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Mokgonyana PJ, Mokwatsi GG, Gwini SM, Gafane-Matemane LF. The relationship between kidney function and the soluble (pro)renin receptor in young adults: the African-PREDICT study. BMC Nephrol 2025; 26:172. [PMID: 40181300 PMCID: PMC11966904 DOI: 10.1186/s12882-025-04038-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/21/2025] [Indexed: 04/05/2025] Open
Abstract
High renin angiotensin-aldosterone system (RAAS) activity is associated with target organ damage. Soluble (pro)renin receptor [s(P)RR] forms part of the RAAS cascade and is associated with kidney damage through both angiotensin II-dependent and -independent pathways. Additionally, s(P)RR levels are higher in hypertension and chronic kidney disease (CKD) patients. However, little is known regarding ethnic and sex differences in s(P)RR levels and its potential associations with kidney function in young healthy adults. Identifying these associations in young populations is essential for identification of areas of intervention to prevent CKD. This study aimed to compare levels of s(P)RR across ethnic and sex groups and determine s(P)RR associations with markers of kidney function, including estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (uACR) and alpha 1-microglobulin (uA1M). The study included 1156 young healthy Black and White South Africans aged 20-30 years (Men, N = 555; Women, N = 601). We measured uA1M, albumin and creatinine in urine to calculate uACR. s(P)RR, cystatin C and creatinine were measured in serum and eGFR was calculated. Independent t-tests and multiple regression analyses were carried out to compare groups and explore associations. s(P)RR levels were higher in White participants, and higher in White men than in women (all p < 0.001). eGFR was higher in both Black men and women than in White men and women (both p ≤ 0.001). Both uA1M and uACR were higher in Black men than in White men (both p ≤ 0.003). We observed an independent negative association between eGFR and s(P)RR in Black women only (Adj.R2 = 0.309; Std. β=-0.141; p = 0.026), while uA1M associated positively with s(P)RR in the White group only (Adj.R2 = 0.063; Std. β = 0.115; p = 0.018). No associations were evident between uACR and s(P)RR in any of the groups. The positive association between uA1M and s(P)RR suggest that s(P)RR may contribute to kidney damage in young White participants through pathways associated with inflammation and fibrosis. A better understanding of mechanisms linking s(P)RR to kidney damage may lead to discovery of areas of therapeutic interventions for the prevention and treatment of CKD in different population groups. Trial registration ClinicalTrials.gov NCT03292094. Registration date 2017-09-12.
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Affiliation(s)
- Phuti J Mokgonyana
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa
| | - Gontse G Mokwatsi
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa
| | - Stella M Gwini
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Lebo F Gafane-Matemane
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa.
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa.
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2
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Das UN, Hacimüftüoglu A, Akpinar E, Gul M, Abd El-Aty AM. Crosstalk between renin and arachidonic acid (and its metabolites). Lipids Health Dis 2025; 24:52. [PMID: 39962508 PMCID: PMC11831833 DOI: 10.1186/s12944-025-02463-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/02/2025] [Indexed: 02/21/2025] Open
Abstract
Renin plays a significant role in the regulation of blood pressure and fluid volume by modulating the renin‒angiotensin‒aldosterone (RAAS) system. Renin suppression reduces serum aldosterone levels and lowers blood pressure in addition to preserving renal function. However, exactly how renin synthesis and action are regulated and how renin suppression preserves renal function are not clear. We propose that arachidonic acid (AA) and its metabolites control renin synthesis, secretion, and action by virtue of its (AA) anti-inflammatory, cytoprotective actions and ability to regulate the secretion of renin. These findings suggest that direct renin suppression results in changes in AA metabolism. This proposal implies that AA and its metabolites may be developed as potential drugs to prevent and manage hypertension and preserve renal function.
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Affiliation(s)
- Undurti N Das
- UND Life Sciences, 2221 NW 5th St, Battle ground, WA, 98604, USA.
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey.
| | - Ahmet Hacimüftüoglu
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
| | - Erol Akpinar
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
| | - Mustafa Gul
- Department of Physiology, Faculty of Medicine, Ataturk University, Erzurum, 25240, Turkey
| | - A M Abd El-Aty
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
- Department of Pharmacology, Cairo University, Giza, 12211, Egypt
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3
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Yang T, Gao ZX, Mao ZH, Wu P. Soluble (pro)renin receptor as a novel regulator of renal medullary Na + reabsorption. Am J Physiol Renal Physiol 2025; 328:F239-F247. [PMID: 39508841 DOI: 10.1152/ajprenal.00156.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 10/14/2024] [Accepted: 10/28/2024] [Indexed: 01/22/2025] Open
Abstract
Epithelial sodium channel (ENaC) represents a major route of Na+ reabsorption in the aldosterone-sensitive distal nephron where the bulk of ENaC activity is considered to occur in the cortical collecting duct (CCD). Relatively, ENaC activity in the medulla, especially the inner medulla, is often neglected. (Pro)renin receptor (PRR), also termed ATP6ap2, a newly characterized member of the renin-angiotensin system, has emerged as an important regulator of ENaC in the distal nephron. The ENaC regulatory action of PRR is largely mediated by the 28 kDa soluble PRR (sPRR). Although all three subunits of ENaC are under the control of aldosterone, sPRR only mediates the upregulation of α-ENaC but not the other two subunits. Furthermore, sPRR-dependent regulation of α-ENaC only occurs in the renal inner medulla but not in the cortex. sPRR also rapidly upregulates ENaC activity via Nox4-derived H2O2. Overall, sPRR has emerged as an important regulator of renal medullary Na+ reabsorption in the context of overactivation of the renin-angiotensin-aldosterone system.
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Affiliation(s)
- Tianxin Yang
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, United States
- Veterans Affairs Medical Center, Salt Lake City, Utah, United States
| | - Zhong-Xiuzi Gao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Zi-Hui Mao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Peng Wu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
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4
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Berber M, Penton D. Calcineurin inhibitors and the renin-angiotensin-aldosterone system. Acta Physiol (Oxf) 2024; 240:e14248. [PMID: 39460458 DOI: 10.1111/apha.14248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 10/07/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024]
Abstract
Calcineurin inhibitors (CnIs) are effective immunosuppressants with decades of accumulated experience in treating immune disorders and, most notably, solid organ transplantation. While CnIs have significantly increased graft survival and transformed the patient standard of care, their use has been overshadowed by a number of undesired side effects. For instance, CnI-associated nephrotoxicity has been reported since early studies and remains a major therapeutic concern. The occurrence of several ion imbalances alongside hypertension was also noted early on, indicating the involvement of the renin-angiotensin-aldosterone system (RAAS) in CnI-mediated toxicity. However, the literature in this field is crowded with conflicting reports from clinical trials as well as studies using animal and invitro models. With this review, we aim to provide a structured and updated overview of the physiological and pathophysiological evidence supporting the involvement of the classical RAAS in CnI-associated toxicity.
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Affiliation(s)
- Mesut Berber
- Department of Pediatrics, Harvard Medical School and Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - David Penton
- Electrophysiology Facility, University of Zurich, Zurich, Switzerland
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Yan Z, Yang T, Li X, Jiang Z, Jia W, Zhou J, Fang H. Apelin-13: a novel approach to suppressing renin production in RVHT. Am J Physiol Cell Physiol 2024; 326:C1683-C1696. [PMID: 38646785 DOI: 10.1152/ajpcell.00092.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/14/2024] [Accepted: 04/15/2024] [Indexed: 04/23/2024]
Abstract
Renovascular hypertension (RVHT) is characterized by renal artery stenosis and overactivated renin-angiotensin system (RAS). Apelin, known for its negative modulation of RAS, has protective effects against cardiovascular diseases. The role and mechanisms of the primary active form of apelin, apelin-13, in RVHT are unclear. In this study, male Sprague-Dawley rats were divided into control, two-kidney one-clip (2K1C) model, and 2K1C with apelin-13 treatment groups. Renin expression was analyzed using immunohistochemistry and molecular techniques. Full-length (pro)renin receptor (fPRR) and soluble PRR (sPRR) levels were assessed via Western blotting, and cAMP levels were measured using ELISA. Plasma renin content, plasma renin activity (PRA), angiotensin II (ANG II), and sPRR levels were determined by ELISA. Human Calu-6 and mouse As4.1 cells were used to investigate renin production mechanisms. The 2K1C model exhibited increased systolic blood pressure, plasma renin content, PRA, sPRR, and ANG II levels, while apelin-13 treatment reduced these elevations. Apelin-13 inhibited cAMP production, renin mRNA expression, protein synthesis, and PRR/sPRR protein expression in renal tissue. In Calu-6 cells, cAMP-induced fPRR and site-1 protease (S1P)-derived sPRR expression, which was blocked by cAMP-responsive element-binding protein (CREB) inhibition. Apelin-13 suppressed cAMP elevation, CREB phosphorylation, fPRR/sPRR protein expression, and renin production. Recombinant sPRR (sPRR-His) stimulated renin production, which was inhibited by the PRR decoy peptide PRO20 and S1P inhibitor PF429242. These findings suggest that apelin-13 inhibits plasma renin expression through the cAMP/PKA/sPRR pathway, providing a potential therapeutic approach for RVHT. Understanding the regulation of renin production is crucial for developing effective treatments.NEW & NOTEWORTHY Our research elucidated that apelin-13 inhibits renin production through the cAMP/PKA/soluble (pro)renin receptor pathway, presenting a promising therapeutic approach for renovascular hypertension (RVHT) by targeting renin expression mechanisms. These findings underscore the potential of apelin-13 as a novel strategy to address RVHT.
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Affiliation(s)
- Ziqing Yan
- School of PharmacyWeifang Medical University, Weifang, Shandong, China
| | - Teng Yang
- School of PharmacyWeifang Medical University, Weifang, Shandong, China
| | - Xinxuan Li
- School of PharmacyWeifang Medical University, Weifang, Shandong, China
| | - Zipeng Jiang
- School of PharmacyWeifang Medical University, Weifang, Shandong, China
| | - Wankun Jia
- School of PharmacyWeifang Medical University, Weifang, Shandong, China
| | - Jin Zhou
- School of PharmacyWeifang Medical University, Weifang, Shandong, China
| | - Hui Fang
- School of PharmacyWeifang Medical University, Weifang, Shandong, China
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Li X, Fu YH, Tong XW, Zhang YT, Shan YY, Xu YX, Pu SD, Gao XY. RAAS in diabetic retinopathy: mechanisms and therapies. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e230292. [PMID: 38652701 PMCID: PMC11081058 DOI: 10.20945/2359-4292-2023-0292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 11/23/2023] [Indexed: 04/25/2024]
Abstract
Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.
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Affiliation(s)
- Xin Li
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Yu-Hong Fu
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Xue-Wei Tong
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Yi-Tong Zhang
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Yong-Yan Shan
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Yu-Xin Xu
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Sheng-Dan Pu
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Xin-Yuan Gao
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China,
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7
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Pan S, A.C. Souza L, Worker CJ, Reyes Mendez ME, Gayban AJB, Cooper SG, Sanchez Solano A, Bergman RN, Stefanovski D, Morton GJ, Schwartz MW, Feng Earley Y. (Pro)renin receptor signaling in hypothalamic tyrosine hydroxylase neurons is required for obesity-associated glucose metabolic impairment. JCI Insight 2024; 9:e174294. [PMID: 38349753 PMCID: PMC11063935 DOI: 10.1172/jci.insight.174294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 02/08/2024] [Indexed: 03/06/2024] Open
Abstract
Glucose homeostasis is achieved via complex interactions between the endocrine pancreas and other peripheral tissues and glucoregulatory neurocircuits in the brain that remain incompletely defined. Within the brain, neurons in the hypothalamus appear to play a particularly important role. Consistent with this notion, we report evidence that (pro)renin receptor (PRR) signaling within a subset of tyrosine hydroxylase (TH) neurons located in the hypothalamic paraventricular nucleus (PVNTH neurons) is a physiological determinant of the defended blood glucose level. Specifically, we demonstrate that PRR deletion from PVNTH neurons restores normal glucose homeostasis in mice with diet-induced obesity (DIO). Conversely, chemogenetic inhibition of PVNTH neurons mimics the deleterious effect of DIO on glucose. Combined with our finding that PRR activation inhibits PVNTH neurons, these findings suggest that, in mice, (a) PVNTH neurons play a physiological role in glucose homeostasis, (b) PRR activation impairs glucose homeostasis by inhibiting these neurons, and (c) this mechanism plays a causal role in obesity-associated metabolic impairment.
