Abstract
The existence of a local renin angiotensin system (RAS) of the kidney has been established. Angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin receptors, and high concentrations of luminal angiotensin II have been found in the proximal tubule. Although functional data have documented the relevance of a local RAS, the dualism between biosynthesis and endocytotic uptake of its components and their cellular processing has been incompletely understood. To resolve this, we have selectively analyzed their distribution, endocytosis, transcytosis, and biosynthesis in the proximal tubule. The presence of immunoreactive AGT, restricted to the early proximal tubule, was due to its retrieval from the ultrafiltrate and storage in endosomal and lysosomal compartments. Cellular uptake was demonstrated by autoradiography of radiolabeled AGT and depended on intact endocytosis. AGT was identified as a ligand of the multiple ligand-binding repeats of megalin. AGT biosynthesis was restricted to the proximal straight tubule, revealing substantial AGT mRNA expression. Transgenic AGT overexpression under the control of an endogenous promoter was also restricted to the late proximal tubule. Proximal handling of renin largely followed the patterns of AGT, whereas its local biosynthesis was not significant. Transcytotic transport of AGT in a proximal cell line revealed a 5% recovery rate after 1 h. ACE was expressed along late proximal brush-border membrane, whereas ACE2 was present along the entire segment. Surface expression of ACE and ACE2 differed as a function of endocytosis. Our data on the localization and cellular processing of RAS components provide new aspects of the functional concept of a "self-contained" renal RAS.
Highlights
The renin angiotensin system (RAS)3 serves to maintain extracellular volume homeostasis, a task that is primarily achieved by the kidney
We could demonstrate (i) that substantial amounts of AGT, as shown earlier for renin, reach the primary ultrafiltrate and that AGT is endocytosed via megalin; (ii) that renin distribution follows the pattern of AGT; (iii) that uptake of these components is restricted to the early proximal tubule, whereas the late proximal tubule only shows AGT mRNA transcription but no cellular storage; (iv) that angiotensinconverting enzyme (ACE) expression is concentrated in late proximal tubule, whereas ACE2 is encountered along the entire proximal nephron; and (v) that ACE and ACE2 display regulatory differences with respect to their apical representation
In the kidney of TGR(hAGT1623) rats, strong AGT mRNA signals were as well restricted to the proximal straight tubules (PST), whereas the proximal convoluted tubules (PCT) were devoid of AGT mRNA (Fig. 1B); by contrast, AGT protein was localized to subapical compartments of the PCT (Fig. 1C)
Summary
Amounts of angiotensin (Ang) II can be formed locally, elements of an intrarenal, “self-contained” RAS have been investigated. We could demonstrate (i) that substantial amounts of AGT, as shown earlier for renin, reach the primary ultrafiltrate and that AGT is endocytosed via megalin; (ii) that renin distribution follows the pattern of AGT; (iii) that uptake of these components is restricted to the early proximal tubule, whereas the late proximal tubule only shows AGT mRNA transcription but no cellular storage; (iv) that ACE expression is concentrated in late proximal tubule, whereas ACE2 is encountered along the entire proximal nephron; and (v) that ACE and ACE2 display regulatory differences with respect to their apical representation. These data allowed us to reconsider the contributions of individual RAS components along the proximal nephron
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