Oxi-Inflamm-Aging Related Cardiorenal Syndrome: Comparison
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Please note this is a comparison between Version 3 by Catherine Yang and Version 2 by Matilde Alique.

Kidney failure is also a major cause of cardiovascular morbidity and mortality. Indeed, epidemiological studies have demonstrated that chronic kidney disease (CKD) is a significant risk for cardiovascular events independently of classical risk. 

  • aging
  • oxidative stress
  • extracellular vesicles
  • cardiorenal syndrome
  • inflammation
  • senescence

1. Age-Related Changes in Renal and Cardiovascular System

Even in the absence of other risk factors, the aging population presented structural and functional alterations in the kidneys, vessels, and heart. (Figure 1).
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Figure 1. Role of aging in the cardiorenal syndrome. Some graphical elements from this figure were obtained from BioRender (http://biorender.com, accessed on 1 December 2021) and the Servier Medical ART (SMART) Powerpoint image bank (http://smart.servier.com, accessed on 1 December 2021).
Age is associated with a decrease in renal function [41][1], including glomerular filtration rate (GFR) decline and impaired urine concentrating capacity [42][2]. Even without any injury, GFR declined approximately 8 mL/min/1.73 m2 per decade after 40 years of age [43][3], but it has been suggested that GFR decline may start even earlier in the patient’s 20s [44][4]. Structurally, the aging kidney presented glomerulosclerosis, tubulointerstitial fibrosis, and tubular atrophy [45][5]. Besides, heart failure is classically related to the elderly [46][6]. An aging heart's most common pathophysiological characteristics are increased left ventricular (LV) hypertrophy and fibrosis [47][7]. Elderly patients presented diastolic dysfunction, increased atrial fibrillation, and a reduction in cardiac reserve [48][8]. Regarding vascular aging, it is characterized by endothelial dysfunction, mainly due to decreased nitric oxide (NO) availability [49][9], large arteries walls thickening, and progressive stiffness of central arteries, particularly the aorta [48[8][10],50], resulting in atherosclerosis Figure 1.
Several mechanisms may participate in aging-induced cardiovascular and renal structural and functional impairments, including cell senescence, inflammation, oxidative stress, and genetic and epigenetic modifications.

2. Cellular Senescence in Cardiovascular and Renal Aging

Cellular senescence is a process characterized by a stable cell–cycle arrest [51][11] that causes inflammation and the capacity to modify the microenvironment through the SASP. The accumulation of senescent cells in the kidney, heart and vascular vessels has been associated with structural and functional changes related to aging [52][12]. Furthermore, acquiring a senescent phenotype by aging or age-related chronic disease, including CKD and CKD-associated CVD, seems to be an irreversible pathophysiological process [22,53][13][14].
In large vessels, aging-associated endothelial cell senescence is a key cause of vascular structural changes and vascular dysfunction observed in atherosclerosis [45][5]. Additionally, human atherosclerotic plaque vulnerability is promoted by senescence vascular smooth muscle cells (VSMCs) [54][15]. Further osteoblastic-like phenotypes acquired by senescent VSMC seem to be responsible for vascular calcification [55][16]. In the kidney, the source of senescent cells depends on the pathology, and proximal tubular cells are the main source of senescent cells in the aged kidneys.

3. Inflammation in Cardiovascular and Renal Aging

Inflammaging describes the pro-inflammatory state observed in the older organism, even in the absence of other risk factors or diseases [13][17]. Several epidemiological studies have pointed to inflammaging as a risk factor of most age-related diseases, including CVD and CKD [56,57][18][19]. Chronic inflammation is a key factor in several CVD pathologies [58][20] and a pivotal contributor to CKD development and its progression to end-stage renal disease (ESRD) [59][21]. Moreover, proinflammatory cytokines and chemokines released by kidneys can reach the circulation, resulting in dysfunction of distant organs, including the cardiovascular system [60][22], a fact that may explain, at least in part, the accelerated cardiovascular aging observed in CKD patients [37][23].
Among the inflammatory mediators elevated in blood during aging, IL-6 and TNF-α are particularly noteworthy [61][24]. An elevation of both IL-6 and TNF-α and other molecules such as C-reactive proteins have been associated with high mortality in the elderly [62][25]. Even in centenarians, elevated levels of TNF-α correlated with morbidity, including CVD and mortality [63][26]. On the other hand, both molecules are also key factors in the onset and development of renal and CVDs [64,65,66,67][27][28][29][30]. Indeed, both molecules are considered uremic toxins and are therefore molecular markers and/or therapeutic targets for the cardiorenal syndrome.
Elevated IL-6 and TNF-α levels have been observed in CKD patients, and these levels are inversely correlated with GFR [68][31]. Moreover, high IL-6 levels and TNF-α have been associated with the development of atherosclerosis and vascular calcification in CKD patients [69,70,71][32][33][34]. Likewise, IL-6 has been proposed as a risk factor for left ventricular hypertrophy in peritoneal dialysis patients [72][35].
The human GG polymorphism at the −174 position in the promoter region of the IL-6 gene, which is associated with increased levels of IL-6, has been related to an increased risk of developing age-associated CVD [73,74][36][37] and with increased mortality in peritoneal dialysis patients [75][38]. On the other hand, this polymorphism is less frequent in centenarians than in young adults [76][39], whereas other IL-6 SNPs have been associated with longevity [77,78][40][41]. Moreover, in aged patients, including centenarians, high levels of TNF-α in the blood were associated with a high prevalence of atherosclerosis [63,79][26][42].