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Affiliation(s)
- Shiyue Pan
- Departments of Pharmacology and Physiology & Cell Biology and
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, USA
| | - Lucas A.C. Souza
- Departments of Pharmacology and Physiology & Cell Biology and
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, USA
| | - Caleb J. Worker
- Departments of Pharmacology and Physiology & Cell Biology and
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, USA
| | - Miriam E. Reyes Mendez
- Departments of Pharmacology and Physiology & Cell Biology and
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, USA
| | - Ariana Julia B. Gayban
- Departments of Pharmacology and Physiology & Cell Biology and
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, USA
| | - Silvana G. Cooper
- Departments of Pharmacology and Physiology & Cell Biology and
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, USA
| | - Alfredo Sanchez Solano
- Departments of Pharmacology and Physiology & Cell Biology and
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, USA
| | - Richard N. Bergman
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Darko Stefanovski
- New Bolton Center, School of Veterinary Medicine, University of Pennsylvania Philadelphia, Pennsylvania, USA
| | - Gregory J. Morton
- University of Washington Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA
| | - Michael W. Schwartz
- University of Washington Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA
| | - Yumei Feng Earley
- Departments of Pharmacology and Physiology & Cell Biology and
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, USA
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8
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Fang H, Lin D, Li X, Wang L, Yang T. Therapeutic potential of Ganoderma lucidum polysaccharide peptide in Doxorubicin-induced nephropathy: modulation of renin-angiotensin system and proteinuria. Front Pharmacol 2023; 14:1287908. [PMID: 37841924 PMCID: PMC10570435 DOI: 10.3389/fphar.2023.1287908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 09/21/2023] [Indexed: 10/17/2023] Open
Abstract
Introduction: In the Doxorubicin (DOX)-induced nephropathy model, proteinuria is a manifestation of progressive kidney injury. The pathophysiology of renal illness is heavily influenced by the renin-angiotensin system (RAS). To reduce renal RAS activation and proteinuria caused by DOX, this study evaluated the effectiveness of Ganoderma lucidum polysaccharide peptide (GL-PP), a new glycopeptide produced from Ganoderma lucidum grown on grass. Methods: Three groups of BALB/c male mice were created: control, DOX, and DOX + GL-PP. GL-PP (100 mg/kg) was administered to mice by intraperitoneal injection for 4 weeks following a single intravenous injection of DOX (10 mg/kg via the tail vein). Results: After 4 weeks, full-length and soluble pro(renin) receptor (fPRR/sPRR) overexpression in DOX mouse kidneys, which is crucial for the RAS pathway, was dramatically inhibited by GL-PP therapy. Additionally, GL-PP successfully reduced elevation of urinary renin activity and angiotensin II levels, supporting the idea that GL-PP inhibits RAS activation. Moreover, GL-PP showed a considerable downregulation of nicotinamide adenine nucleotide phosphate oxidase 4 (NOX4) expression and a decrease in hydrogen peroxide (H2O2) levels. GL-PP treatment effectively reduced glomerular and tubular injury induced by DOX, as evidenced by decreased proteinuria, podocyte damage, inflammation, oxidative stress, apoptosis, and fibrosis. Discussion: GL-PP inhibits intrarenal PRR/sPRR-RAS activation and upregulation of NOX4 and H2O2, suggesting potential therapeutic approaches against DOX-induced nephropathy.
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Affiliation(s)
- Hui Fang
- Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
| | - Dongmei Lin
- National Engineering Research Center of JUNCAO Technology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China
| | - Xinxuan Li
- Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
| | - Lianfu Wang
- National Engineering Research Center of JUNCAO Technology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China
| | - Teng Yang
- Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
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Schofield LG, Kahl RGS, Rodrigues SL, Fisher JJ, Endacott SK, Delforce SJ, Lumbers ER, Martin JH, Pringle KG. Placental deficiency of the (pro)renin receptor ((P)RR) reduces placental development and functional capacity. Front Cell Dev Biol 2023; 11:1212898. [PMID: 37588662 PMCID: PMC10427116 DOI: 10.3389/fcell.2023.1212898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/17/2023] [Indexed: 08/18/2023] Open
Abstract
The (pro)renin receptor ((P)RR; also known as ATP6AP2) is a multifunctional receptor. The (P)RR activates the tissue renin-angiotensin system (RAS) and is also involved in regulating integral intracellular pathways such as V-ATPase and Wnt/β-catenin signalling. Given this, the (P)RR may be associated with essential pathways in placentation, however its role within the context of pregnancy remains poorly characterised. The first trimester/extravillous trophoblast cell line, HTR-8/SVneo, underwent an siRNA knockdown where they were incubated for 24 h with a negative control siRNA or siRNA targeting ATP6AP2 mRNA. xCELLigence real-time cell analysis was performed to assess the effect of ATP6AP2 mRNA knockdown on HTR-8/SVneo cell proliferation, migration, and invasion. In subsequent experiments, GFP-encoding lentiviral packaged gene-constructs were used to knockdown (P)RR expression in the trophectoderm of C57/BL6/CBA-F1 mouse blastocysts. Blastocysts were incubated for 6 h with vehicle (no-virus), control virus (non-targeting shRNA and GFP), or (P)RR-knockdown virus ((P)RR shRNA and GFP) before transfer into recipient pseudo-pregnant Swiss CD1 female mice. Fetal and placental tissues were collected and assessed at embryonic age (EA) 10 and 18. (P)RR levels were measured in the labyrinth zone of day 18 placentae and stereological Merz grid analysis was performed to determine the volumetric distribution of trophoblasts, fetal capillaries, and the maternal blood space. We showed that a reduction of ATP6AP2 expression in HTR-8/SVneo cells in vitro, impaired trophoblast proliferation, migration, and invasion. In vivo, decreasing placental labyrinth (P)RR expression adversely effected placental physiology, decreasing placental trophoblast number and total surface area available for exchange, while also increasing maternal blood space. Additionally, decreased (P)RR affected placental efficacy evident by the reduced fetal-placental weight ratio. Our study shows that the (P)RR is necessary for appropriate placental development and function.
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Affiliation(s)
- Lachlan G. Schofield
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Richard G. S. Kahl
- Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
| | - Samantha L. Rodrigues
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Joshua J. Fisher
- Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
| | - Saije K. Endacott
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Sarah J. Delforce
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Eugenie R. Lumbers
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Jacinta H. Martin
- School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, NSW, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Kirsty G. Pringle
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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10
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Pan S, Worker CJ, Feng Earley Y. The hypothalamus as a key regulator of glucose homeostasis: emerging roles of the brain renin-angiotensin system. Am J Physiol Cell Physiol 2023; 325:C141-C154. [PMID: 37273237 PMCID: PMC10312332 DOI: 10.1152/ajpcell.00533.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 05/26/2023] [Accepted: 05/26/2023] [Indexed: 06/06/2023]
Abstract
The regulation of plasma glucose levels is a complex and multifactorial process involving a network of receptors and signaling pathways across numerous organs that act in concert to ensure homeostasis. However, much about the mechanisms and pathways by which the brain regulates glycemic homeostasis remains poorly understood. Understanding the precise mechanisms and circuits employed by the central nervous system to control glucose is critical to resolving the diabetes epidemic. The hypothalamus, a key integrative center within the central nervous system, has recently emerged as a critical site in the regulation of glucose homeostasis. Here, we review the current understanding of the role of the hypothalamus in regulating glucose homeostasis, with an emphasis on the paraventricular nucleus, the arcuate nucleus, the ventromedial hypothalamus, and lateral hypothalamus. In particular, we highlight the emerging role of the brain renin-angiotensin system in the hypothalamus in regulating energy expenditure and metabolic rate, as well as its potential importance in the regulation of glucose homeostasis.
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Affiliation(s)
- Shiyue Pan
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Department of Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, United States
| | - Caleb J Worker
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Department of Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, United States
| | - Yumei Feng Earley
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Department of Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, United States
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11
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Heilmann RM, Csukovich G, Burgener IA, Dengler F. Time to eRAASe chronic inflammation: current advances and future perspectives on renin-angiotensin-aldosterone-system and chronic intestinal inflammation in dogs and humans. Front Vet Sci 2023; 10:1180125. [PMID: 37456955 PMCID: PMC10340121 DOI: 10.3389/fvets.2023.1180125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 06/16/2023] [Indexed: 07/18/2023] Open
Abstract
Chronic idiopathic intestinal inflammation is an increasing worldwide problem that affects companion animals, especially dogs, and human patients. Although these disease entities have been intensely investigated recently, many questions remain, and alternative therapeutic options are needed. Diarrhea caused by dysregulation of intestinal electrolyte transport and subsequent fluid and electrolyte losses often leads to secondary consequences for the patient. Currently, it is not exactly clear which mechanisms are involved in the dysregulation of intestinal fluid absorption, but differences in intestinal electrolyte shifts between human and canine patients suggest species-specific regulatory or counterregulatory mechanisms. Several intestinal electrolyte transporters are differentially expressed in human patients with inflammatory bowel disease (IBD), whereas there are virtually no studies on electrolyte transporters and their endocrine regulation in canine chronic inflammatory enteropathy. An important mechanism involved in regulating fluid and electrolyte homeostasis is the renin-angiotensin-aldosterone-system (RAAS), which may affect intestinal Na+ transport. While RAAS has previously been considered a systemic regulator of blood pressure, additional complex roles of RAAS in inflammatory processes have been unraveled. These alternative RAAS pathways may pose attractive therapeutic targets to address diarrhea and, thus, electrolyte shifts in human IBD and canine chronic inflammatory enteropathy. This article comparatively summarizes the current knowledge about electrolyte transport in human IBD and canine chronic inflammatory enteropathy and the role of RAAS and offers perspectives for novel therapeutic avenues.
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Affiliation(s)
- Romy M. Heilmann
- Department for Small Animals, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany
| | - Georg Csukovich
- Small Animal Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Iwan A. Burgener
- Small Animal Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Franziska Dengler
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine Vienna, Vienna, Austria
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12
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Taguchi T, Kimura K, Suzuki A, Fujishima R, Shimizu N, Hoshiyama A, Masaki T, Inoue M, Kato Y, Satomi T, Takano K, Imada T, Sasaki S, Miyatsuka T. ATP6AP2 is robustly expressed in pancreatic β cells and neuroendocrine tumors, and plays a role in maintaining cellular viability. Sci Rep 2023; 13:9260. [PMID: 37286698 DOI: 10.1038/s41598-023-36265-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 05/31/2023] [Indexed: 06/09/2023] Open
Abstract
ATP6AP2, also known as (pro)renin receptor, has been shown to be expressed in several tissues including pancreatic β cells. Whereas ATP6AP2 plays an important role in regulating insulin secretion in mouse pancreatic β cells, the expression profiles and roles of ATP6AP2 in human pancreatic endocrine cells and neuroendocrine tumor cells remain unclear. Here in this study, we investigated the expression profiles of ATP6AP2 in pancreatic endocrine cells, and found that ATP6AP2 is robustly expressed in pancreatic insulinoma cells as well as in normal β cells. Although ATP6AP2 was also expressed in low-grade neuroendocrine tumors, it was not or faintly detected in intermediate- and high-grade neuroendocrine tumors. Knockdown experiments of the Atp6ap2 gene in rat insulinoma-derived INS-1 cells demonstrated decreased cell viability accompanied by a significant increase in apoptotic cells. Taken together, these findings suggest that ATP6AP2 plays a role in maintaining cellular homeostasis in insulinoma cells, which could lead to possible therapeutic approaches for endocrine tumors.
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Affiliation(s)
- Tomomi Taguchi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan.
| | - Kaori Kimura
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Agena Suzuki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Rei Fujishima
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Naoya Shimizu
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Ayako Hoshiyama
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Tsuguto Masaki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Mitsuko Inoue
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
- Health Care Center, Kitasato University, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yukiko Kato
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Takebe Satomi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Koji Takano
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Tasuku Imada
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shugo Sasaki
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takeshi Miyatsuka
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitazato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan.
