Lactacystin-induced kidney fibrosis: Protection by melatonin and captopril.

Lactacystin is a specific proteasome inhibitor that blocks the hydrolysis of intracellular proteins by ubiquitin/proteasome system inhibition. The administration of lactacystin to rats induced hypertension and remodeling of the left ventricle and aorta. This study tested whether lactacystin induces structural and fibrotic rebuilding of the kidneys and whether melatonin and captopril can prevent these potential changes. Six weeks of lactacystin administration to rats increased their average systolic blood pressure (SBP). In the kidneys, lactacystin reduced glomerular density, increased the glomerular tuft area, and enhanced hydroxyproline concentrations. It also elevated the intraglomerular proportion including the amounts of collagen (Col) I and Col III. Lactacystin also raised the tubulointerstitial amounts of Col I and the sum of Col I and Col III with no effect on vascular/perivascular collagen. Six weeks of captopril treatment reduced SBP, while melatonin had no effect. Both melatonin and captopril increased glomerular density, reduced the glomerular tuft area, and lowered the hydroxyproline concentration in the kidneys. Both drugs reduced the proportion and total amounts of intraglomerular and tubulointerstitial Col I and Col III. We conclude that chronic lactacystin treatment stimulated structural and fibrotic remodeling of the kidneys, and melatonin and captopril partly prevented these alterations. Considering the effect of lactacystin on both the heart and kidneys, chronic treatment with this drug may be a prospective model of cardiorenal damage suitable for testing pharmacological drugs as protective agents.

Renin-Angiotensin-Aldosterone System: Friend or Foe-The Matter of Balance. Insight on History, Therapeutic Implications and COVID-19 Interactions.

The renin-angiotensin-aldosterone system (RAAS) ranks among the most challenging puzzles in cardiovascular medicine [...].

Renin-Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is characterized by massive inflammation, increased vascular permeability and pulmonary edema. Mortality due to ARDS remains very high and even in the case of survival, acute lung injury can lead to pulmonary fibrosis. The renin-angiotensin system (RAS) plays a significant role in these processes. The activities of RAS molecules are subject to dynamic changes in response to an injury. Initially, increased levels of angiotensin (Ang) II and des-Arg9-bradykinin (DABK), are necessary for an effective defense. Later, augmented angiotensin converting enzyme (ACE) 2 activity supposedly helps to attenuate inflammation. Appropriate ACE2 activity might be decisive in preventing immune-induced damage and ensuring tissue repair. ACE2 has been identified as a common target for different pathogens. Some Coronaviruses, including SARS-CoV-2, also use ACE2 to infiltrate the cells. A number of questions remain unresolved. The importance of ACE2 shedding, associated with the release of soluble ACE2 and ADAM17-mediated activation of tumor necrosis factor-α (TNF-α)-signaling is unclear. The roles of other non-classical RAS-associated molecules, e.g., alamandine, Ang A or Ang 1-9, also deserve attention. In addition, the impact of established RAS-inhibiting drugs on the pulmonary RAS is to be elucidated. The unfavorable prognosis of ARDS and the lack of effective treatment urge the search for novel therapeutic strategies. In the context of the ongoing SARS-CoV-2 pandemic and considering the involvement of humoral disbalance in the pathogenesis of ARDS, targeting the renin-angiotensin system and reducing the pathogen's cell entry could be a promising therapeutic strategy in the struggle against COVID-19.

Renin-angiotensin system and SARS-CoV-2 interaction: underlying mechanisms and potential clinical implications.

Renin-angiotensin system (RAS) inhibition supposedly increases the expression of angiotensin converting enzyme 2, serving as a binding site for SARS-CoV-2. Concerns arose regarding therapy with RAS inhibition during the COVID-19 pandemic. However, the pharmacological restraining the classical RAS axis might be beneficial due to the reduction of deleterious effects of angiotensin II and enhancement of the anti-inflammatory angiotensin 1-7 pathway. Unless large controlled studies are performed, RAS inhibition remains the cornerstone therapy in populations with cardiovascular disorders.

Angiotensin A/Alamandine/MrgD Axis: Another Clue to Understanding Cardiovascular Pathophysiology.

