Tissue-Specific Expression of Human Angiotensin II AT1 and AT2 Receptors and Cellular Localization of Subtype mRNAs in Adult Human Renal Cortex Using in situ Hybridization

Abstract

All studies analyzing the localization of angiotensin II (Ang II) receptors in the human kidney have been performed at the protein level using ¹²⁵I-Ang II as a probe. In this study, cellular localizations of Ang II type l (AT1-R) and type 2 (AT2-R) receptor mRNAs in the adult human renal cortex were examined for the first time using in situ hybridization, and their expression patterns determined by RNase protection assay were compared with those in other human tissues. In the human renal cortex obtained from tumor-free portions in renal cell carcinoma, AT1-R mRNA levels were about 8- to 10-fold higher than AT2-R mRNA levels. Human liver and aorta predominantly expressed AT1-R mRNA, while human right atrium contained both AT1-R and AT2-R mRNAs. Ligand-binding assays revealed that the total Ang II receptor number in the human renal cortex was 16.0 ± 3.3 fmol/mg protein, similar to that in liver (17.7 ± 5.8) but significantly higher than in right atrium (11.6 ± 3.2) and aorta (5.6 ± 2.7). Relative distribution ratios of AT1-R and AT2-R numbers in the renal cortex and right atrium were 82/17 and 56/42%, respectively. In situ hybridization study indicated that strongest AT1-R mRNA signals were located in interlobular arteries and tubulointerstitial fibrous regions surrounding interlobular arteries and glomeruli, followed in decreasing order by glomeruli and cortical tubules. Expression of AT2-R mRNA was highly localized in interlobular arteries. Cells present in tubulointerstitial regions were positive for vimentin and collagen type 1, indicating that the majority of the cells present in the regions are fibroblasts. Presence of strong AT1-R mRNA signals in the tubulointerstitial fibrous regions surrounding arteries and glomeruli and the expression of AT2-R mRNA in the interlobular artery were the first evidence, suggesting a pharmacological framework for the differential effects of Ang II receptor subtype mediated renal function in the adult human kidney.

Interstitial Fibroblast-Like Cells Express Renin-Angiotensin System Components in a Fibrosing Murine Kidney

“…The activity of angiotensin II via AT 2 R in the tubular epithelium remains to be clarified in this pathological condition. 25 Moreover, AT 2 R has not been detected previously in rodent renal interstitial FbLCs, either in vivo or in vitro, 10,19,23,29 while there is convincing evidence of the expression of AT 2 R in human cardiac fibroblasts. 30 The localization and expression levels of other components of RAS, REN, AGTN, and ACE, were also found to be uniquely altered in the fibrosing kidney.…”

Redox Control of Renal Function and Hypertension

“…AT 1 R is expressed most prominently in the interlobular arteries and tubulointerstitial fibrous regions surrounding interlobular arteries and glomeruli, followed in decreasing order by glomeruli and cortical tubules (296,329). Among the tubular cells, the proximal tubule brush-border and basolateral membranes (204,295,329), distal tubules, and cortical and medullary collecting ducts exhibited specific immunoreactivity. Glomerular staining for AT 1 R was observed in mesangial cells and podocytes.…”

Increased Renal Vascular Endothelial Growth Factor and Angiopoietins by Angiotensin II Infusion Is Mediated by Both AT1 and AT2 Receptors

“…The AT 2 receptor is mainly expressed in fetal tissues (14) and neonatal kidneys (15)(16)(17) and has been considered to play its major role during kidney organogenesis. In the adult, however, the AT 2 receptor is expressed at very low levels, particularly in kidney (18,19) but also in the heart (15,20) and vasculature. There is increasing evidence that the AT 2 receptor plays a pivotal role in the pathogenesis of vascular injury by mediating a range of angiotensin II-mediated effects, including effects on vasoreactivity, cytokine expression, cellular proliferation, and apoptosis (21)(22)(23)(24)(25).…”