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13
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Visniauskas B, Reverte V, Abshire CM, Ogola BO, Rosales CB, Galeas-Pena M, Sure VN, Sakamuri SSVP, Harris NR, Kilanowski-Doroh I, Mcnally AB, Horton AC, Zimmerman M, Katakam PVG, Lindsey SH, Prieto MC. High-plasma soluble prorenin receptor is associated with vascular damage in male, but not female, mice fed a high-fat diet. Am J Physiol Heart Circ Physiol 2023; 324:H762-H775. [PMID: 36930656 PMCID: PMC10151046 DOI: 10.1152/ajpheart.00638.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/02/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 wk to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and ANG II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 wk in females fed either an NFD or HFD. Significant sex differences were found after 28 wk of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and ANG II. T2DM in males was accompanied by nondipping hypertension, carotid artery stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and systolic blood pressure. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex.NEW & NOTEWORTHY High-fat diet (HFD) for 28 wk leads to type 2 diabetes mellitus (T2DM) phenotype, concomitant with increased plasma soluble prorenin receptor (sPRR), nondipping blood pressure, and vascular stiffness in male mice. HFD-fed female mice exhibiting a preserved cardiometabolic phenotype until ovariectomy revealed increased plasma sPRR and blood pressure. Plasma sPRR may indicate the status of systemic renin-angiotensin-aldosterone system (RAAS) activation and the onset of vascular complications during T2DM in a sex-dependent manner.
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Affiliation(s)
- Bruna Visniauskas
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Tulane Center for Sex-Based Biology and Medicine, New Orleans, Louisiana, United States
| | - Virginia Reverte
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Caleb M Abshire
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Benard O Ogola
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
| | - Carla B Rosales
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Michelle Galeas-Pena
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Venkata N Sure
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Siva S V P Sakamuri
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Nicholas R Harris
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Isabella Kilanowski-Doroh
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Alexandra B Mcnally
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Alec C Horton
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Margaret Zimmerman
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Prasad V G Katakam
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Sarah H Lindsey
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Tulane Center for Sex-Based Biology and Medicine, New Orleans, Louisiana, United States
- Tulane Hypertension and Renal Center of Excellence, New Orleans, Louisiana, United States
| | - Minolfa C Prieto
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Tulane Center for Sex-Based Biology and Medicine, New Orleans, Louisiana, United States
- Tulane Hypertension and Renal Center of Excellence, New Orleans, Louisiana, United States
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14
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Kanugula AK, Kaur J, Batra J, Ankireddypalli AR, Velagapudi R. Renin-Angiotensin System: Updated Understanding and Role in Physiological and Pathophysiological States. Cureus 2023; 15:e40725. [PMID: 37350982 PMCID: PMC10283427 DOI: 10.7759/cureus.40725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2023] [Indexed: 06/24/2023] Open
Abstract
The classical view of the renin-angiotensin system (RAS) is that of the circulating hormone pathway involved in salt and water homeostasis and blood pressure regulation. It is also involved in the pathogenesis of cardiac and renal disorders. This led to the creation of drugs blocking the actions of this classical pathway, which improved cardiac and renal outcomes. Our understanding of the RAS has significantly expanded with the discovery of new peptides involved in this complex pathway. Over the last two decades, a counter-regulatory or protective pathway has been discovered that opposes the effects of the classical pathway. Components of RAS are also implicated in the pathogenesis of obesity and its metabolic diseases. The continued discovery of newer molecules also provides novel therapeutic targets to improve disease outcomes. This article aims to provide an overview of an updated understanding of the RAS, its role in physiological and pathological processes, and potential novel therapeutic options from RAS for managing cardiorenal disorders, obesity, and related metabolic disorders.
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Affiliation(s)
- Ashok Kumar Kanugula
- Department of Internal Medicine, Wellstar Health System - Spalding Regional Hospital, Griffin, USA
| | - Jasleen Kaur
- Department of Endocrinology, Diabetes, and Metabolism, HealthPartners, Minneapolis, USA
| | - Jaskaran Batra
- Department of Internal Medicine, Univerity of Pittsburg Medical Center (UPMC) McKeesport, McKeesport, USA
| | | | - Ravikanth Velagapudi
- Department of Pulmonary and Critical Care Medicine, Spectrum Health/Michigan State University, Grand Rapids, USA
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15
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Yamaguchi T, Morimoto S, Suda C, Ichihara A, Ishihara N, Nakamura S, Tanaka S, Watanabe Y, Imamura H, Ohira M, Shimizu N, Saiki A, Tatsuno I. Soluble (Pro)Renin Receptor Level in Patients with Severe Obesity Is Associated with Visceral Adiposity and Is Involved with Insulin Resistance and Renal Injury. Obes Facts 2023; 16:335-343. [PMID: 37231878 PMCID: PMC10427953 DOI: 10.1159/000531076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 05/09/2023] [Indexed: 05/27/2023] Open
Abstract
INTRODUCTION High soluble (pro)renin receptor (s[P]RR) level in circulation is reported in obese patients; however, it is unclear which body composition components are responsible for it. In this study, the authors examined blood s(P)RR levels and ATP6AP2 gene expression levels in visceral and subcutaneous adipose tissue (VAT, SAT) in severely obese patients who underwent laparoscopic sleeve gastrectomy (LSG), with the aim of clarifying the relationship with body composition and metabolic factors. METHODS Seventy five cases who underwent LSG between 2011 and 2015 and were postoperatively followed-up for 12 months at the Toho University Sakura Medical Center were included in the analysis of the cross-sectional survey at baseline, and 33 cases were included in the analysis of the longitudinal survey during the 12 months after LSG. We evaluated body composition, glycolipid parameters, liver/renal function, as well as serum s(P)RR level and ATP6AP2 mRNA expression level in VAT and SAT. RESULTS The mean serum s(P)RR level at baseline was 26.1 ng/mL, this value was considered higher than values in healthy subjects. There was no significant difference in the expression level of ATP6AP2 mRNA between VAT and SAT. At baseline, multiple regression analysis for the association between s(P)RR and variables identified that visceral fat area, HOMA2-IR, and UACR showed the independent relationships with s(P)RR. During the 12 months after LSG, body weight, serum s(P)RR level showed a significant decrease (from 30.0 ± 7.0 to 21.9 ± 4.3). Multiple regression analysis for the association between the change in s(P)RR and variables showed that changes in visceral fat area, and alanine transaminase were independently related to the change in s(P)RR. CONCLUSION This study showed that blood s(P)RR level was high in severely obese patients, decreased with weight loss by LSG, and was associated with visceral fat area in both pre- and postoperative changes. The results suggest that blood s(P)RR levels in obese patients may reflect the involvement of visceral adipose (P)RR in insulin resistance and renal damage mechanisms associated with obesity.
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Affiliation(s)
- Takashi Yamaguchi
- Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Satoshi Morimoto
- Department of Endocrinology and Hypertension, Tokyo Womens’ Medical University, Tokyo, Japan
| | - Chikahito Suda
- Department of Endocrinology and Hypertension, Tokyo Womens’ Medical University, Tokyo, Japan
| | - Atsuhiro Ichihara
- Department of Endocrinology and Hypertension, Tokyo Womens’ Medical University, Tokyo, Japan
| | - Noriko Ishihara
- Clinical Laboratory Program, Faculty of Science, Toho University, Chiba, Japan
| | - Shoko Nakamura
- Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Sho Tanaka
- Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Yasuhiro Watanabe
- Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Haruki Imamura
- Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Masahiro Ohira
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Medical Center, Tokyo, Japan
| | - Naomi Shimizu
- Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Atsuhito Saiki
- Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Ichiro Tatsuno
- Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
- Chiba Prefectural University of Health Science, Chiba, Japan
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16
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Wang B, Jie H, Wang S, Dong B, Zou Y. The role of (pro)renin receptor and its soluble form in cardiovascular diseases. Front Cardiovasc Med 2023; 10:1086603. [PMID: 36824459 PMCID: PMC9941963 DOI: 10.3389/fcvm.2023.1086603] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/17/2023] [Indexed: 02/05/2023] Open
Abstract
The renin-angiotensin system (RAS) is a major classic therapeutic target for cardiovascular diseases. In addition to the circulating RAS, local tissue RAS has been identified in various tissues and plays roles in tissue inflammation and tissue fibrosis. (Pro)renin receptor (PRR) was identified as a new member of RAS in 2002. Studies have demonstrated the effects of PRR and its soluble form in local tissue RAS. Moreover, as an important part of vacuolar H+-ATPase, it also contributes to normal lysosome function and cell survival. Evidently, PRR participates in the pathogenesis of cardiovascular diseases and may be a potential therapeutic target of cardiovascular diseases. This review focuses on the effects of PRR and its soluble form on the physiological state, hypertension, myocardial ischemia reperfusion injury, heart failure, metabolic cardiomyopathy, and atherosclerosis. We aimed to investigate the possibilities and challenges of PRR and its soluble form as a new therapeutic target in cardiovascular diseases.
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Affiliation(s)
- Boyang Wang
- Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China,Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China,Department of Cardiology, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Haipeng Jie
- Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China,Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shuangxi Wang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China,Shuangxi Wang,
| | - Bo Dong
- Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China,Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China,Department of Cardiology, Shandong University of Traditional Chinese Medicine, Jinan, China,*Correspondence: Bo Dong,
| | - Yunzeng Zou
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China,Yunzeng Zou,
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17
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Fu Z, Zheng H, Kaewsaro K, Lambert J, Chen Y, Yang T. Mutagenesis of the cleavage site of (pro)renin receptor abrogates aldosterone-salt-induced hypertension and renal injury in mice. Am J Physiol Renal Physiol 2023; 324:F1-F11. [PMID: 36302140 PMCID: PMC9762973 DOI: 10.1152/ajprenal.00088.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 09/29/2022] [Accepted: 10/17/2022] [Indexed: 02/04/2023] Open
Abstract
Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease and furin. It has been reported that sPRR functions as an important regulator of intrarenal renin contributing to angiotensin II (ANG II)-induced hypertension. Relatively, less is known for the function of sPRR in ANG II-independent hypertension such as mineralocorticoid excess. In the present study, we used a novel mouse model with mutagenesis of the cleavage site in PRR (termed as PRRR279V/L282V or mutant) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of mutant mice to Aldo-salt treatment was blunted in parallel with the attenuated response of plasma volume expansion and renal medullary α-epithelial Na+ channel expression. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied by blunted polydipsia and polyuria. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury.NEW & NOTEWORTHY We used a novel mouse model with mutagenesis of the cleavage site of PRR to support soluble PRR as an essential mediator of aldosterone-salt-induced hypertension and also as a potential therapeutic target for patients with mineralocorticoid excess. We firstly report that soluble PRR-dependent pathway medicates the Na+-retaining action of aldosterone in the distal nephron, which opens up a new area for a better understanding of the molecular basis of renal handling of Na+ balance and blood pressure.
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Affiliation(s)
- Ziwei Fu
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah
| | - Huaqing Zheng
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah
- Renal Section, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah
| | - Kannaree Kaewsaro
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah
| | - Jacob Lambert
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah
| | - Yanting Chen
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah
| | - Tianxin Yang
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah
- Renal Section, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah
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18
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Devaux CA, Camoin-Jau L. An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection. Front Microbiol 2022; 13:1042200. [PMID: 36519165 PMCID: PMC9742611 DOI: 10.3389/fmicb.2022.1042200] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/07/2022] [Indexed: 08/01/2023] Open
Abstract
It has been known for many years that the angiotensin-converting enzyme 2 (ACE2) is a cell surface enzyme involved in the regulation of blood pressure. More recently, it was proven that the severe acute respiratory syndrome coronavirus (SARS-CoV-2) interacts with ACE2 to enter susceptible human cells. This functional duality of ACE2 tends to explain why this molecule plays such an important role in the clinical manifestations of coronavirus disease 2019 (COVID-19). At the very start of the pandemic, a publication from our Institute (entitled "ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome"), was one of the first reviews linking COVID-19 to the duplicitous nature of ACE2. However, even given that COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin system (RAS), we were still far from understanding the complexity of the mechanisms which are controlled by ACE2 in different cell types. To gain insight into the physiopathology of SARS-CoV-2 infection, it is essential to consider the polymorphism and expression levels of the ACE2 gene (including its alternative isoforms). Over the past 2 years, an impressive amount of new results have come to shed light on the role of ACE2 in the pathophysiology of COVID-19, requiring us to update our analysis. Genetic linkage studies have been reported that highlight a relationship between ACE2 genetic variants and the risk of developing hypertension. Currently, many research efforts are being undertaken to understand the links between ACE2 polymorphism and the severity of COVID-19. In this review, we update the state of knowledge on the polymorphism of ACE2 and its consequences on the susceptibility of individuals to SARS-CoV-2. We also discuss the link between the increase of angiotensin II levels among SARS-CoV-2-infected patients and the development of a cytokine storm associated microvascular injury and obstructive thrombo-inflammatory syndrome, which represent the primary causes of severe forms of COVID-19 and lethality. Finally, we summarize the therapeutic strategies aimed at preventing the severe forms of COVID-19 that target ACE2. Changing paradigms may help improve patients' therapy.