4. Oxidative Stress in Cardiovascular and Renal Aging

As previously indicated, the oxidative stress theory of aging states that age-associated loss of functionality would be due to the accumulation of oxidative damage to lipids, DNA, and proteins by ROS and RNS [5][43]. However, recent studies have demonstrated a more complex relation between oxidant and antioxidant mechanisms in aging and age-related diseases [80][44].
Oxidative stress is a key component of several age-related pathologies, including CVDs and acute CKD. The role of different pro-oxidant molecules and the therapeutic effects of several antioxidants have been widely studied in experimental models and clinical trials [81,82,83,84,85,86,87,88][45][46][47][48][49][50][51][52].
CKD and ESRD patients show increased levels of different oxidative stress markers, including advanced oxidation protein products, malondialdehyde, and oxidized low-density lipoproteins (ox-LDL), which have been associated with a decline in renal function. Furthermore, an increase in ox-LDL, together with high IL-6 levels, has been associated with an increased risk of CVD events and CVD-related mortality in CKD patients in hemodialysis (HD) [89][53] and accelerated atherosclerosis development observed in CKD [82][46]. Besides its role in foam cells formation within the arterial wall, ox-LDLs also participate in other proatherogenic events, including endothelial dysfunction and smooth muscle proliferation, suggesting an essential role of ox-LDLs in atherosclerotic plaque development and destabilization [90,91][54][55].
Furthermore, increased levels of ox-LDL in older adults have also been associated with arterial stiffening [92][56]. However, another study in aged patients reported no correlation between ox-LDL levels and cardiovascular morbidity nor mortality, suggesting that in elderly patients, the ox-LDL may not be a good marker [93][57]. What seems clear is that ox-LDL levels are related to endothelial dysfunction observed in adults and elderly individuals [49][9].
Oxidative stress induces endothelial dysfunction by decreasing NO bioavailability [94][58], mainly by the formation of peroxynitrite (ONOO−), through its combination with superoxide anion (O2•−), which is elevated in atherosclerotic lesions [95][59]. Moreover, ONOO− leads to endothelial nitric oxide synthase (eNOS) uncoupling activity, thus perpetuating the detrimental response. In addition to its role in endothelial function, NO has other effects, including antithrombotic, anti-inflammatory, and anti-atherogenic effects [49][9]. Therefore, in vascular endothelium, ox-LDL and NO exert antagonistic actions in all phases of atherogenesis. Indeed, some authors have proposed using ox-LDL to NO ratio (ox-LDL/NO) as a new biomarker for endothelial dysfunction in atherosclerosis [49][9]. Curiously, whereas NO produced by eNOS seems to have atheroprotective effects, excessive NO produced by inducible nitric oxide synthase (iNOS), under proinflammatory conditions, had a detrimental impact on the endothelium [95][59]. Conversely, elderly humans presented elevated NO production within the vasculature but a reduced NO bioavailability. In the kidney, aging-associated NO reduction increases renal vascular vasoconstriction, Na+ retention, and renal fibrosis, thus contributing to enhanced hypertension and declined renal function [45][5].
Finally, given the close relationship between oxidative stress, inflammation, and aging, the free radical theory of aging has been updated, giving rise to the oxidation-inflammatory theory of aging or oxi-inflamm-aging [96][60]. This new theory postulates that aging is a loss of body homeostasis due to sustained oxidative stress that activates different systems, including the immune system, thus inducing an inflammatory response that increases oxidative stress and perpetuates positive feedback of oxidative stress and inflammation.

