependent pathway. The precise mechanism, however, needs to be clarified via additional studies in proximal tubule-specific RAS knockout animals. However, to date, there is still no in-vivo ‘loss-of-function’ evidence demonstrating an association between augmentation of the intraproximal tubular RAS, albuminuria, ROS, renal injury and blood pressure.

It is now generally accepted that the intrarenal RAS plays an important role in the pathogenesis of renal injury through the activation of AT1 receptors. Therefore, assessment of intrarenal RAS is essential in understanding the mechanisms that mediate the pathophysiology of renal function and injury. In the current issue, Cao et al. [13] demonstrated that albumin exposure to PTCs could trigger the activation of intraproximal tubular RAS. However, as previously mentioned, significant amounts of leaked albumin from glomeruli could be retrieved via the proximal tubules. Therefore, the urinary excretion rate of albumin may not reflect the actual amount of albumin exposure that PTCs undergo. Conversely, urinary angiotensinogen, which is mainly synthesized via a de-novo intraproximal tubule-dependent RAS pathway [34], could be a potential biomarker for monitoring intrarenal RAS status [35,36]. Thus, it can be speculated that an increase in urinary angiotensinogen may also reflect proximal tubular albumin exposure and may be a predictive marker for chronic kidney disease and hypertension risk.

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