Effects Of Vasoactive Substances On Renal Ischemia-reperfusion Injury

Ischemia-reperfusion injury (IRI) refers to that after the ischemic tissue or organ regains blood perfusion or oxygen supply, it not only fails to restore the function of the tissue and organ but also leads to an aggravation of tissue and organ dysfunction and structural damage. Renal ischemia-reperfusion injury (RIRI) caused by hypovolemia, septic shock, renal transplantation, and cardiovascular surgery can easily lead to acute kidney injury (AKI). The molecular mechanisms involved in renal damage during renal ischemia-reperfusion include hypoxia-induced depletion of adenosine triphosphate (ATP), production of reactive oxygen species, activation of phospholipase, neutrophil infiltration, and release of vasoactive substances. Vasoactive substances such as endothelin-1 (ET-1), nitric oxide (NO), and renin-angiotensin system (RAS) participate in the occurrence and development of RIRI through paracrine or autocrine forms. A brief description of the mechanism of action.

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Endothelin 1 (ET-1)

ET-1 is the most potent endogenous vasoconstrictor known so far21, which can act on ETA and ETB receptors on target cell membranes to exert biological effects. Experiments found that ET-1 combined with ETA receptors can exert a strong vasoconstriction effect; while binding with ETB receptors promotes the release of endothelial-derived vasodilatory substances (such as NO, prostacyclin, etc.), which play a role in dilating blood vessels, and finally, The effect depends on the location and proportion of the distribution of the two types of receptors [3].

Both ETA and ETB receptors were expressed on renal human glomerulus and efferent arteriole smooth muscle cells. In renal blood vessels, ETA receptors are only expressed on vascular smooth muscle cells of interlobar and arcuate arteries, perivascular cells of descending straight vessels, and mesangial cells, while ETB receptors are only expressed on peritubular and renal vasculature. Glomerular capillaries and vascular endothelial cells. ETA receptors are also expressed on epithelial cells of distal tubules and cortical collecting ducts, while ETB receptors are only expressed on proximal convoluted tubule cells and inner medullary collecting duct epithelial cells [4].

Under normal circumstances, endothelial cells produce less ET-1, while NO has greater bioavailability. Both act on vascular smooth muscle cells to keep blood vessels in a normal state. Once this dynamic balance is disrupted, ET-1 is produced in large quantities. , NO production is reduced, resulting in endothelial dysfunction. After ischemia-reperfusion, the levels of ET-1 in the renal cortex and medulla were significantly increased, and the increase in the medulla was more pronounced and lasted longer. Experiments have found that ETA and ETB receptors are jointly involved in ET-1-mediated constriction of human glomerular arterioles, resulting in increased renal vascular resistance and decreased glomerular blood flow 51.

In addition, the binding of ET-1 to ETA receptors causes mesangial cells to shrink, the glomerular filtration area and ultrafiltration coefficient to decrease, and the renal blood flow and glomerular filtration rate (GFR) to decrease, thereby causing The renal blood flow decreases again, further aggravating the renal injury. The massive production and continuous action of ET-1 can cause dysfunction of vascular endothelial cells and cause renal microcirculation disorders [5].

In addition to vasoconstriction, ET-1 can also stimulate the expression of adhesion molecules in renal tubular endothelial cells, promote the release of cytokines and reactive oxygen species from monocytes and neutrophils, promote the occurrence of inflammatory responses, and make damaged extracellular matrix products Synthesis is reduced, and cell fibrosis is promoted due to the reduced expression of a large number of enzymes such as extracellular matrix metalloenzymes [7]. Animal studies of ET-1-mediated renal injury have found that dual ET receptor antagonists are better than single selective ETA or ETB receptor antagonists [3].

Nitric Oxide (NO)

NO is an important messenger molecule catalyzed and synthesized by nitric oxide synthase (NOS) with L-arginine and molecular oxygen as substrates and plays an important role in regulating renal hemodynamics and renal tubular function. NOS can be divided into neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS) [9].

The roles of eNOS and iNOS are more important in RIRI, among which eNOS is a short-term regulator, which synthesizes NO in the early stage of injury, plays the role of dilating blood vessels, inhibiting cell apoptosis and resisting oxidative stress, and protecting the injured kidney tissue [10] ]; iNOS is lasting regulation, with the prolonged injury time, a large amount of NO is produced, which feedback inhibits the activity of eNOS, leading to endothelial dysfunction and antagonizing the self-regulation ability of the kidney at the same time [1].