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Affiliation(s)
- Christian A. Devaux
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU–Méditerranée Infection, Marseille, France
- Center National de la Recherche Scientifique, Marseille, France
| | - Laurence Camoin-Jau
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU–Méditerranée Infection, Marseille, France
- Laboratoire d’Hématologie, Hôpital de La Timone, APHM, Boulevard Jean-Moulin, Marseille, France
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19
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Yang T. Potential of soluble (pro)renin receptor in kidney disease: can it go beyond a biomarker? Am J Physiol Renal Physiol 2022; 323:F507-F514. [PMID: 36074917 PMCID: PMC9602801 DOI: 10.1152/ajprenal.00202.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/25/2022] [Accepted: 08/29/2022] [Indexed: 12/14/2022] Open
Abstract
(Pro)renin receptor (PRR), also termed ATPase H+-transporting accessory protein 2 (ATP6AP2), is a type I transmembrane receptor and is capable of binding and activating prorenin and renin. Apart from its association with the renin-angiotensin system, PRR has been implicated in diverse developmental, physiological, and pathophysiological processes. Within the kidney, PRR is predominantly expressed in the distal nephron, particularly the intercalated cells, and activation of renal PRR contributes to renal injury in various rodent models of chronic kidney disease. Moreover, recent evidence demonstrates that PRR is primarily cleaved by site-1 protease to produce 28-kDa soluble PRR (sPRR). sPRR seems to mediate most of the known pathophysiological functions of renal PRR through modulating the activity of the intrarenal renin-angiotensin system and provoking proinflammatory and profibrotic responses. Not only does sPRR activate renin, but it also directly binds and activates the angiotensin II type 1 receptor. This review summarizes recent advances in understanding the roles and mechanisms of sPRR in the context of renal pathophysiology.
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Affiliation(s)
- Tianxin Yang
- Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah
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20
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Ouyang X, Xu C. Targeting the (pro)renin receptor in cancers: from signaling to pathophysiological effects. J Cancer Res Clin Oncol 2022; 149:2595-2605. [PMID: 36153775 DOI: 10.1007/s00432-022-04373-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 09/19/2022] [Indexed: 10/14/2022]
Abstract
Cancer is a major public health problem, currently affecting hundreds of millions of people worldwide, and its clinical results are unpredictable, partly due to the lack of reliable biomarkers of cancer progression. Recently, it has been reported that (pro)renin receptor (PRR), as a new biomarker, plays an important role in different types of cancer, such as colorectal cancer, breast cancer, glioma, aldosterone-producing adenoma, endometrial cancer, urothelial cancer, and pancreatic ductal adenocarcinoma. In order to comprehensively and systematically understand the relationship and role of PRR with various cancers, this review will summarize the current research on targeting PRR in cancer from signaling to pathophysiological effects, including the correlation between PRR/sPRR expression level and different cancers, potential mechanisms regulated by PRR in the progress of cancers, and PRR in cancer treatment. PRR can be a novel and promising biomarker and potential therapeutic target for diagnosis, treatment, and prognosis in cancer, which is worthy of extensive development and application in clinics.
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21
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Wang YN, Liu HJ, Ren LL, Suo P, Zou L, Zhang YM, Yu XY, Zhao YY. Shenkang injection improves chronic kidney disease by inhibiting multiple renin-angiotensin system genes by blocking the Wnt/β-catenin signalling pathway. Front Pharmacol 2022; 13:964370. [PMID: 36059935 PMCID: PMC9432462 DOI: 10.3389/fphar.2022.964370] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 07/20/2022] [Indexed: 12/05/2022] Open
Abstract
Chronic kidney disease (CKD) is a major worldwide public health problem. The increase in the number of patients with CKD and end-stage kidney disease requesting renal dialysis or transplantation will progress to epidemic proportions in the next several decades. Although blocking the renin-angiotensin system (RAS) has been used as a first-line standard therapy in patients with hypertension and CKD, patients still progress towards end-stage kidney disease, which might be closely associated with compensatory renin expression subsequent to RAS blockade through a homeostatic mechanism. The Wnt/β-catenin signalling pathway is the master upstream regulator that controls multiple intrarenal RAS genes. As Wnt/β-catenin regulates multiple RAS genes, we inferred that this pathway might also be implicated in blood pressure control. Therefore, discovering new medications to synchronously target multiple RAS genes is necessary and essential for the effective treatment of patients with CKD. We hypothesized that Shenkang injection (SKI), which is widely used to treat CKD patients, might ameliorate CKD by inhibiting the activation of multiple RAS genes via the Wnt/β-catenin signalling pathway. To test this hypothesis, we used adenine-induced CKD rats and angiotensin II (AngII)-induced HK-2 and NRK-49F cells. Treatment with SKI inhibited renal function decline, hypertension and renal fibrosis. Mechanistically, SKI abrogated the increased protein expression of multiple RAS elements, including angiotensin-converting enzyme and angiotensin II type 1 receptor, as well as Wnt1, β-catenin and downstream target genes, including Snail1, Twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1 and fibroblast-specific protein 1, in adenine-induced rats, which was verified in AngII-induced HK-2 and NRK-49F cells. Similarly, our results further indicated that treatment with rhein isolated from SKI attenuated renal function decline and epithelial-to-mesenchymal transition and repressed RAS activation and the hyperactive Wnt/β-catenin signalling pathway in both adenine-induced rats and AngII-induced HK-2 and NRK-49F cells. This study first revealed that SKI repressed epithelial-to-mesenchymal transition by synchronously targeting multiple RAS elements by blocking the hyperactive Wnt/β-catenin signalling pathway.
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Affiliation(s)
- Yan-Ni Wang
- Faculty of Life Science and Medicine, Northwest University, Xi’an, Shaanxi, China
| | - Hong-Jiao Liu
- Faculty of Life Science and Medicine, Northwest University, Xi’an, Shaanxi, China
| | - Li-Li Ren
- Faculty of Life Science and Medicine, Northwest University, Xi’an, Shaanxi, China
| | - Ping Suo
- Faculty of Life Science and Medicine, Northwest University, Xi’an, Shaanxi, China
| | - Liang Zou
- Key Disciplines Team of Clinical Pharmacy, School of Food and Bioengineering, Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, Sichuan, China
| | - Ya-Mei Zhang
- Clinical Genetics Laboratory, Affiliated Hospital and Clinical Medical College of Chengdu University, Chengdu, Sichuan, China
| | - Xiao-Yong Yu
- Department of Nephrology, Shaanxi Traditional Chinese Medicine Hospital, Xi’an, Shaanxi, China
| | - Ying-Yong Zhao
- Faculty of Life Science and Medicine, Northwest University, Xi’an, Shaanxi, China
- Clinical Genetics Laboratory, Affiliated Hospital and Clinical Medical College of Chengdu University, Chengdu, Sichuan, China
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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22
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Pelle MC, Provenzano M, Busutti M, Porcu CV, Zaffina I, Stanga L, Arturi F. Up-Date on Diabetic Nephropathy. Life (Basel) 2022; 12:1202. [PMID: 36013381 PMCID: PMC9409996 DOI: 10.3390/life12081202] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/27/2022] [Accepted: 08/02/2022] [Indexed: 12/11/2022] Open
Abstract
Diabetes is one of the leading causes of kidney disease. Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide, and it is linked to an increase in cardiovascular (CV) risk. Diabetic nephropathy (DN) increases morbidity and mortality among people living with diabetes. Risk factors for DN are chronic hyperglycemia and high blood pressure; the renin-angiotensin-aldosterone system blockade improves glomerular function and CV risk in these patients. Recently, new antidiabetic drugs, including sodium-glucose transport protein 2 inhibitors and glucagon-like peptide-1 agonists, have demonstrated additional contribution in delaying the progression of kidney disease and enhancing CV outcomes. The therapeutic goal is regression of albuminuria, but an atypical form of non-proteinuric diabetic nephropathy (NP-DN) is also described. In this review, we provide a state-of-the-art evaluation of current treatment strategies and promising emerging treatments.
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Affiliation(s)
- Maria Chiara Pelle
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Michele Provenzano
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Marco Busutti
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Clara Valentina Porcu
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Isabella Zaffina
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Lucia Stanga
- Oncology Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Franco Arturi
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
- Research Centre for the Prevention and Treatment of Metabolic Diseases (CR METDIS), University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
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23
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Yang T. Soluble (Pro)Renin Receptor in Hypertension. Nephron Clin Pract 2022; 147:234-243. [PMID: 35871512 PMCID: PMC9867785 DOI: 10.1159/000525635] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 05/27/2022] [Indexed: 01/26/2023] Open
Abstract
The (pro)renin receptor (PRR) was originally cloned as a specific single-transmembrane receptor for prorenin and renin and has now emerged as a multifunctional protein implicated in a wide variety of developmental and physiopathological processes. Activation of PRR in the kidney causes Na+ and water retention, contributing to elevation of blood pressure in response to various hypertensive stimuli. Part of the renal action of PRR depends on activation of intrarenal renin-angiotensin system. In recent years, accumulating evidence suggests that the prohypertensive action of renal PRR was largely mediated by production of the 28-kDa soluble (pro)renin receptor through protease-mediated cleavage of the extracellular domain of PRR. The generation of multiple isoforms of PRR due to the protease-mediated cleavage partially explains diversified actions of PRR. The current review will summarize recent advances in understanding the roles of sPPR in animal models of hypertension.
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Affiliation(s)
- Tianxin Yang
- Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA
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24
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Kawamura S, Fujimoto K, Hayashi A, Kamata Y, Moriguchi I, Kobayashi N, Shichiri M. Plasma and serum prorenin concentrations in diabetes, hypertension, and renal disease. Hypertens Res 2022; 45:1977-1985. [PMID: 35689092 DOI: 10.1038/s41440-022-00959-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 04/20/2022] [Accepted: 05/07/2022] [Indexed: 11/09/2022]
Abstract
Although the renin-angiotensin-aldosterone system plays a crucial role in fluid homeostasis and cardiovascular disease pathophysiology, measurements of plasma prorenin levels are still unavailable in clinical practice. We previously found that prorenin molecules in human blood underwent significant posttranslational modifications and were undetectable using immunological assays that utilized antibodies specifically recognizing unmodified recombinant prorenin. Using a sandwich enzyme-linked immunosorbent assay that captures posttranslationally modified prorenins with their prosegment antibodies, we measured plasma and serum prorenin concentrations in 219 patients with diabetes mellitus, hypertension and/or renal disease and compared them with those of 40 healthy controls. The measured values were not significantly different from those of the healthy controls and were 1,000- to 100,000-fold higher than previously reported levels determined using conventional assay kits. Multiple regression analyses showed that body weight, serum albumin levels, and serum creatinine levels negatively correlated with plasma prorenin levels, while the use of loop diuretics was associated with elevated plasma prorenin levels. Blood pressure, HbA1c, and plasma renin activity were not independent variables affecting plasma prorenin levels. In contrast, serum prorenin levels were unaffected by any of the above clinical parameters. The association of the plasma prorenin concentration with indices reflecting body fluid status suggests the need to scrutinize its role as a biomarker, while serum prorenins are less likely to have immediate diagnostic value.
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Affiliation(s)
- Sayuki Kawamura
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Kazumi Fujimoto
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Akinori Hayashi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yuji Kamata
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Ibuki Moriguchi
- Sohbudai Nieren Clinic, 1-35-10, Sohbudai, Zama, Kanagawa, 252-0011, Japan
| | - Naoyuki Kobayashi
- Sohbudai Nieren Clinic, 1-35-10, Sohbudai, Zama, Kanagawa, 252-0011, Japan
| | - Masayoshi Shichiri
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan. .,Tokyo Kyosai Hospital, 2-3-8, Nakameguro, Meguro, Tokyo, 153-8934, Japan.
