Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system (RAS) plays an important role in the regulation of inflammation and in the progression of chronic kidney disease. Accumulation of inflammatory cells into the renal parenchyma has been a hallmark of chronic kidney disease; however, little is known concerning the presence and the function of RAS elements in T and natural killer (NK) cells. Here is reported a co-stimulatory effect of angiotensin II (AngII) by showing an augmentation of mitogen and anti-CD3-stimulated T and NK cell proliferation with AngII treatment. Angiotensinogen and AngI also generated the same effect, suggesting that NK and T cells have functional renin and angiotensin-converting enzyme activity. Indeed, they express renin, the renin receptor, angiotensinogen, and angiotensin-converting enzyme by mRNA analysis. Flow cytometric analysis and Western blot revealed angiotensin receptor 2 (AT(2)) expression in T and NK cells, whereas AT(1) expression was found in T and NK cells and monocytes by Western blot. These receptors were shown to be functional in calcium signaling, chemotaxis, and proliferation. However, AT(1) and AT(2) antagonists alone or in combination were unable to abrogate completely the effects of AngII, suggesting that another AngII receptor may also be functional in leukocytes. This is the first study to show that T and NK cells are fully equipped with RAS elements and are potentially capable of producing and delivering AngII to sites of inflammation. Because their chemotaxis is enhanced by AngII, this creates a potential inflammatory amplification system.
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PMID:Human T and natural killer cells possess a functional renin-angiotensin system: further mechanisms of angiotensin II-induced inflammation. 1732 76

Recent evidence indicates that renin itself might be profibrotic, independent of angiotensin II; however, the signaling system by which renin exerts a direct effect is not known. We tested the hypothesis that renin receptor activation, in turn, activates the extracellular-signal regulated kinase 1 and 2 (ERK1/2) of the mitogen-activated protein kinase system in mesangial cells. Recombinant rat renin induced a rapid phosphorylation of ERK1/2 and subsequent cell proliferation in a dose- and time-dependent manner. ERK1/2 activation by renin addition was not altered by angiotensin-converting enzyme inhibition or angiotensin receptor blockade. An ERK kinase inhibitor significantly reduced the renin-induced ERK1/2 phosphorylation and the subsequent increase in transforming growth factor-beta1 (TGF-beta1) and plasminogen activator inhibitor-1 mRNA expression. A small-inhibiting RNA, siRNA, against the renin receptor completely blocked ERK1/2 activation by rat renin. We conclude that renin induces ERK1/2 activation though a receptor-mediated, angiotensin II-independent mechanism in mesangial cells. This renin-activated pathway triggers cell proliferation along with TGF-beta1 and plasminogen activator inhibitor-1 gene expression. This system may play an important role in the overall profibrotic actions of renin.
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PMID:Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. 1739 11

The previous dogma that the renin-angiotensin system exerts its effects entirely through angiotensin II is now under challenge as scientists explore the properties of the prorenin/renin receptor and start to study local vascular actions of renin independent of its production of angiotensin in the plasma. The demonstrated blood pressure effects of the first clinically developed renin inhibitor, aliskiren, have confirmed the validity of this new class of drugs. Future research, exploring effects on the renin-angiotensin system that perhaps cannot be provided by the currently used blockers of this system, will test whether enhanced clinical benefits might result from this new pharmacologic strategy in patients at risk of cardiovascular events.
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PMID:Expanding the opportunities for blocking the renin-angiotensin system: introduction to a special supplement. 1740 11

Activation of the renin-angiotensin system (RAS) and generation of angiotensin II (Ang II) play a crucial role in fibrotic renal disease beyond this system's hemodynamic actions. Ang II blockade was a great therapeutic breakthrough for renal and cardiovascular diseases; however, this slows, but does not stop, disease progression. These limitations leave other molecules unopposed to sustain disease progression. One is renin, which is markedly elevated by Ang II blockade. Recently, a new renin receptor was cloned in renal mesangial cells. This receptor acts as a renin/prorenin cofactor on the cell surface, enhancing efficiency of angiotensinogen cleavage by renin and unmasking prorenin catalytic activity. Unexpectedly, the receptor induces angiotensin-independent cellular effects in renal mesangial cells, suggesting that renin has novel receptor-mediated actions that could play a role in renal fibrosis. Proof of this could lead to a pharmacological compound blocking renin/prorenin binding and activity as an alternative or adjunct to classical inhibitors of the RAS.
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PMID:Functional renin receptors in renal mesangial cells. 1744 25

Activation of prorenin by (pro)renin receptor stimulates the tissue renin-angiotensin system and plays a significant role in the development of nephropathy in diabetic animals. This study examined whether (pro)renin receptor blockade inhibits the progression of nephropathy that has already developed in diabetic rats. Seventeen-week-old heminephrectomized streptozotocin-induced diabetic rats with an increased urinary protein excretion and a significant glomerulosclerosis had been treated for 12 wk with the (pro)renin receptor blocker (PRRB), angiotensin-converting enzyme inhibitor (ACEi), or vehicle peptide by using subcutaneously implanted osmotic minipumps. At the end of observation, in diabetic rats that were treated with vehicle, urinary protein excretion was progressively increased and a significant progression of glomerulosclerosis was observed. In diabetic rats that were treated with PRRB, however, no further increase in urinary protein excretion or glomerulosclerosis was observed, but 12-wk treatment with ACEi only attenuated further increases in urinary protein excretion and glomerulosclerosis. The enhanced expression of activated prorenin was observed in the kidneys of diabetic rats that were treated with vehicle, whereas it was markedly suppressed in the kidneys of diabetic rats that were treated with PRRB but not ACEi. These results suggest that (pro)renin receptor blockade does not only inhibit the progression of nephropathy but also reverses the glomerulosclerosis that has already developed in diabetic rats.
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PMID:Regression of nephropathy developed in diabetes by (Pro)renin receptor blockade. 1759 35