5. Extracellular Vesicles in Cardiovascular and Renal Aging

In human renal and cardiovascular pathologies, EVs' changes in composition and levels have been described [97][61]. In addition, different studies showed the effect of drug treatment on EVs’ profile in other diseases [98][62]. Altogether these results point to a potential role of EVs as biomarkers for diagnosis and as tools for therapy by drug administration of different cargo.
In CKD, circulating EVs are augmented and are key players in vascular calcification [99][63], endothelial dysfunction [100][64], and vascular mortality [101][65]. In hemodialyzed patients with CKD, plasma circulating EVs were increased compared with elderly subjects without CKD used as controls [102][66]. In this study, the level of EVs released by proinflammatory monocytes was high, and no differences in total monocyte-derived EVs were found as other authors had previously described [103,104,105][67][68][69]. The uremic toxin proinflammatory environment in these CKD patients induces proinflammatory monocytes activation, alters miR-126-3p, miR-233-3p, miR-192-5p expression, and increases the release of proinflammatory EVs that enhance vascular inflammation. As miR-126-3p participates in endothelial proliferation and endothelization in large vessels [106,107[70][71][72],108], the decreased miR-126-3p circulating levels reported in these hemodialyzed patients indicate its implication in the vascular dysfunction observed [102][66].
In addition, the decrease in miRNA-233-3p expression and circulating levels observed in CKD patients was reversed and even increased after kidney transplantation [109,110][73][74], indicating its participation in vascular complications development. The lower expression of miR-192-5p was also found in hemodialyzed patients [102][66], venous thromboembolism [111][75], and hypertension [112][76]. As the expression of several miRNAs can be positively or negatively correlated with different diseases and inflammatory states, authors consider those miRNA ratios to be a clinical feature of every disease and a diagnostic and therapeutic biomarker.
The mentioned studies suggest that serum levels and the profile of miRNAs and EVs depend on CKD’s uremic inflammatory state and promote cardiovascular damage [102][66].
The progressive decrease in renal function is a risk factor in most CVDs and worsens the clinical outcomes [113,114][77][78].
For example, non-valvular atrial fibrillation is linked to kidney disease because of increased thromboembolism mediated by higher EV levels from the prothrombotic endothelial-platelet origin but not by other markers of thrombotic state and cellular activation [115][79] even in anticoagulated patients.
In hypertensive patients, the presence of EVs indicating podocyte injury, a characteristic expression of miRNAs, and peritubular capillaries damage has been described [116][80]. Furthermore, EVs released by endothelial cells from perivascular capillaries had been detected in the urine of essential and renovascular hypertensive patients, the concentration of which directly correlates with clinical parameters and capillary rarefaction but inversely with renal perfusion [117][81]. Therefore, the levels of urinary EVs in hypertension could be an early marker of renal injury due to peritubular capillaries damage, and the said levels inversely correlate with renal function (estimated glomerular filtration, eGFR) after medical treatment in essential and renovascular hypertensive patients [117][81].
Intensive treatment of T2DM patients suffering an acute coronary attack showed decreased endothelial CD31+/CD41+ EVs levels [118][82]. Administration of pioglitazone to patients with metabolic syndrome reduced endothelial EV levels [119][83]. In patients with T2DM and hypertension, endothelial EV levels correlate directly with the mean systolic and pulse blood pressure but inversely with eGFR compared with normotensive diabetic patients [120][84]. CD31+/CD42− [121,122][85][86] and CD31+/CD42−/CD51+ [123][87] endothelial-derived EVs are increased in hypertensive patients with T2DM correlating these levels with mean arterial pressure and mean systolic blood pressure.
Endothelial-derived EVs can be considered an endothelial damage marker from the studies explained above. In addition, along with EVs secreted from other sources such as platelets and leukocytes, endothelial-derived EVs play an active role in the pathogenesis of hypertension. Furthermore, increased levels of EVs relate to a minor ability of vessels to regenerate, increasing cardiovascular risk and nephropathy [124][88]. All these studies point to the importance of assessing plasma EV levels to establish the risk of organ damage in diabetes.
In a different approach, EVs would have beneficial effects as carriers of signals to preserve, for example, endothelial function and vessel integrity in vascular diseases [125,126][89][90]. Indeed, EVs have therapeutic potential as vehicles for transferring and secreting different molecules (cytokines, chemokines, growth factors, nucleic acids, etc.) to other targets in disease [127][91]. Furthermore, EVs from mesenchymal stem cells can preserve myocardial function after ischemia/reperfusion in animal models and humans [128,129,130][92][93][94]. Moreover, EVs derived from bone marrow CD34+, or endothelial progenitor cells, increase cardiac viability by decreasing oxidative stress and activating PI3K/Akt pathway, and promoting angiogenesis [131,132,133][95][96][97]. In addition, EVs derived from cardiac progenitor cells protect the myocardium from ischemia/reperfusion injury [134][98].
EVs have advantages in regenerative medicine and therapy because they maintain their properties during long storage periods. Thus, the limitations of using viable cells that can undergo aberrant differentiation are avoided.
EVs could be helpful to vectors in gene therapy by transporting and delivering nucleic acids. For instance, PI3K/Akt pathway mRNAs carried by endothelial progenitor cells-derived EVs promote angiogenesis response in endothelial cells after EVs and endothelial cell fusion [135][99]. Circulating EVs also carry miRNAs known for their implication in the pathophysiology of cardiovascular and other diseases by modulating target cell gene expression [136][100], and specific miRNAs are expressed and packed in circulating EVs in these diseases [137][101]. This compartmentalization is stimulus-dependent. This is similar to hypoxia which determines the regenerative properties of mesenchymal stem cells-derived EVs and the expression of pro-angiogenic miRNAs in endothelial progenitor cells-derived EVs [128,138,139][92][102][103]. In addition, it has been demonstrated that miR-126 is carried by circulating EVs for regulating angiogenesis and vascular integrity [108,140,141][72][104][105]. miR-126 transported into recipient human coronary artery endothelial cells by endothelial EVs released by apoptotic endothelial cells promoted reendothelialization. Still, hyperglycemia lowered the amounts of miR-126 transported and reduced endothelial repair capacity in vivo [141][105]. Interestingly, patients with coronary artery disease have low levels or lack miR-126 compared with healthy subjects [138,139][102][103], indicating the importance of EVs cargo in developing and treating the disease.

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