Enzymatic sources and physio-pathological functions of soluble (pro)renin receptor

Zhu, Qing; Yang, Tianxin

doi:10.1097/mnh.0000000000000396

Cited by 18 publications

(10 citation statements)

References 58 publications

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“…In addition to the use of PRR as a tissue biomarker for CRC detection and prognosis, we aimed to complementarily measure it in CRC patients’ plasma samples to explore its potential as a CRC biomarker in liquid biopsies. In fact, PRR is a membrane protein expressed in several tissues that, after cleavage, can be released to the extracellular space and can be detected in plasma and urine from subjects with different physiological and pathological conditions [28,30,55,56]. Shibayama et al recently reported higher sPRR levels in patients with pancreatic ductal adenocarcinoma than in healthy controls [36].…”

Section: Discussionmentioning

confidence: 99%

(Pro)renin Receptor Expression Increases throughout the Colorectal Adenoma—Adenocarcinoma Sequence and It Is Associated with Worse Colorectal Cancer Prognosis

Beitia

Solano-Iturri

Errarte

et al. 2019

Cancers

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(Pro)renin receptor (PRR) is a protein that takes part in several signaling pathways such as Renin Angiotensin System and Wnt signalling. Its biological role has recently been related to cancer progression and in this study, we investigated its relevance in colorectal cancer (CRC). To that end, we analysed the immunohistochemical expression of PRR in adenomatous polyps and CRCs from the same patients (n = 42), and in primary tumours and nodal and liver metastases from advanced CRC patients (n = 294). In addition, the soluble fraction of PRR was measured by ELISA in plasma samples from 161 CRC patients. The results showed that PRR expression was gradually augmented along the uninvolved mucosa–adenoma–adenocarcinoma sequence. Besides, the stronger expression of PRR in primary tumours was markedly associated with local tumour extent and the onset of metastases. Moreover, PRR expression in both primary and distant metastases was associated with worse 5- and 10-year survival of CRC patients. Plasmatic PRR levels did not change with respect to controls and were not associated with CRC aggressiveness. These results suggest a key role of PRR in the development and progression of CRC and a potential use of this protein as a new prognostic biomarker and/or therapeutic target for this disease.

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Section: Discussionmentioning

confidence: 99%

(Pro)renin Receptor Expression Increases throughout the Colorectal Adenoma—Adenocarcinoma Sequence and It Is Associated with Worse Colorectal Cancer Prognosis

Beitia

Solano-Iturri

Errarte

et al. 2019

Cancers

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“…Furthermore, PRR can interact with the membrane receptor complex of the Wnt/␤-catenin pathway and with vacuolar-type H ϩ -ATPase (9,38). Previous studies have shown that kidney PRR and brain PRR are essential in the maintenance of fluid homeostasis and blood pressure (21,22,37,40,41) and that sPRR participates in fluid homeostasis and chronic kidney diseases (15,16,24,61). However, whether there is a link between sPRR and the local RAS and blood pressure is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Losartan prevents the elevation of blood pressure in adipose-PRR deficient female mice while elevated circulating sPRR activates the renin-angiotensin system