Recently, a (pro)renin receptor has been identified which mediates profibrotic effects independent of angiotensin II. Because antihypertensive therapy induces renal injury in the clipped kidney of two kidney-1-clip hypertensive rats, we examined the regulation of renin and the (pro)renin receptor in this model. Hypertensive Goldblatt rats were treated with increasing doses of the vasopeptidase inhibitor AVE 7688 after which the plasma renin and prorenin as well as the renal renin and (pro)renin receptor expression were measured. The vasopeptidase inhibitor dose-dependently lowered blood pressure, which was associated with a massive increase in plasma prorenin and renin as well as increased renal renin expression. The (pro)renin receptor was upregulated in the clipped kidney of the Goldblatt rat indicating a parallel upregulation of renin and its receptor in vivo. Immunohistochemistry showed a redistribution of renin upstream from the glomerulus in preglomerular vessels and renin staining in tubular cells. Expression of the (pro)renin receptor was increased in the vessels and tubules. This upregulation was associated with thickening of renin-positive vessels and tubulointerstitial damage. We propose that renin and the (pro)renin receptor may play a profibrotic role in the clipped kidney of Goldblatt rats treated for hypertension.
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PMID:Antihypertensive therapy upregulates renin and (pro)renin receptor in the clipped kidney of Goldblatt hypertensive rats. 1759 96

The first renin inhibitor, aliskiren, will soon enter the clinical arena. This review summarizes the potential differences between renin inhibitors and the currently existing blockers of the renin-angiotensin system (RAS) [ie, the ACE inhibitors and the angiotensin II type 1 (AT(1)) receptor antagonists], taking also into consideration the recently discovered (pro)renin receptor. This receptor not only activates the inactive precursor of renin, prorenin, but it also exerts direct renin/prorenin-induced effects, independently of angiotensin. The review ends with a brief overview of the available (pre)clinical aliskiren data and a description of its safety profile.
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PMID:Novel drugs targeting hypertension: renin inhibitors. 1770 26

The circulating RA (renin-angiotensin) system is essential for the regulation of blood pressure and electrolyte balance. Recently, plasma prorenin has been reported to significantly increase its level in diabetes and to be possibly non-proteolytically activated by binding to the PRR [(pro)renin receptor] on the cell membrane reported in several tissues during circulation. Although many pathological aspects have been researched, there is a lack of sufficient information on the biochemical structure and biological function of this hPRR (human PRR) because of the difficulty in increasing hPRR expression. In the present study, GFP(uv)-hPRR (hPRR fused with green fluorescence protein when excited with long-wave UV light) was successfully expressed by using BmMNPV (Bombyx mori multiple nucleopolyhedrovirus) bacmid DNA in silkworm (Bombyx mori) larvae. Some of the hPRR was expressed in the haemolymph of silkworm larvae and some of the hPRR was located in the fat body of silkworm larvae. The binding ability of hPRR expressed in the haemolymph and fat body with renin or prorenin was analysed by ELISA and surface plasmon resonance using a biosensor respectively. These binding assays suggest that the expressed hPRR has a functional bioactivity. hPRR preparation in silkworm larvae would, therefore, be useful for biochemical and biomedical researches related to PRR.
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PMID:Expression of functional human (pro)renin receptor in silkworm (Bombyx mori) larvae using BmMNPV bacmid. 1770 88

Renin inhibitors are now available in therapeutic doses and it is accepted that they decrease blood pressure as efficiently as the classic inhibitors of the renin-angiotensin system (RAS): angiotensin converting enzyme inhibitors and angiotensin II-receptor blockers (ARBs). One major issue will be to know how, beyond the normalization of blood pressure, renin inhibitors (RIs) will compare with angiotensin converting enzyme inhibitors and ARBs for their ability to protect the organs against the tissue damage associated with overactivation of the RAS. The mechanism(s) of tissue protection may involve the inhibition of a direct cellular effect of renin and prorenin mediated by the (pro)renin receptor ([P]RR). This review updates the recent findings on (P)RR; its role in hypertension, cardiac fibrosis, diabetic nephropathy, and retinopathy; and the effects of a putative (P)RR antagonist.
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PMID:The (pro)renin receptor: a new kid in town. 1786 88

Prorenin binding to the (pro)renin receptor not only causes a nonproteolytic activation of prorenin leading to the activation of the renin-angiotensin system (RAS), but also stimulates the receptor's own intracellular signaling pathways independent of the RAS. Within the kidneys, the (pro)renin receptor is present in the glomerular mesangium and podocytes, which play an important role in the maintenance of the glomerular filtration barrier. Therefore, prorenin-receptor blockers, which competitively bind to the receptor as a decoy peptide, have superior benefits with regard to proteinuria and glomerulosclerosis in experimental animal models with elevated plasma prorenin levels such as diabetes and hypertension compared with conventional RAS inhibitors, possibly by inhibiting both the nonproteolytic activation of prorenin and RAS-independent intracellular signals.
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PMID:The (pro)renin receptor and the kidney. 1786 89


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