Increased plasma soluble (pro)renin receptor levels are correlated with renal dysfunction in patients with heart failure

Fukushima, Arata; Kinugawa, Shintaro; Homma, Tsuneaki; Masaki, Yoshihiro; Furihata, Takaaki; Abe, Takahiro; Suga, Tadashi; Takada, Shingo; Kadoguchi, Tomoyasu; Okita, Koichi; Matsushima, Shouji; Tsutsui, Hiroyuki

doi:10.1016/j.ijcard.2013.04.176

Cited by 47 publications

(44 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased plasma soluble PRR levels are correlated with renal dysfunction in patients with heart failure and predict gestational diabetes mellitus during the first trimester PRR. 25,26 In contrast to the work by Burckle et al, 18 plasma aldosterone levels were not increased in our transgenic mice. The strength of the present study is that we examined two strains of mice with different genetic backgrounds, analyses of the results in both genders and in three genotypes (hemi-, hetero-and homozygous).…”

Section: Discussioncontrasting

confidence: 99%

Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice

Rosendahl

Niemann

Lange

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is still unclear. To determine whether increased expression of PRR is sufficient to induce cardiac or renal injury, we generated a mouse that constitutively overexpresses PRR by knocking-in the Atp6ap2/PRR gene in the hprt locus under the control of a CMV immediate early enhancer/chicken betaactin promoter. Mice were backcrossed in the C57Bl/6 and FVB/N strain and studied at the age of 12 months. In spite of a 25-to 80-fold renal and up to 400-fold cardiac increase in Atp6ap2/PRR expression, we found no differences in systolic blood pressure or albuminuria between wild-type and PRR overexpressing littermates. Histological examination did not show any renal or cardiac fibrosis in mutant mice. This was supported by real-time PCR analysis of inflammatory markers as well as of pro-fibrotic genes in the kidney and collagen in cardiac tissue. To determine whether the concomitant increase of renin would trigger fibrosis, we treated PRR overexpressing mice with the angiotensin receptor-1 blocker losartan over a period of 6 weeks. Renin expression increased eightfold in the kidney but no renal injury could be detected. In conclusion, our results suggest no major role for PRR in organ damage per se or related to its function as a receptor of renin.

show abstract

Section: Discussioncontrasting

confidence: 99%

Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice

Rosendahl

Niemann

Lange

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

Section: Plasma Concentrations Of S(p)rr In Various Pathological Cmentioning

confidence: 99%

“…Increased plasma s(P)RR concentrations were also correlated with renal dysfunction in patients with heart failure [25]. Hamada et al [24] and Fukushima et al [25] speculated that s(P)RR might be involved in the development and progression of renal injury. Moreover, high serum s(P)RR levels were associated with low ankle-brachial index (an indicator of severe atherosclerosis) in maintenance hemodialysis patients, suggesting that serum s(P)RR reflected atherosclerotic conditions [26].…”

Section: Plasma Concentrations Of S(p)rr In Various Pathological Cmentioning

confidence: 99%

Soluble (Pro)renin Receptor and Obstructive Sleep Apnea Syndrome: Oxidative Stress in Brain?

Takahashi

Ohba

Tajima

et al. 2017

IJMS

View full text Add to dashboard Cite

(Pro)renin receptor ((P)RR) is a multi-functional molecule that is related to both the renin-angiotensin system (RAS) and vacuolar H+-ATPase (v-ATPase), an ATP-dependent multi-subunit proton pump. Soluble (P)RR (s(P)RR), which consists of the extracellular domain of (P)RR, is present in blood and urine. Elevated plasma s(P)RR concentrations are reported in patients with chronic kidney disease and pregnant women with hypertension or diabetes mellitus. In addition, we have shown that plasma s(P)RR concentrations are elevated in patients with obstructive sleep apnea syndrome (OSAS). Interestingly, the levels are elevated in parallel with the severity of OSAS, but are not related to the presence of hypertension or the status of the circulating RAS in OSAS. It is known that v-ATPase activity protects cells from endogenous oxidative stress, and loss of v-ATPase activity results in chronic oxidative stress. We hypothesize that hypoxia and subsequent oxidative stress, perhaps in the brain, may be one of the factors that elevate plasma s(P)RR levels in OSAS.

show abstract

“…An sPRR ELISA kit has been developed to detect sPRR in plasma and urine samples (7) . With this assay, increased serum sPRR levels have been demonstrated in patients with heart failure (8), kidney disease (9,10), hypertension (11), and preeclampsia (2). Moreover, serum sPRR is positively associated with serum creatinine, blood urea nitrogen, and urine protein and is inversely associated with the estimated glomerular filtration rate in patients with chronic kidney disease caused by hypertension and type 2 diabetes (9).…”

mentioning

confidence: 99%

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

135

View full text Add to dashboard Cite

The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent β-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.soluble (pro)renin receptor | liver X receptor | aquaporin-2 | frizzled-8 | β-catenin F ull-length (Pro)renin receptor (PRR), a 350-amino acid transmembrane receptor for prorenin and renin, is subjected to protease-mediated cleavage to produce a 28-kDa protein of the N-terminal extracellular domain, the soluble (pro)renin receptor (sPRR), and the 8.9-kDa C-terminal intracellular domain called "M8.9" (1, 2). Before the cloning of full-length PRR in mesangial cells as an integral 39-kDa membrane protein (3), M8.9 was identified as a truncated protein associated with the vacuolar H + -ATPase (V-ATPase) from bovine chromatin granules (4). The cleavage occurs in Golgi apparatus through furin (5) or ADMA19 (6). An sPRR ELISA kit has been developed to detect sPRR in plasma and urine samples (7) . With this assay, increased serum sPRR levels have been demonstrated in patients with heart failure (8), kidney disease (9, 10), hypertension (11), and preeclampsia (2). Moreover, serum sPRR is positively associated with serum creatinine, blood urea nitrogen, and urine protein and is inversely associated with the estimated glomerular filtration rate in patients with chronic kidney disease caused by hypertension...

show abstract

Increased plasma soluble (pro)renin receptor levels are correlated with renal dysfunction in patients with heart failure

Cited by 47 publications

References 11 publications

Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice

Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice

Soluble (Pro)renin Receptor and Obstructive Sleep Apnea Syndrome: Oxidative Stress in Brain?

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

Contact Info

Product

Resources

About