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25
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Du XY, Xiang DC, Gao P, Peng H, Liu YL. Inhibition of (Pro)renin Receptor-Mediated Oxidative Stress Alleviates Doxorubicin-Induced Heart Failure. Front Oncol 2022; 12:874852. [PMID: 35574363 PMCID: PMC9106363 DOI: 10.3389/fonc.2022.874852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 03/31/2022] [Indexed: 11/22/2022] Open
Abstract
Aim Clinical utility of doxorubicin (DOX) is limited by its cardiotoxic side effect, and the underlying mechanism still needs to be fully elucidated. This research aimed to examine the role of (pro)renin receptor (PRR) in DOX-induced heart failure (HF) and its underlying mechanism. Main Methods Sprague Dawley (SD) rats were injected with an accumulative dosage of DOX (15 mg/kg) to induce HF. Cardiac functions were detected by transthoracic echocardiography examination. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) in serum were detected, and oxidative stress related injuries were evaluated. Furthermore, the mRNA expression of PRR gene and its related genes were detected by real-time PCR (RT-PCR), and protein levels of PRR, RAC1, NOX4 and NOX2 were determined by Western blot. Reactive oxygen species (ROS) were determined in DOX-treated rats or cells. Additionally, PRR and RAC1 were silenced with their respective siRNAs to validate the in vitro impacts of PRR/RAC1 on DOX-induced cardiotoxicity. Moreover, inhibitors of PRR and RAC1 were used to validate their effects in vivo. Key Findings PRR and RAC1 expressions increased in DOX-induced HF. The levels of CK and LDH as well as oxidative stress indicators increased significantly after DOX treatment. Oxidative injury and apoptosis of cardiomyocytes were attenuated both in vivo and in vitro upon suppression of PRR or RAC1. Furthermore, the inhibition of PRR could significantly down-regulate the expressions of RAC1 and NOX4 but not that of NOX2, while the inhibition of RAC1 did not affect PRR. Significance Our findings showed that PRR inhibition could weaken RAC1-NOX4 pathway and alleviate DOX-induced HF via decreasing ROS production, thereby suggesting a promising target for the treatment of DOX-induced HF.
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Affiliation(s)
- Xiao-yi Du
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Pediatrics, Maternal and Child Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dao-chun Xiang
- Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Gao
- Department of Clinical Pharmacy, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Peng
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Hua Peng, ; Ya-li Liu,
| | - Ya-li Liu
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Hua Peng, ; Ya-li Liu,
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26
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Inhibitory Potential of Shen-Shuai-Ling Formulation on Renal Interstitial Fibrosis via Upregulation of PLZF. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5967804. [PMID: 35399631 PMCID: PMC8991406 DOI: 10.1155/2022/5967804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/27/2022] [Indexed: 11/18/2022]
Abstract
Background Renal interstitial fibrosis (RIF) is an important cause of kidney disease, which seriously affects people's health. As a traditional Chinese medicine, Shen-Shuai-Ling Formulation (SSLF) has obvious kidney function. However, the therapeutic effect of SSLF on RIF and its molecular mechanism are still unclear. Methods First, the potential targets and pathways of SSLF for RIF were predicted by network pharmacology, and then, the binding of luteolin and target protein to SSLF was verified by molecular docking and Co-IP experiments. Finally, the effects of SSLF and luteolin on PLZF and (Pro) renin receptor (PRR) were verified by western blot and qPCR experiments. Angiotensin (Ang)-1, Ang-2, and transforming growth factor-β (TGF-β) were the indexes of renal interstitial fibrosis. Results Through the drug-active component-target network diagram, we found that luteolin has the most connections, and promyelocytic leukemia zinc finger (PLZF) is the target protein. GO analysis and KEGG pathway analysis of targets were performed using Cytoscape ClueGO. Molecular docking experiments and Co-IP are used to prove that luteolin and PLZF can be combined. Western blot and qPCR results showed that both SSLF and luteolin significantly upregulated the expression of PLZF and decreased the levels of PRR, Ang-1, Ang-2, and TGF-β. The overexpression of PLZF decreased the expression of PRR, the knockdown of PLZF increased the expression of PRR, and the overexpression of PRR decreased the expression of Ang-1, Ang-2, and TGF-β. Conclusions SSLF inhibits PRR and renal interstitial fibers by the upregulation of PLZF levels.
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27
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Martin JH, Mohammed R, Delforce SJ, Skerrett-Byrne DA, de Meaultsart CC, Almazi JG, Stephens AN, Verrills NM, Dimitriadis E, Wang Y, Lumbers ER, Pringle KG. Role of the prorenin receptor in endometrial cancer cell growth. Oncotarget 2022; 13:587-599. [PMID: 35401936 PMCID: PMC8986267 DOI: 10.18632/oncotarget.28224] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/14/2022] [Indexed: 11/25/2022] Open
Affiliation(s)
- Jacinta H. Martin
- School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
- These authors contributed equally to this work
| | - Riazuddin Mohammed
- School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
- These authors contributed equally to this work
| | - Sarah J. Delforce
- School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
| | - David A. Skerrett-Byrne
- School of Environmental and Life Sciences, Priority Research Centre for Reproductive Science, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
| | - Celine Corbisier de Meaultsart
- School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
| | - Juhura G. Almazi
- School of Biomedical Sciences and Pharmacy, Priority Research Centre for Cancer Research, Innovation and Translation, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, New South Wales, Australia
| | - Andrew N. Stephens
- Hudson Institute of Medical Research, Australia and Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
| | - Nicole M. Verrills
- School of Biomedical Sciences and Pharmacy, Priority Research Centre for Cancer Research, Innovation and Translation, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
| | - Evdokia Dimitriadis
- Department of Obstetrics and Gynaecology, University of Melbourne, Gynaecology Research Centre, The Women’s Hospital, Melbourne, Victoria, Australia
| | - Yu Wang
- School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
| | - Eugenie R. Lumbers
- School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
| | - Kirsty G. Pringle
- School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
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28
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Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor-Mediated Intrarenal Renin-Angiotensin System and Nox4-H 2O 2 Signaling. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5710440. [PMID: 34873430 PMCID: PMC8642821 DOI: 10.1155/2021/5710440] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/20/2021] [Accepted: 11/09/2021] [Indexed: 12/22/2022]
Abstract
Full-length (pro)renin receptor (fPRR), a research hotspot of the renin-angiotensin system (RAS), plays a serious role in kidney injury. However, the relationship between fPRR and advanced oxidation protein product (AOPP) remains largely unexplored. This study was aimed at exploring the effect of fPRR, especially its 28 kDa soluble form called soluble PRR (sPRR), in AOPP-induced oxidative stress in HK-2 cells, a renal proximal tubular epithelial cell line. Incubation of HK-2 cells with 100 μg/ml AOPP resulted in significant upregulation of fPRR expression and caused an approximately fourfold increase in medium sPRR secretion. However, unmodified albumin did not demonstrate the same effects under the same concentration. Treatment of HK-2 cells with the site-1 protease (S1P) inhibitor PF429242 (40 μM) or S1P siRNA significantly inhibited AOPP-induced sPRR generation. fPRR decoy inhibitor PRO20 and PF429242 treatment for 24 h remarkably attenuated the AOPP-induced upregulation of RAS components. Furthermore, PF429242 significantly reduced the AOPP-stimulated expression of NADPH oxidase 4 (Nox4) and H2O2 expression. The use of a small recombinant protein, named sPRR-His, reversed these alterations. In conclusion, these results provided the first demonstration of AOPP-promoted activation of sPRR. Increased renal proximal tubule Nox4-derived H2O2 contributed to the aggravation of oxidative stress. Targeting S1P-derived sPRR is a promising intervention strategy for chronic kidney disease.
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29
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Culver SA, Akhtar S, Rountree-Jablin C, Keller SR, Cathro HP, Gildea JJ, Siragy HM. Knockout of Nephron ATP6AP2 Impairs Proximal Tubule Function and Prevents High-Fat Diet-Induced Obesity in Male Mice. Endocrinology 2021; 162:bqab200. [PMID: 34534267 PMCID: PMC8489432 DOI: 10.1210/endocr/bqab200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Indexed: 12/24/2022]
Abstract
ATP6AP2 expression is increased in the nephron during high-fat diet (HFD) and its knockout (ATP6AP2 KO) reduces body weight (WT) in mice. We evaluated the contribution of ATP6AP2 to urinary glucose (UG) and albumin (Ualb) handling during HFD. We hypothesized that nephron ATP6AP2 KO increases UG and Ualb and minimizes HFD-induced obesity. Eight-week-old male C57BL/6J mice with inducible nephron-specific ATP6AP2 KO and noninduced controls were fed either normal diet (ND, 12% kcal fat) or HFD (45% kcal fat) for 6 months. ATP6AP2 KO mice on ND had 20% (P < 0.01) lower WT compared with controls. HFD-fed mice had 41% (P < 0.05) greater WT than ND-fed control mice. In contrast, ATP6AP2 KO abrogated the increase in WT induced by HFD by 40% (P < 0.05). Mice on HFD had less caloric intake compared with ND controls (P < 0.01). There were no significant differences in metabolic rate between all groups. UG and Ualb was significantly increased in ATP6AP2 KO mice on both ND and HFD. ATP6AP2 KO showed greater levels of proximal tubule apoptosis and histologic evidence of proximal tubule injury. In conclusion, our results demonstrate that nephron-specific ATP6AP2 KO is associated with glucosuria and albuminuria, most likely secondary to renal proximal tubule injury and/or dysfunction. Urinary loss of nutrients may have contributed to the reduced WT of knockout mice on ND and lack of WT gain in response to HFD. Future investigation should elucidate the mechanisms by which loss of renal ATP6AP2 causes proximal tubule injury and dysfunction.
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Affiliation(s)
- Silas A Culver
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Safia Akhtar
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Callie Rountree-Jablin
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Susanna R Keller
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Helen P Cathro
- Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - John J Gildea
- Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Helmy M Siragy
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
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30
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Larrinaga G, Calvete-Candenas J, Solano-Iturri JD, Martín AM, Pueyo A, Nunes-Xavier CE, Pulido R, Dorado JF, López JI, Angulo JC. (Pro)renin Receptor Is a Novel Independent Prognostic Marker in Invasive Urothelial Carcinoma of the Bladder. Cancers (Basel) 2021; 13:cancers13225642. [PMID: 34830803 PMCID: PMC8616163 DOI: 10.3390/cancers13225642] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 01/01/2023] Open
Abstract
Simple Summary This is a novel description of (Pro)renin receptor (PRR) protein and its prognostic role in invasive urothelial cancer of the bladder. Using a tissue microarray, we investigated PRR expression and other immunohistochemical markers including p53, immune-checkpoint inhibition, and basal and luminal phenotypes in a series of patients with invasive urothelial carcinoma of the bladder treated with radical cystectomy. PRR expression is an independent prognostic marker and could be a potential target in urothelial carcinoma that should be further investigated. Abstract (Pro)renin receptor (PRR) is being investigated in several malignancies as it activates pathogenic pathways that contribute to cell proliferation, immunosuppressive microenvironments, and acquisition of aggressive neoplastic phenotypes. Its implication in urothelial cancer (UC) has not been evaluated so far. We retrospectively evaluate the prognostic role of PRR expression in a series of patients with invasive UC treated with radical cystectomy and other clinical and histopathological parameters including p53, markers of immune-checkpoint inhibition, and basal and luminal phenotypes evaluated by tissue microarray. Cox regression analyses using stepwise selection evaluated candidate prognostic factors and disease-specific survival. PRR was expressed in 77.3% of the primary tumors and in 70% of positive lymph nodes. PRR expression correlated with age (p = 0.006) and was associated with lower preoperatively hemoglobin levels. No other statistical association was evidenced with clinical and pathological variables (gender, ASA score, Charlson comorbidity index, grade, pT, pN) or immunohistochemical expressions evaluated (CK20, GA-TA3, CK5/6, CD44, PD-L1, PD-1, B7-H3, VISTA, and p53). PRR expression in primary tumors was associated with worse survival (log-rank, p = 0.008). Cox regression revealed that PRR expression (HR 1.85, 95% CI 1.22–2.8), pT (HR 7.02, 95% CI 2.68–18.39), pN (HR 2.3, 95% CI 1.27–4.19), and p53 expression (HR 1.95, 95% CI 1.1–3.45) were independent prognostic factors in this series. In conclusion, we describe PRR protein and its prognostic role in invasive UC for the first time. Likely mechanisms involved are MAPK/ERK activation, Wnt/β-catenin signaling, and v-ATPAse function.
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Affiliation(s)
- Gorka Larrinaga
- Department of Nursing, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
- Biomarkers in Cancer Unit, Biocruces-Bizkaia Institute, 48903 Barakaldo, Spain; (J.D.S.-I.); (C.E.N.-X.); (R.P.); (J.I.L.)
- Correspondence:
| | | | - Jon Danel Solano-Iturri
- Biomarkers in Cancer Unit, Biocruces-Bizkaia Institute, 48903 Barakaldo, Spain; (J.D.S.-I.); (C.E.N.-X.); (R.P.); (J.I.L.)