A large number of experiments have shown that inhibition of eNOS activity is one of the characteristics of impaired vascular endothelial function [1]. Increasing eNOS activity by ischemic preconditioning can reduce ischemia-reperfusion renal injury [[3]]. The study also found that the expression of eNOS was down-regulated during ischemia and hypoxia in endothelial cells, which was related to the increase of Rho kinase activity and the inhibition of eNOS phosphorylation [1]. Activated to increase NO release and prevent the reduction of renal blood flow during reperfusion. In addition, whether iNOS selective inhibitor [L-N6-(1-iminoethyl) lysine, L-Nil] or gene knockout method is used to remove iNOS to interfere with the RIRI model, both have renoprotective effects, which may be related to iNOS producing excessive NO, the effect on renal tubular epithelial cell damage was inhibited.

Experimental studies have found an association between ET-1 and NO in RIRI. Kurata et al. injected different doses of FK409 (exogenous NO donor, which releases NO when decomposed) and L-NAME (non-selective NOS inhibitor, can reduce endogenous NO production) at different doses 5 minutes before ischemia to interfere with renal ischemia. In the blood reperfusion model, it was found that the content of ET-1 in renal tissue decreased significantly after administration of FK409; on the contrary, when L-NAME was administered, the content of ET-1 in renal tissue continued to increase, indicating that an appropriate increase in NO during RIRI can inhibit the production of ET-1 in renal tissue. overproduced. Nakajima et al. [7] injected FK 409 5 min before ischemia and 6 h after reperfusion, respectively. The pre-ischemia injection had a good protective effect on RIRI and its possible mechanism was described above; in contrast, FK 409 was injected 6 h after reperfusion. , not only did not increase the content of ET-1 in renal tissue but aggravated renal tissue damage. The mechanism was not related to the increase of ET-1 during reperfusion but was related to the excessive production of NO. Mahmoud et al[[[] further proposed that using L-arginine to increase the NO synthesis substrate during RIRI can increase the NO content, and the combined use has the functions of dilating blood vessels, inhibiting platelet synthesis of TXA: and inhibiting neutrophil activation and other biological functions. Active prostaglandin 1 can achieve better renal protection.

Renin-angiotensin system (RAS)

Experiments have found that local RAS in the kidney also plays an important role in RIRI. It has always been recognized that the axis involved in RIRI is an angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-AT1 receptor. Regulation pathway: Ang II is degraded by ACE2 to generate Ang (1-7), which then binds to G protein-coupled receptors (Mas receptors) to play a role, namely ACE2-Ang (1-7)-Mas receptors. The study found that the level of Ang II in the kidney increased after renal ischemia-reperfusion, and was accompanied by the down-regulation of cortical angiotensinogen and ATI receptor mRNA expression in the proximal convoluted tubule.

Recently, da Silvein et al. [9] compared these two routes in the RAS in a rat renal ischemia-reperfusion model and found that Ang II levels increased while Ang (1-7) decreased after 4 h of reperfusion. Perfusion significantly decreased both renin mRNA and ATI receptor expression in kidneys, as well as ACE and ACE2 activity, while significantly increasing Mas receptor expression. It can be seen that ACE2-Ang(1-7)-Mas receptor plays an important role in antagonizing another route.

By binding to the AT1 receptor, Ang II exerts the effects of vasoconstriction, water and sodium retention, inflammatory response, and renal tubular epithelial cell proliferation [20, 21].

However, experiments have shown that Ang (1-7) can antagonize the vasoconstriction and cell proliferation effects of Ang II by binding to Mas receptors. Among them, Ang (1-7) antagonizes the vasoconstriction effect of Ang II by increasing NO, prostacyclin (vasodilator), and bradykinin which has an antihypertensive effect. In addition, the binding of Ang (1-7) to Mas receptors on proximal convoluted renal tubular epithelial cells can inhibit Ang II-induced phosphorylation of mitogen-activated protein kinase, which is mainly involved in cell growth, differentiation, and proliferation23. Studies have found that Mas receptor gene knockout can lead to glomerular ultrafiltration, structural changes, and renal fibrosis24]. Velkoska et al [2] confirmed that the application of ACE inhibitors in partial nephrectomy can restore ACE2 activity, thereby improving renal damage through its route of action.

To sum up, many factors and etiologies are involved in the occurrence and development of RIRI, and the factors are interconnected and influence each other. The exact mechanism of RIRI has not been fully elucidated, and various vasoactive substances play an important role. With the continuous deepening of basic and clinical research, the intervention of vasoactive substances is expected to improve the prognosis of RIRI, increase the success rate of kidney transplantation, and prolong the survival time of transplanted kidneys.

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