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The Intrarenal Renin-angiotensin System Is Activated Immediately after Kidney Donation in Kidney Transplant Donors.

ABSTRACT: Objective The intrarenal renin-angiotensin system (RAS) is activated in clinical settings, such as chronic kidney disease (CKD), as well as in CKD animal models, and kidney transplant donors have a greater risk of end-stage renal disease than healthy controls. However, whether or not the intrarenal RAS is activated immediately after kidney donation in kidney transplant donors is unclear, and the mechanism underlying intrarenal RAS activation is unknown. Methods We investigated 10 kidney transplant donors (4 men and 6 women, 58.6±9.0 years of age). Their blood pressure (BP), estimated glomerular filtration rate (eGFR), plasma angiotensinogen (AGT) and plasma angiotensin II (AngII) levels (which reflect circulating RAS activation), urinary albumin excretion, and urinary AGT excretion (which reflects intrarenal RAS activation) were evaluated before kidney donation (-1.2±0.40 days) and after kidney donation (7.5±1.7 days). Results The renal function after kidney donation was significantly lower than before donation. There were no significant differences in the BP during 24-h ambulatory BP monitoring, plasma AngII levels, or urinary albumin excretion after kidney donation. In contrast, the levels of plasma AGT and urinary AGT excretion were significantly increased after kidney donation. The urinary AGT excretion after kidney donation did not show a significant relationship with the systolic BP, plasma AGT, plasma AngII, or urinary albumin excretion. In addition, the percentage change in urinary AGT excretion after kidney donation was not associated with the percentage change in other clinical parameters. Conclusion The intrarenal RAS is activated in kidney transplant donors immediately after kidney donation, independent of the systemic BP and filtration of increased plasma AGT, due to augmented inflammation.

SUBMITTER: Ohashi N

PROVIDER: S-EPMC6443563 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The Intrarenal Renin-angiotensin System Is Activated Immediately after Kidney Donation in Kidney Transplant Donors.

Ohashi Naro N Isobe Shinsuke S Matsuyama Takashi T Ishigaki Sayaka S Suzuki Takahisa T Tsuji Takayuki T Otsuka Atsushi A Kato Akihiko A Miyake Hideaki H Yasuda Hideo H

Internal medicine (Tokyo, Japan) 20181017 5

Objective The intrarenal renin-angiotensin system (RAS) is activated in clinical settings, such as chronic kidney disease (CKD), as well as in CKD animal models, and kidney transplant donors have a greater risk of end-stage renal disease than healthy controls. However, whether or not the intrarenal RAS is activated immediately after kidney donation in kidney transplant donors is unclear, and the mechanism underlying intrarenal RAS activation is unknown. Methods We investigated 10 kidney transpla ...[more]

PMID: 30333423

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Project description:Environmental stress during early life is an important factor that affects the postnatal renal development. We have previously shown that male rats exposed to maternal separation (MatSep), a model of early life stress, are normotensive but display a sex-specific reduced renal function and exacerbated angiotensin II (AngII)-mediated vascular responses as adults. Since optimal AngII levels during postnatal life are required for normal maturation of the kidney, this study was designed to investigate both short- and long-term effect of MatSep on (1) the renal vascular architecture and function, (2) the intrarenal renin-angiotensin system (RAS) components status, and (3) the genome-wide expression of genes in isolated renal vasculature. Renal tissue and plasma were collected from male rats at different postnatal days (P) for intrarenal RAS components mRNA and protein expression measurements at P2, 6, 10, 14, 21, and 90 and microCT analysis at P21 and 90. Although with similar body weight and renal mass trajectories from P2 to P90, MatSep rats displayed decreased renal filtration capacity at P90, while increased microvascular density at both P21 and P90 (p < 0.05). MatSep increased renal expression of renin, and angiotensin type 1 (AT1) and type 2 (AT2) receptors (p < 0.05), but reduced ACE2 mRNA expression and activity from P2-14 compared to controls. However, intrarenal levels of AngII peptide were reduced (p < 0.05) possible due to the increased degradation to AngIII by aminopeptidase A. In isolated renal vasculature from neonates, Enriched Biological Pathways functional clusters (EBPfc) from genes changed by MatSep reported to modulate extracellular structure organization, inflammation, and pro-angiogenic transcription factors. Our data suggest that male neonates exposed to MatSep could display permanent changes in the renal microvascular architecture in response to intrarenal RAS imbalance in the context of the atypical upregulation of angiogenic factors.

Project description:Emerging evidence has demonstrated that (pro)renin receptor (PRR)-mediated activation of intrarenal renin-angiotensin system (RAS) plays an essential role in renal handling of Na+ and water balance and blood pressure. The present study tested the possibility that the intrarenal RAS served as a molecular target for the protective action of ELABELA (ELA), a novel endogenous ligand of apelin receptor, in the distal nephron. By RNAscope and immunofluorescence, mRNA and protein expression of endogenous ELA was consistently localized to the collecting duct (CD). Apelin was also found in the medullary CDs as assessed by immunofluorescence. In cultured CD-derived M1 cells, exogenous ELA induced parallel decreases of full-length PRR (fPRR), soluble PRR (sPRR), and prorenin/renin protein expression as assessed by immunoblotting and medium sPRR and prorenin/renin levels by ELISA, all of which were reversed by 8-bromoadenosine 3',5'-cyclic monophosphate. Conversely, deletion of PRR in the CD or nephron in mice elevated Apela and Apln mRNA levels as well as urinary ELA and apelin excretion, supporting the antagonistic relationship between the two systems. Administration of exogenous ELA-32 infusion (1.5 mg·kg-1·day-1, minipump) to high salt (HS)-loaded Dahl salt-sensitive (SS) rats significantly lowered mean arterial pressure, systolic blood pressure, diastolic blood pressure, and albuminuria, accompanied with a reduction of urinary sPRR, angiotensin II, and prorenin/renin excretion. HS upregulated renal medullary protein expression of fPRR, sPRR, prorenin, and renin in Dahl SS rats, all of which were significantly blunted by exogenous ELA-32 infusion. Additionally, HS-induced upregulation of inflammatory cytokines (IL-1β, IL-2, IL-6, IL-17A, IFN-γ, VCAM-1, ICAM-1, and MCP-1), fibrosis markers (TGF-β1, FN, Col1A1, PAI-1, and TIMP-1), and kidney injury markers (NGAL, Kim-1, albuminuria, and urinary NGAL excretion) were markedly blocked by exogenous ELA infusion. Together, these results support the antagonistic interaction between ELA and intrarenal RAS in the distal nephron that appears to exert a major impact on blood pressure regulation.

Dataset Information

The Intrarenal Renin-angiotensin System Is Activated Immediately after Kidney Donation in Kidney Transplant Donors.

Publications

The Intrarenal Renin-angiotensin System Is Activated Immediately after Kidney Donation in Kidney Transplant Donors.

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