- Service of Pathology, Donostia University Hospital, 20014 San Sebastian, Spain
| | - Ana M. Martín
- Service of Pathology, University Hospital of Getafe, 28905 Madrid, Spain;
| | - Angel Pueyo
- Foundation for Biomedical Research and Innovation of University Hospitals Infanta Leonor and South-East, 28003 Madrid, Spain;
- Heath Science PhD Program, UCAM Universidad Católica San Antonio de Murcia, Guadalupe de Maciascoque, 30107 Murcia, Spain
| | - Caroline E. Nunes-Xavier
- Biomarkers in Cancer Unit, Biocruces-Bizkaia Institute, 48903 Barakaldo, Spain; (J.D.S.-I.); (C.E.N.-X.); (R.P.); (J.I.L.)
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0310 Oslo, Norway
| | - Rafael Pulido
- Biomarkers in Cancer Unit, Biocruces-Bizkaia Institute, 48903 Barakaldo, Spain; (J.D.S.-I.); (C.E.N.-X.); (R.P.); (J.I.L.)
- Ikerbasque, The Basque Foundation for Science, 48011 Bilbao, Spain
| | | | - José I. López
- Biomarkers in Cancer Unit, Biocruces-Bizkaia Institute, 48903 Barakaldo, Spain; (J.D.S.-I.); (C.E.N.-X.); (R.P.); (J.I.L.)
- Department of Pathology, Cruces University Hospital, 48903 Barakaldo, Spain
| | - Javier C. Angulo
- Clinical Department, Faculty of Medical Sciences, European University of Madrid, 28005 Madrid, Spain;
- Department of Urology, University Hospital of Getafe, 28907 Madrid, Spain
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Serum soluble (pro)renin receptor level as a prognostic factor in patients undergoing maintenance hemodialysis. Sci Rep 2021; 11:17402. [PMID: 34465835 PMCID: PMC8408265 DOI: 10.1038/s41598-021-96892-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/29/2021] [Indexed: 01/05/2023] Open
Abstract
The (pro)renin receptor [(P)RR)] is a multifunctional protein that is cleaved to generate the soluble (P)RR [s(P)RR], reflecting the status of the tissue renin-angiotensin system and/or activity of the (P)RR. The serum s(P)RR level is associated with arteriosclerosis, independent of other risk factors, in patients undergoing hemodialysis (HD). This study was conducted to investigate whether the s(P)RR level was associated with new-onset cardiovascular events or malignant diseases and poor prognosis in patients undergoing HD. Overall, 258 patients [70 (61–76) years, 146 males] undergoing maintenance HD were prospectively followed up for 60 months. We investigated the relationships between s(P)RR levels and new-onset cardiovascular events/ malignant diseases and mortality during the follow-up period using Cox proportional hazard analyses. The cumulative incidence of new-onset cardiovascular events (P = 0.009) and deaths (P < 0.001), but not of malignant diseases, was significantly greater in patients with higher serum s(P)RR level (≥ 29.8 ng/ml) than in those with lower s(P)RR level (< 29.8 ng/ml). A high serum s(P)RR level was independently correlated with cardiovascular mortality (95% CI 1.001–1.083, P = 0.046). The serum s(P)RR level was associated with cardiovascular events and mortality, thus qualifying as a biomarker for identifying patients requiring intensive care.
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NADPH-Oxidase, Rho-Kinase and Autophagy Mediate the (Pro)renin-Induced Pro-Inflammatory Microglial Response and Enhancement of Dopaminergic Neuron Death. Antioxidants (Basel) 2021; 10:antiox10091340. [PMID: 34572972 PMCID: PMC8472832 DOI: 10.3390/antiox10091340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/12/2021] [Accepted: 08/20/2021] [Indexed: 11/16/2022] Open
Abstract
Dysregulation of the tissue renin–angiotensin system (RAS) is involved in tissue oxidative and inflammatory responses. Among RAS components, renin, its precursor (pro)renin and its specific receptor (PRR) have been less investigated, particularly in the brain. We previously showed the presence of PRR in neurons and glial cells in the nigrostriatal system of rodents and primates, including humans. Now, we used rat and mouse models and cultures of BV2 and primary microglial cells to study the role of PRR in microglial pro-inflammatory responses. PRR was upregulated in the nigral region, particularly in microglia during the neuroinflammatory response. In the presence of the angiotensin type-1 receptor blocker losartan, to exclude angiotensin-related effects, treatment of microglial cells with (pro)renin induces the expression of microglial pro-inflammatory markers, which is mediated by upregulation of NADPH-oxidase and Rho-kinase activities, downregulation of autophagy and upregulation of inflammasome activity. Conditioned medium from (pro)renin-treated microglia increased dopaminergic cell death relative to medium from non-treated microglia. However, these effects were blocked by pre-treatment of microglia with the Rho-kinase inhibitor fasudil. Activation of microglial PRR enhances the microglial pro-inflammatory response and deleterious effects of microglia on dopaminergic cells, and microglial NADPH-oxidase, Rho-Kinase and autophagy are involved in this process.
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Effect of Angiotensin II on Chondrocyte Degeneration and Protection via Differential Usage of Angiotensin II Receptors. Int J Mol Sci 2021; 22:ijms22179204. [PMID: 34502113 PMCID: PMC8430521 DOI: 10.3390/ijms22179204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/20/2021] [Accepted: 08/23/2021] [Indexed: 11/17/2022] Open
Abstract
The renin–angiotensin system (RAS) controls not only systemic functions, such as blood pressure, but also local tissue-specific events. Previous studies have shown that angiotensin II receptor type 1 (AT1R) and type 2 (AT2R), two RAS components, are expressed in chondrocytes. However, the angiotensin II (ANG II) effects exerted through these receptors on chondrocyte metabolism are not fully understood. In this study, we investigated the effects of ANG II and AT1R blockade on chondrocyte proliferation and differentiation. Firstly, we observed that ANG II significantly suppressed cell proliferation and glycosaminoglycan content in rat chondrocytic RCS cells. Additionally, ANG II decreased CCN2, which is an anabolic factor for chondrocytes, via increased MMP9. In Agtr1a-deficient RCS cells generated by the CRISPR-Cas9 system, Ccn2 and Aggrecan (Acan) expression increased. Losartan, an AT1R antagonist, blocked the ANG II-induced decrease in CCN2 production and Acan expression in RCS cells. These findings suggest that AT1R blockade reduces ANG II-induced chondrocyte degeneration. Interestingly, AT1R-positive cells, which were localized on the surface of the articular cartilage of 7-month-old mice expanded throughout the articular cartilage with aging. These findings suggest that ANG II regulates age-related cartilage degeneration through the ANG II–AT1R axis.
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Figueiredo M, Daryadel A, Sihn G, Müller DN, Popova E, Rouselle A, Nguyen G, Bader M, Wagner CA. The (pro)renin receptor (ATP6ap2) facilitates receptor-mediated endocytosis and lysosomal function in the renal proximal tubule. Pflugers Arch 2021; 473:1229-1246. [PMID: 34228176 PMCID: PMC8302575 DOI: 10.1007/s00424-021-02598-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/26/2021] [Accepted: 06/16/2021] [Indexed: 12/16/2022]
Abstract
The ATP6ap2 (Pro)renin receptor protein associates with H+-ATPases which regulate organellar, cellular, and systemic acid-base homeostasis. In the kidney, ATP6ap2 colocalizes with H+-ATPases in various cell types including the cells of the proximal tubule. There, H+-ATPases are involved in receptor-mediated endocytosis of low molecular weight proteins via the megalin/cubilin receptors. To study ATP6ap2 function in the proximal tubule, we used an inducible shRNA Atp6ap2 knockdown rat model (Kd) and an inducible kidney-specific Atp6ap2 knockout mouse model. Both animal lines showed higher proteinuria with elevated albumin, vitamin D binding protein, and procathepsin B in urine. Endocytosis of an injected fluid-phase marker (FITC- dextran, 10 kDa) was normal whereas processing of recombinant transferrin, a marker for receptor-mediated endocytosis, to lysosomes was delayed. While megalin and cubilin expression was unchanged, abundance of several subunits of the H+-ATPase involved in receptor-mediated endocytosis was reduced. Lysosomal integrity and H+-ATPase function are associated with mTOR signaling. In ATP6ap2, KO mice mTOR and phospho-mTOR appeared normal but increased abundance of the LC3-B subunit of the autophagosome was observed suggesting a more generalized impairment of lysosomal function in the absence of ATP6ap2. Hence, our data suggests a role for ATP6ap2 for proximal tubule function in the kidney with a defect in receptor-mediated endocytosis in mice and rats.
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Affiliation(s)
- Marta Figueiredo
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
| | - Arezoo Daryadel
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
| | - Gabin Sihn
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Dominik N Müller
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany
- Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
| | - Elena Popova
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Anthony Rouselle
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | | | - Michael Bader
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
- Charite University Medicine Berlin, Berlin, Germany.
- Institute for Biology, University of Lübeck, Lübeck, Germany.
| | - Carsten A Wagner
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
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Sasaki N, Morimoto S, Suda C, Shimizu S, Ichihara A. Urinary soluble (pro)renin receptor excretion is associated with urine pH in humans. PLoS One 2021; 16:e0254688. [PMID: 34310595 PMCID: PMC8312976 DOI: 10.1371/journal.pone.0254688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 07/02/2021] [Indexed: 11/29/2022] Open
Abstract
The (pro)renin receptor [(P)RR] binds to renin and its precursor prorenin to activate the tissue renin-angiotensin system. It is cleaved to generate soluble (P)RR and M8–9, a residual hydrophobic truncated protein. The (pro)renin receptor also functions as an intracellular accessory protein of vacuolar-type H+-ATPase, which plays an essential role in controlling the intracellular vesicular acid environment. Thus, in the kidney, (P)RR may play a role in transporting H+ to urine in the collecting duct. Although blood soluble (P)RR has been recognized as a biomarker reflecting the status of the tissue renin-angiotensin system and/or tissue (P)RR, the significance of urinary soluble (P)RR excretion has not been determined. Therefore, this study aimed to investigate the characteristics of urinary soluble (P)RR excretion. Urinary soluble (P)RR excretion was measured, and its association with background factors was investigated in 441 patients. Relationships between changes in urine pH due to vitamin C treatment, which reduce urine pH, and urinary soluble (P)RR excretion were investigated in 10 healthy volunteers. Urinary soluble (P)RR excretion was 1.46 (0.44–2.92) ng/gCre. Urine pH showed a significantly positive association with urinary soluble (P)RR excretion, independent of other factors. Changes in urine pH and urinary soluble (P)RR excretion due to vitamin C treatment were significantly and positively correlated (ρ = 0.8182, p = 0.0038). These data showed an association between urinary soluble (P)RR excretion and urine pH in humans, suggesting that (P)RR in the kidney might play a role in urine pH regulation.
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Affiliation(s)
- Nobukazu Sasaki
- Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Tokyo, Japan
| | - Satoshi Morimoto
- Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Tokyo, Japan
- * E-mail:
| | - Chikahito Suda
- Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Tokyo, Japan
| | - Satoru Shimizu
- School of Arts and Sciences, Tokyo Woman’s Christian University, Tokyo, Japan
| | - Atsuhiro Ichihara
- Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Tokyo, Japan
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Diabetic Nephropathy: Challenges in Pathogenesis, Diagnosis, and Treatment. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1497449. [PMID: 34307650 PMCID: PMC8285185 DOI: 10.1155/2021/1497449] [Citation(s) in RCA: 438] [Impact Index Per Article: 109.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/02/2021] [Indexed: 12/15/2022]
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Chronic hyperglycemia and high blood pressure are the main risk factors for the development of DN. In general, screening for microalbuminuria should be performed annually, starting 5 years after diagnosis in type 1 diabetes and at diagnosis and annually thereafter in type 2 diabetes. Standard therapy is blood glucose and blood pressure control using the renin-angiotensin system blockade, targeting A1c < 7%, and <130/80 mmHg. Regression of albuminuria remains an important therapeutic goal. However, there are problems in diagnosis and treatment of nonproteinuric DN (NP-DN), which does not follow the classic pattern of DN. In fact, the prevalence of DN continues to increase, and additional therapy is needed to prevent or ameliorate the condition. In addition to conventional therapies, vitamin D receptor activators, incretin-related drugs, and therapies that target inflammation may also be promising for the prevention of DN progression. This review focuses on the role of inflammation and oxidative stress in the pathogenesis of DN, approaches to diagnosis in classic and NP-DN, and current and emerging therapeutic interventions.
