Functions of the (pro)renin receptor (Atp6ap2) at molecular and system levels: pathological implications in hypertension, renal and brain development, inflammation, and fibrosis

Hoffmann, Nadin; Peters, Jörg

doi:10.1016/j.phrs.2021.105922

Cited by 21 publications

(20 citation statements)

References 162 publications

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“…However, Rosendahl et al reported that constitutively overexpressed murine (P)RR in mice did not cause hypertension or cardiac and renal fibrosis [ 15 ], which was contradictive to previous researches. Although it remained inconclusive about the cause of difference of these consequences, one may argue that the overexpression of a protein foreign to the species investigated (human Atp6ap2 in rats) may easily result in artefacts than the overexpression of an endogenous protein [ 16 ]. To investigate the role of tubular (P)RR in blood pressure regulation, Ramkumar et al generated an inducible renal tubule (P)RR KO mouse to avoid the lethal effects of (P)RR deletion on organ development [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products

Saigo

Kino

Uchida

et al. 2021

IJMS

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The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

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Section: Introductionmentioning

confidence: 99%

Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products

Saigo

Kino

Uchida

et al. 2021

IJMS

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“…A heatmap analysis revealed the expression of ATP6AP2 , PCRP , KLK2 and PREP in our PAN-treated, but not in the untreated kidney organoids. Upon pathological conditions such as renal dysfunction, previous studies observed the activation of pro-inflammatory and pro-fibrotic molecules by ATP6AP2 [ 54 ]. Similarly, KLK2 plays a major role in inflammatory kidney diseases, where it is involved in various physiological processes [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

The Nephrotoxin Puromycin Aminonucleoside Induces Injury in Kidney Organoids Differentiated from Induced Pluripotent Stem Cells

Nguyen

Wruck

Erichsen

et al. 2022

Cells

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Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), which can progress to end stage renal disease (ESRD), are a worldwide health burden. Organ transplantation or kidney dialysis are the only effective available therapeutic tools. Therefore, in vitro models of kidney diseases and the development of prospective therapeutic options are urgently needed. Within the kidney, the glomeruli are involved in blood filtration and waste excretion and are easily affected by changing cellular conditions. Puromycin aminonucleoside (PAN) is a nephrotoxin, which can be employed to induce acute glomerular damage and to model glomerular disease. For this reason, we generated kidney organoids from three iPSC lines and treated these with PAN in order to induce kidney injury. Morphological observations revealed the disruption of glomerular and tubular structures within the kidney organoids upon PAN treatment, which were confirmed by transcriptome analyses. Subsequent analyses revealed an upregulation of immune response as well as inflammatory and cell-death-related processes. We conclude that the treatment of iPSC-derived kidney organoids with PAN induces kidney injury mediated by an intertwined network of inflammation, cytoskeletal re-arrangement, DNA damage, apoptosis and cell death. Furthermore, urine-stem-cell-derived kidney organoids can be used to model kidney-associated diseases and drug discovery.

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“…It has been shown that 90% of brain angiotensinogen is mainly produced by astrocytes and little from neurons and glial cells 41 . In addition, components of RAS as well as pro‐renin are also expressed in the basal ganglion, mainly in the nigrostriatal pathway 42 . AT1, AT2, and pro‐renin receptors are highly expressed in glial cells, suggesting the role of RAS in inflammatory and oxidative stress in the brain 43 .…”

Section: Brain Rasmentioning

confidence: 99%

Role of brain renin–angiotensin system in depression: A new perspective

Ali,

Al‐Kuraishy,

Al‐Gareeb

et al. 2023

CNS Neurosci Ther

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Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin–angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS‐induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain‐derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non‐classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation.

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Functions of the (pro)renin receptor (Atp6ap2) at molecular and system levels: pathological implications in hypertension, renal and brain development, inflammation, and fibrosis

Cited by 21 publications

References 162 publications

Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products

Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products

The Nephrotoxin Puromycin Aminonucleoside Induces Injury in Kidney Organoids Differentiated from Induced Pluripotent Stem Cells

Role of brain renin–angiotensin system in depression: A new perspective

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