Gatineau

Cohn

Poglitsch³

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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Deletion of the prorenin receptor (PRR) in adipose tissue elevates systolic blood pressure (SBP) and the circulating soluble form of PRR (sPRR) in male mice fed a high-fat (HF) diet. However, sex differences in the contribution of adipose-PRR and sPRR to the regulation of the renin-angiotensin system (RAS) in key organs for blood pressure control are undefined. Therefore, we assessed blood pressure and the systemic and intrarenal RAS status in adipose-PRR knockout (KO) female mice. Blockade of RAS with losartan blunted SBP elevation in HF diet-fed adipose-PRR KO mice. ANG II levels were significantly increased in the renal cortex of HF diet-fed adipose-PRR KO female mice, but not systemically. HF diet-fed adipose-PRR KO mice exhibited higher vasopressin levels, water retention, and lower urine output than wild-type (WT) mice. The results also showed that deletion of adipose-PRR increased circulating sPRR and total hepatic sPRR contents, suggesting the liver as a major source of elevated plasma sPRR in adipose-PRR KO mice. To mimic the elevation of circulating sPRR and define the direct contribution of systemic sPRR to the regulation of the RAS and vasopressin, C57BL/6 female mice fed a standard diet were infused with recombinant sPRR. sPRR infusion increased plasma renin levels, renal and hepatic angiotensinogen expression, and vasopressin. Together, these results demonstrate that the deletion of adipose-PRR induced an elevation of SBP likely mediated by an intrarenal ANG II-dependent mechanism and that sPRR participates in RAS regulation and body fluid homeostasis via its capacity to activate the RAS and increase vasopressin levels. NEW & NOTEWORTHY The elevation of systolic blood pressure appears to be primarily mediated by cortical ANG II in high-fat diet-fed adipose-prorenin receptor knockout female mice. In addition, our data support a role for soluble prorenin receptor in renin-angiotensin system activation and vasopressin regulation.

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“…However, it might be linked to a well-described proteolytic cleavage event in the Golgi apparatus that produces an N-terminal and a C-terminal fragment (NTF and CTF, respectively) ( Cousin et al. , 2009 ; Zhu and Yang, 2018 ). While mosaic analysis in flies demonstrated that the NTF from the hemolymph or from the secretion by neighboring cells can localize to PCP domains ( Hermle et al.…”

Section: Introductionmentioning

confidence: 99%

ATP6AP2 functions as a V-ATPase assembly factor in the endoplasmic reticulum

Guida

Hermle

Graham

et al. 2018

MBoC

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ATP6AP2 (also known as the [pro]renin receptor) is a type I transmembrane protein that can be cleaved into two fragments in the Golgi apparatus. While in Drosophila ATP6AP2 functions in the planar cell polarity (PCP) pathway, recent human genetic studies have suggested that ATP6AP2 could participate in the assembly of the V-ATPase in the endoplasmic reticulum (ER). Using a yeast model, we show here that the V-ATPase assembly factor Voa1 can functionally be replaced by Drosophila ATP6AP2. This rescue is even more efficient when coexpressing its binding partner ATP6AP1, indicating that these two proteins together fulfill Voa1 functions in higher organisms. Structure–function analyses in both yeast and Drosophila show that proteolytic cleavage is dispensable, while C-terminus-dependent ER retrieval is required for ATP6AP2 function. Accordingly, we demonstrate that both overexpression and lack of ATP6AP2 causes ER stress in Drosophila wing cells and that the induction of ER stress is sufficient to cause PCP phenotypes. In summary, our results suggest that full-length ATP6AP2 contributes to the assembly of the V-ATPase proton pore and that impairment of this function affects ER homeostasis and PCP signaling.

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Enzymatic sources and physio-pathological functions of soluble (pro)renin receptor

Abstract: sPRR is a 28 kDa product of PRR cleavage via S1P-mediated protease activity. Not only does sPRR regulate renal tubular water transport, but it also mediates pathogenic responses to renal cellular injury. sPRR is likely involved in a wide range of physio-pathological processes.

Cited by 18 publications

References 58 publications

(Pro)renin Receptor Expression Increases throughout the Colorectal Adenoma—Adenocarcinoma Sequence and It Is Associated with Worse Colorectal Cancer Prognosis

(Pro)renin Receptor Expression Increases throughout the Colorectal Adenoma—Adenocarcinoma Sequence and It Is Associated with Worse Colorectal Cancer Prognosis

Losartan prevents the elevation of blood pressure in adipose-PRR deficient female mice while elevated circulating sPRR activates the renin-angiotensin system

ATP6AP2 functions as a V-ATPase assembly factor in the endoplasmic reticulum

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