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Mehranfard D, Perez G, Rodriguez A, Ladna JM, Neagra CT, Goldstein B, Carroll T, Tran A, Trivedi M, Speth RC. Alterations in Gene Expression of Renin-Angiotensin System Components and Related Proteins in Colorectal Cancer. J Renin Angiotensin Aldosterone Syst 2021; 2021:9987115. [PMID: 34285715 PMCID: PMC8277508 DOI: 10.1155/2021/9987115] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/13/2021] [Accepted: 06/07/2021] [Indexed: 12/16/2022] Open
Abstract
MATERIALS AND METHODS Quantitative expression of the RNA of these 17 genes in normal and cancerous tissues obtained using chip arrays from the public functional genomics data repository, Gene Expression Omnibus (GEO) application, was compared statistically. RESULTS Expression of four genes, AGT (angiotensinogen), ENPEP (aminopeptidase A) MME (neprilysin), and PREP (prolyl endopeptidase), was significantly upregulated in CRC specimens. Expression of REN (renin), THOP (thimet oligopeptidase), NLN (neurolysin), PRCP (prolyl carboxypeptidase), ANPEP (aminopeptidase N), and MAS1 (Mas receptor) was downregulated in CRC specimens. CONCLUSIONS Presuming gene expression parallel protein expression, these results suggest that increased production of the angiotensinogen precursor of angiotensin (ANG) peptides, with the reduction of the enzymes that metabolize it to ANG II, can lead to accumulation of angiotensinogen in CRC tissues. Downregulation of THOP, NLN, PRCP, and MAS1 gene expression, whose proteins contribute to the ACE2/ANG 1-7/Mas axis, suggests that reduced activity of this RAS branch could be permissive for oncogenicity. Components of the RAS may be potential therapeutic targets for treatment of CRC.
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Affiliation(s)
- Danial Mehranfard
- College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Gabriela Perez
- Department of Internal Medicine, Palmetto General Hospital, Hialeah, FL, USA
| | - Andres Rodriguez
- Department of Internal Medicine, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
| | | | | | | | - Timothy Carroll
- College of Psychology, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Alice Tran
- Halmos College of Arts and Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Malav Trivedi
- College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Robert C. Speth
- College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
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High glucose induces trafficking of prorenin receptor and stimulates profibrotic factors in the collecting duct. Sci Rep 2021; 11:13815. [PMID: 34226610 PMCID: PMC8257763 DOI: 10.1038/s41598-021-93296-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/08/2021] [Indexed: 12/13/2022] Open
Abstract
Growing evidence indicates that prorenin receptor (PRR) is upregulated in collecting duct (CD) of diabetic kidney. Prorenin is secreted by the principal CD cells, and is the natural ligand of the PRR. PRR activation stimulates fibrotic factors, including fibronectin, collagen, and transforming growth factor-β (TGF-β) contributing to tubular fibrosis. However, whether high glucose (HG) contributes to this effect is unknown. We tested the hypothesis that HG increases the abundance of PRR at the plasma membrane of the CD cells, thus contributing to the stimulation of downstream fibrotic factors, including TGF-β, collagen I, and fibronectin. We used streptozotocin (STZ) male Sprague–Dawley rats to induce hyperglycemia for 7 days. At the end of the study, STZ-induced rats showed increased prorenin, renin, and angiotensin (Ang) II in the renal inner medulla and urine, along with augmented downstream fibrotic factors TGF-β, collagen I, and fibronectin. STZ rats showed upregulation of PRR in the renal medulla and preferential distribution of PRR on the apical aspect of the CD cells. Cultured CD M-1 cells treated with HG (25 mM for 1 h) showed increased PRR in plasma membrane fractions compared to cells treated with normal glucose (5 mM). Increased apical PRR was accompanied by upregulation of TGF-β, collagen I, and fibronectin, while PRR knockdown prevented these effects. Fluorescence resonance energy transfer experiments in M-1 cells demonstrated augmented prorenin activity during HG conditions. The data indicate HG stimulates profibrotic factors by inducing PRR translocation to the plasma membrane in CD cells, which in perspective, might be a novel mechanism underlying the development of tubulointerstitial fibrosis in diabetes mellitus.
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Prieto MC, Gonzalez AA, Visniauskas B, Navar LG. The evolving complexity of the collecting duct renin-angiotensin system in hypertension. Nat Rev Nephrol 2021; 17:481-492. [PMID: 33824491 PMCID: PMC8443079 DOI: 10.1038/s41581-021-00414-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2021] [Indexed: 02/07/2023]
Abstract
The intrarenal renin-angiotensin system is critical for the regulation of tubule sodium reabsorption, renal haemodynamics and blood pressure. The excretion of renin in urine can result from its increased filtration, the inhibition of renin reabsorption by megalin in the proximal tubule, or its secretion by the principal cells of the collecting duct. Modest increases in circulating or intrarenal angiotensin II (ANGII) stimulate the synthesis and secretion of angiotensinogen in the proximal tubule, which provides sufficient substrate for collecting duct-derived renin to form angiotensin I (ANGI). In models of ANGII-dependent hypertension, ANGII suppresses plasma renin, suggesting that urinary renin is not likely to be the result of increased filtered load. In the collecting duct, ANGII stimulates the synthesis and secretion of prorenin and renin through the activation of ANGII type 1 receptor (AT1R) expressed primarily by principal cells. The stimulation of collecting duct-derived renin is enhanced by paracrine factors including vasopressin, prostaglandin E2 and bradykinin. Furthermore, binding of prorenin and renin to the prorenin receptor in the collecting duct evokes a number of responses, including the non-proteolytic enzymatic activation of prorenin to produce ANGI from proximal tubule-derived angiotensinogen, which is then converted into ANGII by luminal angiotensin-converting enzyme; stimulation of the epithelial sodium channel (ENaC) in principal cells; and activation of intracellular pathways linked to the upregulation of cyclooxygenase 2 and profibrotic genes. These findings suggest that dysregulation of the renin-angiotensin system in the collecting duct contributes to the development of hypertension by enhancing sodium reabsorption and the progression of kidney injury.
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Affiliation(s)
- Minolfa C. Prieto
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, USA.,Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, USA.,
| | - Alexis A. Gonzalez
- Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaiso, Chile
| | - Bruna Visniauskas
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, USA
| | - L. Gabriel Navar
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, USA.,Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, USA
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Ramkumar N, Stuart D, Peterson CS, Hu C, Wheatley W, Cho JM, Symons JD, Kohan DE. Loss of Soluble (Pro)renin Receptor Attenuates Angiotensin-II Induced Hypertension and Renal Injury. Circ Res 2021; 129:50-62. [PMID: 33890822 PMCID: PMC8225587 DOI: 10.1161/circresaha.120.317532] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Nirupama Ramkumar
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
| | - Deborah Stuart
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
| | - Caitlin S. Peterson
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
| | - Chunyan Hu
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
| | - William Wheatley
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
| | - Jae Min Cho
- Nutrition and Integrative Physiology, University of Utah Health,Salt Lake City, UT
| | - J David Symons
- Nutrition and Integrative Physiology, University of Utah Health,Salt Lake City, UT
- Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT
| | - Donald E Kohan
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
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Hsieh YC, Lee KC, Lei HJ, Lan KH, Huo TI, Lin YT, Chan CC, Schnabl B, Huang YH, Hou MC, Lin HC. (Pro)renin Receptor Knockdown Attenuates Liver Fibrosis Through Inactivation of ERK/TGF-β1/SMAD3 Pathway. Cell Mol Gastroenterol Hepatol 2021; 12:813-838. [PMID: 34087453 PMCID: PMC8340309 DOI: 10.1016/j.jcmgh.2021.05.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Activation of the (pro)renin receptor (PRR) up-regulates the expression of profibrotic genes in the kidney and heart. We aimed to investigate the role of PRR in hepatic fibrogenesis. METHODS Human hepatic PRR levels were measured in patients with or without liver fibrosis. PRR expression was analyzed in primary mouse hepatic stellate cells (HSCs). Experimental fibrosis was studied in thioacetamide (TAA)-treated or methionine choline-deficient (MCD) diet-fed C57BL/6 mice. Lentivirus-mediated PRR short hairpin RNA was used to knockdown hepatic PRR expression. Lentiviral vectors expressing PRR short hairpin RNA or complementary DNA from the α-smooth muscle actin promoter were used for myofibroblast-specific gene knockdown or overexpression. RESULTS PRR is up-regulated in human and mouse fibrotic livers, and in activated HSCs. Hepatic PRR knockdown reduced liver fibrosis by suppressing the activation of HSCs and expression of profibrotic genes in TAA or MCD diet-injured mice without significant changes in hepatic inflammation. Renin and prorenin increased the expression of PRR and production of TGF-β1 in human activated HSC Lieming Xu-2 cells, and knockdown of PRR inactivated Lieming Xu-2 cells with decreased production of transforming growth factor (TGF)-β1 and Mothers against decapentaplegic homolog 3 (Smad3) phosphorylation. Myofibroblast-specific PRR knockdown also attenuated liver fibrosis in TAA or MCD diet-injured mice. Mice with both myofibroblast-specific and whole-liver PRR knockdown showed down-regulation of the hepatic extracellular signal-regulated kinase (ERK)/TGF-β1/Smad3 pathway. Myofibroblast-specific PRR overexpression worsened TAA-induced liver fibrosis by up-regulating the ERK/TGF-β1/Smad3 pathway. CONCLUSIONS PRR contributes to liver fibrosis and HSC activation, and its down-regulation attenuates liver fibrosis through inactivation of the ERK/TGF-β1/Smad3 pathway. Therefore, PRR is a promising therapeutic target for liver fibrosis.
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Affiliation(s)
- Yun-Cheng Hsieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Kuei-Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan.
| | - Hao-Jan Lei
- Department of Medicine, Taipei, Taiwan; Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Keng-Hsin Lan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Teh-Ia Huo
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Yi-Tsung Lin
- Department of Medicine, Taipei, Taiwan; Division of Infectious Disease, Department of Medicine, Taipei, Taiwan
| | - Che-Chang Chan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan
| | - Bernd Schnabl
- Department of Medicine, VA San Diego Healthcare System, San Diego, California
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan
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Fujimoto K, Kawamura S, Bando S, Kamata Y, Kodera Y, Shichiri M. Circulating prorenin: its molecular forms and plasma concentrations. Hypertens Res 2021; 44:674-684. [PMID: 33564180 DOI: 10.1038/s41440-020-00610-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 11/15/2020] [Accepted: 11/29/2020] [Indexed: 01/31/2023]
Abstract
The renin-angiotensin-aldosterone system plays pivotal roles in the maintenance of fluid homeostasis and in the pathophysiology of major human diseases. However, the molecular forms of plasma renin/prorenin have not been fully elucidated, and measurements of plasma prorenin levels are still unavailable for clinical practice. We attempted to evaluate the molecular forms of human plasma prorenin and to directly measure its concentration without converting it to renin to determine its activity. Polyacrylamide gel electrophoresis and subsequent immunoblotting using antibodies that specifically recognise prosegment sequences were used to analyse its molecular forms in plasma. We also created a sandwich enzyme-linked immunosorbent assay suitable for directly quantifying the plasma concentration. The plasma level in healthy people was 3.0-13.4 μg/mL, which is from 3 to 4 orders of magnitude higher than the levels reported thus far. Plasma immunoreactive prorenin consists of three major distinct components: a posttranslationally modified full-length protein, an albumin-bound form and a smaller protein truncated at the common C-terminal renin/prorenin portion. In contrast to plasma renin activity, plasma prorenin concentrations were not affected by the postural changes of the donor. Hence, plasma prorenin molecules may be posttranslationally modified/processed or bound to albumin and are present in far higher concentrations than previously thought.
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Affiliation(s)
- Kazumi Fujimoto
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.,Department of Physics and Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Sayuki Kawamura
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Satoru Bando
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yuji Kamata
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yoshio Kodera
- Department of Physics and Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Masayoshi Shichiri
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
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Xiong J, Dong X, Li S, Jiang F, Chen J, Yu S, Dong B, Su Q. Effects of (Pro)renin Receptor on Diabetic Cardiomyopathy Pathological Processes in Rats via the PRR-AMPK-YAP Pathway. Front Physiol 2021; 12:657378. [PMID: 34122131 PMCID: PMC8191636 DOI: 10.3389/fphys.2021.657378] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/08/2021] [Indexed: 01/12/2023] Open
Abstract
Diabetic cardiomyopathy (DCM) is a common complication associated with diabetes. The (pro)renin receptor (PRR) is an important member of the local tissue renin-angiotensin system and plays a vital role in many cardiovascular diseases. Yes-associated protein (YAP) also plays a crucial role in many cardiovascular diseases. However, the mechanism responsible for the effects of PRR and YAP on DCM remains unclear. The purpose of this study was to determine the role of PRR in the pathological progression of DCM and whether PRR influences the pathological processes of diabetic cardiomyopathy through YAP. We first established diabetic cardiomyopathy rats model, downregulated the expression of PRR, and upregulated and downregulated the expression of YAP. The levels of myocardial inflammation and fibrosis were then measured and cardiac function was evaluated. In vitro, primary rat cardiac fibroblasts (CFs) were cultured with high glucose, with or without transfection with recombinant adenovirus expressing PRR, and GSK621 was used to observe the effect of AMPK. The levels of inflammation and fibrosis were measured in vitro. The results showed that PRR and YAP silencing alleviated myocardial inflammation and fibrosis. GSK621 blocked the effect of PRR on AMPK and YAP and improved CF inflammation and fibrosis. The inhibition of PRR expression offers a new therapeutic strategy for the treatment of DCM. The effects of PRR on the pathological process of DCM in rats may be mediated via the PRR-AMPK-YAP pathway.