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of cardioprotective strategies. However, many biological effects of these drugs cannot be explained by the known mode of action. Our comprehension of the RAS is thus far from complete. The RAS represents an ingenious system of "checks and balances". It incorporates vasoconstrictive, pro-proliferative, and pro-inflammatory compounds on one hand and molecules with opposing action on the other hand. The list of these molecules is still not definitive because new biological properties can be achieved by minor alteration of the molecular structure. The angiotensin A/alamandine-MrgD cascade associates the deleterious and protective branches of the RAS. Its identification provided a novel clue to the understanding of the RAS. Angiotensin A (Ang A) is positioned at the "crossroad" in this system since it either elicits direct vasoconstrictive and pro-proliferative actions or it is further metabolized to alamandine, triggering opposing effects. Alamandine, the central molecule of this cascade, can be generated both from the "deleterious" Ang A as well as from the "protective" angiotensin 1-7. This pathway modulates peripheral and central blood pressure regulation and cardiovascular remodeling. Further research will elucidate its interactions in cardiovascular pathophysiology and its possible therapeutic implications.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP): Potential target molecule in research of heart, kidney and brain.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous molecule generated in all mammalian tissues from the N-terminal sequence of thymosin ß4 (Tß4) by the action of propyl oligopeptidase. Ac-SDKP is an alternative substrate for angiotensin converting enzyme (ACE). There are several indications that Ac-SDKP may be protective in the cardiovascular system. First, the level of Ac- SDKP in plasma and tissues is reduced in some cardiovascular pathologies such as hypertension. Second, an administration of Ac-SDKP to rodents attenuates inflammation, cell differentiation, proliferation, and migration resulting in a reduction of fibrosis in the heart, vessels and kidneys in conditions of their disorders. Third, the treatment with ACE-inhibitors is associated with a reduced degradation and hence increased levels of Ac-SDKP, while a simultaneous treatment with monoclonal antibodies against Ac- SDKP partly counteracts the benefit of ACE-inhibition. Since Ac-SDKP fails to reduce blood pressure and left ventricular hypertrophy (LVH), its potential structural benefit is obviously mediated by direct action on tissue in preventing or reversing excessive fibrosis. The protection by ACE-inhibition seems to be partly mediated by increased availability of Ac-SDKP. Thus, it is to suppose that harvesting the knowledge on the role of Ac-SDKP in cardiovascular physiology and pathology could deepen our insight into the mechanisms of action of the renin-angiotensin system (RAS) as well as agents interfering with this system. The exciting protective potential of Ac-SDKP suggests that this compound could be a focused drug target not only in animal experiments but also in the clinical cardio-pharmacologic research in the near future.

Melatonin and renal protection: novel perspectives from animal experiments and human studies (review).

Chronic kidney disease (CKD) is a serious public health problem. Current therapies are designed to slow down progression of the disease and avoid the necessity of dialysis or kidney transplantation. CKD is characterized by chronic inflammation and progressive cell death resulting in fibrotic rebuilding of renal tissue. Melatonin, the primary product of the pineal gland, has been shown to have pluripotent protective effects in many organs and tissues. It exerts anti-hypertensive, anti-inflammatory, anti-apoptotic, and antiremodelling actions. A principal mechanism of these numerous melatonin benefits resides in its extraordinary high efficacy as an antioxidant and scavenger protecting cells both extracellularly and in all subcellular structures. In addition to these receptor-independent actions, the effects of melatonin via specific MT-receptors may be beneficial. In several animal models of CKD, involving experimental hypertension, diabetes mellitus and various models of nephrotoxicity, melatonin reduced the oxidative burden, attenuated the chronic inflammation and limited apoptosis. These effects were associated with the reduction of proteinuria, damage of parenchymal cells and fibrosis. In humans, melatonin's chronobiological action attenuates sleep disturbances in hemodialyzed patients suffering from a relative melatonin deficiency. Moreover, melatonin reduces the oxidative burden and improves iron metabolism in hemodialyzed patients. In conclusion, the pleiotropic physiological actions of melatonin induce beneficial effects at numerous pathophysiological levels related to CKD both under experimental and clinical conditions. It is hoped that this review will prompt a large clinical trial to determine the efficacy of this nontoxic indoleamine as a potential treatment for this debilitating disease.

Melatonin reduces cardiac remodeling and improves survival in rats with isoproterenol-induced heart failure.

Melatonin was previously shown to reduce blood pressure and left ventricular (LV) remodeling in several models of experimental heart damage. This study investigated whether melatonin prevents LV remodeling and improves survival in isoproterenol-induced heart failure. In the first experiment, four groups of 3-month-old male Wistar rats (12 per group) were treated for 2 wk as follows: controls, rats treated with melatonin (10 mg/kg/day) (M), rats treated with isoproterenol (5 mg/kg/day intraperitoneally the second week) (Iso), and rats treated with melatonin (2 wk) and isoproterenol (the second week) in corresponding doses (IsoM). In the second experiment, 30 rats were treated with isoproterenol and 30 rats with isoproterenol plus melatonin for a period of 28 days and their mortality was investigated. Isoproterenol-induced heart failure with hypertrophy of the left and right ventricles (LV, RV), lowered systolic blood pressure (SBP) and elevated pulmonary congestion. Fibrotic rebuilding was accompanied by alterations of tubulin level in the LV and oxidative stress development. Melatonin failed to reduce the weight of the LV or RV; however, it curtailed the weight of the lungs and attenuated the decline in SBP. Moreover, melatonin decreased the level of oxidative stress and of insoluble and total collagen and partly prevented the beta-tubulin alteration in the LV. Most importantly, melatonin reduced mortality and prolonged the average survival time. In conclusion, melatonin exerts cardioprotective effects and improves outcome in a model of isoproterenol-induced heart damage. The antiremodeling effect of melatonin may be of potential benefit in patients with heart failure.