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Affiliation(s)
- Jie Xiong
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Qilu Hospital of Shandong University, Jinan, China
| | - Xuefei Dong
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Department of Sport, Health and Exercise Science, University of Hull, Hull, United Kingdom
| | - Shengnan Li
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Qilu Hospital of Shandong University, Jinan, China
| | - Fan Jiang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Qilu Hospital of Shandong University, Jinan, China
| | - Jing Chen
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
| | - Shiran Yu
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Qilu Hospital of Shandong University, Jinan, China
| | - Bo Dong
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Qilu Hospital of Shandong University, Jinan, China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Ren Q, Chen J, Liu Y. LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence. Front Cell Dev Biol 2021; 9:670960. [PMID: 34026761 PMCID: PMC8134664 DOI: 10.3389/fcell.2021.670960] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/14/2021] [Indexed: 12/15/2022] Open
Abstract
The canonical Wnt/β-catenin signaling plays a fundamental role in regulating embryonic development, injury repair and the pathogenesis of human diseases. In vertebrates, low density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6), the single-pass transmembrane proteins, act as coreceptors of Wnt ligands and are indispensable for Wnt signal transduction. LRP5 and LRP6 are highly homologous and widely co-expressed in embryonic and adult tissues, and they share similar function in mediating Wnt signaling. However, they also exhibit distinct characteristics by interacting with different protein partners. As such, each of them possesses its own unique functions. In this review, we systematically discuss the similarity and divergence of LRP5 and LRP6 in mediating Wnt and other signaling in the context of kidney diseases. A better understanding of the precise role of LRP5 and LRP6 may afford us to identify and refine therapeutic targets for the treatment of a variety of human diseases.
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Affiliation(s)
- Qian Ren
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiongcheng Chen
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Youhua Liu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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45
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Chen Y, Xu C, Hu J, Deng M, Qiu Q, Mo S, Du Y, Yang T. Diuretic Action of Apelin-13 Mediated by Inhibiting cAMP/PKA/sPRR Pathway. Front Physiol 2021; 12:642274. [PMID: 33868005 PMCID: PMC8044521 DOI: 10.3389/fphys.2021.642274] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/03/2021] [Indexed: 11/13/2022] Open
Abstract
Emerging evidence is showing that apelin plays an important role in regulating salt and water balance by counteracting the antidiuretic action of vasopressin (AVP). However, the underlying mechanism remains unknown. Here, we hypothesized that (pro) renin receptor (PRR)/soluble prorenin receptor (sPRR) might mediate the diuretic action of apelin in the distal nephron. During water deprivation (WD), the urine concentrating capability was impaired by an apelin peptide, apelin-13, accompanied by the suppression of the protein expression of aquaporin 2 (AQP2), NKCC2, PRR/sPRR, renin and nuclear β-catenin levels in the kidney. The upregulated expression of AQP2 or PRR/sPRR both induced by AVP and 8-Br-cAMP was blocked by apelin-13, PKA inhibitor (H89), or β-catenin inhibitor (ICG001). Interestingly, the blockage of apelin-13 on AVP-induced AQP2 protein expression was reversed by exogenous sPRR. Together, the present study has defined the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/sPRR pathway in the CD as the molecular target of the diuretic action of apelin.
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Affiliation(s)
- Yanting Chen
- Zhongshan School of Medicine, Institute of Hypertension, Sun Yat-sen University, Guangzhou, China
| | - Chuanming Xu
- Zhongshan School of Medicine, Institute of Hypertension, Sun Yat-sen University, Guangzhou, China.,Center for Translational Medicine, Jiangxi University of Traditional Chinese, Nanchang, China
| | - Jiajia Hu
- Zhongshan School of Medicine, Institute of Hypertension, Sun Yat-sen University, Guangzhou, China
| | - Mokan Deng
- Zhongshan School of Medicine, Institute of Hypertension, Sun Yat-sen University, Guangzhou, China
| | - Qixiang Qiu
- Zhongshan School of Medicine, Institute of Hypertension, Sun Yat-sen University, Guangzhou, China
| | - Shiqi Mo
- Zhongshan School of Medicine, Institute of Hypertension, Sun Yat-sen University, Guangzhou, China
| | - Yanhua Du
- Department of Pharmacology, Sun Yat-sen University School of Medicine, Guangzhou, China
| | - Tianxin Yang
- Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, United States
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46
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(Pro)renin Receptor Is Present in Human Sperm and It Adversely Affects Sperm Fertility Ability. Int J Mol Sci 2021; 22:ijms22063215. [PMID: 33809946 PMCID: PMC8004193 DOI: 10.3390/ijms22063215] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/14/2021] [Accepted: 03/17/2021] [Indexed: 12/18/2022] Open
Abstract
Sperm fertility ability may be modulated by different molecular systems, such as the renin-angiotensin system (RAS). Although renin is one of its most relevant peptides, the presence and role of the (pro)renin receptor (PRR) is completely unknown. We have proved for the first time the existence of PRR and its transcript in human sperm by western blot and RT-PCR. Immunofluorescence studies showed that this receptor is mainly located in the apical region over the acrosome and in the postacrosomal region of the sperm head and along the sperm tail. In addition, this prospective cohort study also proves that semen samples with higher percentages of PRR-positive spermatozoa are associated with poor sperm motility, worse blastocyst development and no-viable blastocysts. Our results provide insight into how PRR play a negative role in sperm physiology that it may condition human embryo quality and development. An in-depth understanding of the role of PRR in sperm fertility can help elucidate its role in male infertility, as well as establish biomarkers for the diagnosis or selection of sperm to use during assisted reproductive techniques.
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Quadri SS, Cooper C, Ghaffar D, Vaishnav H, Nahar L. The Pathological Role of Pro(Renin) Receptor in Renal Inflammation. J Exp Pharmacol 2021; 13:339-344. [PMID: 33776491 PMCID: PMC7989955 DOI: 10.2147/jep.s297682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 02/23/2021] [Indexed: 12/17/2022] Open
Abstract
(Pro)renin receptor (PRR) is the recently discovered component of the renin-angiotensin-aldosterone system (RAS). Many organs contain their own RAS, wherein PRR can exert organ-specific localized effects. The Binding of prorenin/renin to PRR activates angiotensin-dependent and independent pathways which leads to the development of physiological and pathological effects. Continued progress in PRR research suggests that the upregulation of PRR contributes to the development of hypertension, glomerular injury, and progression of kidney disease and inflammation. In the current review, we highlight the function of the PRR in renal inflammation in pathophysiological conditions.
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Affiliation(s)
- Syed S Quadri
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, TN, USA
| | - Caleb Cooper
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Harrogate, TN, USA
| | - Dawood Ghaffar
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, TN, USA
| | - Hitesh Vaishnav
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, TN, USA
| | - Ludmila Nahar
- Department of Medicine, School of Medicine/John D. Bower School of Population Health, University of Mississippi Medical Center, Jackson, MS, USA
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Cho ME, Sweeney C, Fino N, Greene T, Ramkumar N, Huang Y, Ricardo AC, Shafi T, Deo R, Anderson A, Mills KT, Cheung AK. Longitudinal Changes in Prorenin and Renin in the Chronic Renal Insufficiency Cohort. Am J Nephrol 2021; 52:141-151. [PMID: 33735863 PMCID: PMC8049970 DOI: 10.1159/000514302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/08/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Prorenin, a precursor of renin, and renin play an important role in regulation of the renin-angiotensin system. More recently, receptor-bound prorenin has been shown to activate intracellular signaling pathways that mediate fibrosis, independent of angiotensin II. Prorenin and renin may thus be of physiologic significance in CKD, but their plasma concentrations have not been well characterized in CKD. METHODS We evaluated distribution and longitudinal changes of prorenin and renin concentrations in the plasma samples collected at follow-up years 1, 2, 3, and 5 of the Chronic Renal Insufficiency Cohort (CRIC) study, an ongoing longitudinal observational study of 3,939 adults with CKD. Descriptive statistics and multivariable regression of log-transformed values were used to describe cross-sectional and longitudinal variation and associations with participant characteristics. RESULTS A total of 3,361 CRIC participants had plasma available for analysis at year 1. The mean age (±standard deviation, SD) was 59 ± 11 years, and the mean estimated glomerular filtration rate (eGFR, ± SD) was 43 ± 17 mL/min per 1.73 m2. Median (interquartile range) values of plasma prorenin and renin at study entry were 4.4 (2.1, 8.8) ng/mL and 2.0 (0.8, 5.9) ng/dL, respectively. Prorenin and renin were positively correlated (Spearman correlation 0.51, p < 0.001) with each other. Women and non-Hispanic blacks had lower prorenin and renin values at year 1. Diabetes, lower eGFR, and use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, and diuretics were associated with higher levels. Prorenin and renin decreased by a mean of 2 and 5% per year, respectively. Non-Hispanic black race and eGFR <30 mL/min/1.73 m2 at year 1 predicted a steeper decrease in prorenin and renin over time. In addition, each increase in urinary sodium excretion by 2 SDs at year 1 increased prorenin and renin levels by 4 and 5% per year, respectively. DISCUSSION/CONCLUSIONS The cross-sectional clinical factors associated with prorenin and renin values were similar. Overall, both plasma prorenin and renin concentrations decreased over the years, particularly in those with severe CKD at study entry.
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Affiliation(s)
- Monique E. Cho
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT
| | - Carol Sweeney
- Division of Epidemiology, University of Utah, Salt Lake City, UT
| | - Nora Fino
- Division of Epidemiology, University of Utah, Salt Lake City, UT
| | - Tom Greene
- Division of Epidemiology, University of Utah, Salt Lake City, UT
| | - Nirupama Ramkumar
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT
| | - Yufeng Huang
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT
| | - Ana C. Ricardo
- Department of Medicine, University of Illinois, Chicago, IL
| | - Tariq Shafi
- Division of Nephrology, University of Mississippi, Jackson, MS
| | - Rajat Deo
- Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, PA
| | - Amanda Anderson
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA
| | - Katherine T. Mills
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA
| | - Alfred K. Cheung
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT
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Renin-angiotensin system in mammalian kidney development. Pediatr Nephrol 2021; 36:479-489. [PMID: 32072306 DOI: 10.1007/s00467-020-04496-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/30/2020] [Accepted: 01/31/2020] [Indexed: 12/20/2022]
Abstract
Mutations in the genes of the renin-angiotensin system result in congenital anomalies of the kidney and urinary tract (CAKUT), the main cause of end-stage renal disease in children. The molecular mechanisms that cause CAKUT are unclear in most cases. To improve the care of children with CAKUT, it is critical to determine the underlying mechanisms of CAKUT. In this review, we discuss recent advances that have helped to better understand how disruption of the renin-angiotensin system during kidney development contributes to CAKUT.
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Ziaja M, Urbanek KA, Kowalska K, Piastowska-Ciesielska AW. Angiotensin II and Angiotensin Receptors 1 and 2-Multifunctional System in Cells Biology, What Do We Know? Cells 2021; 10:cells10020381. [PMID: 33673178 PMCID: PMC7917773 DOI: 10.3390/cells10020381] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 12/13/2022] Open
Abstract
For years, the renin-angiotensin system (RAS) has been perceived as a system whose role is to primarily modulate the functioning of the cardiovascular system. Years of research into the role of RAS have provided the necessary data to confirm that the role of RAS is very complex and not limited to the cardiovascular system. The presence of individual elements of the renin-angiotensin (RA) system allows to control many processes, ranging from the memorization to pro-cancer processes. Maintaining the proportions between the individual axes of the RA system allows for achieving a balance, often called homeostasis. Thus, any disturbance in the expression or activity of individual RAS elements leads to pathophysiological processes.
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