| Nephron segments and their main physiological function. The nephron is the functional unit of the kidney and is composed by the renal corpuscle and the renal tubule. In the renal corpuscle, the glomerular filtrate is generated by filtration of water, ions, and small molecules from the bloodstream. The glomerular filtrate is transformed into urine by reabsorption and secretion of different molecules through the different sections of the renal tubule (proximal convoluted tubule, loop of Henle, and distal convoluted tubule) and the collecting duct system. Kidney and nephron image adapted from Smart Servier Medical Art under Creative Commons Attribution 3.0 Unported License. 

| Nephron segments and their main physiological function. The nephron is the functional unit of the kidney and is composed by the renal corpuscle and the renal tubule. In the renal corpuscle, the glomerular filtrate is generated by filtration of water, ions, and small molecules from the bloodstream. The glomerular filtrate is transformed into urine by reabsorption and secretion of different molecules through the different sections of the renal tubule (proximal convoluted tubule, loop of Henle, and distal convoluted tubule) and the collecting duct system. Kidney and nephron image adapted from Smart Servier Medical Art under Creative Commons Attribution 3.0 Unported License. 

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Kidney disease is worldwide the 12th leading cause of death affecting 8–16% of the entire population. Kidney disease encompasses acute (short-lasting episode) and chronic (developing over years) pathologies both leading to renal failure. Since specific treatments for acute or chronic kidney disease are limited, more than 2 million people a year req...

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... regulate body fluid balance, blood pressure, waste removal, and red blood cells production (Preuss, 1993;Adamson, 1996). Kidney functions take place through mechanisms of filtration, reabsorption and secretion occurring in the nephrons, the basic structural and functional units of the kidney (Figure 1). Nephron components filter the blood free of cells and large proteins, producing an ultrafiltrate composed of the other smaller circulating elements. ...

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... Lysosomes are responsible for catabolism and recycling of multiple macromolecules and are key degradative compartments in the cell. There are two major proteins that mediate lysosomal activity; lysosomal membrane proteins and lysosomal hydrolases including the cathepsins (2). Their activity is facilitated by the acidic lysosomal environment. ...
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... Among these enzymes, cathepsins constitute a significant class of lysosomal proteases, which consist of aspartic, cysteine, and serine cathepsins 32 . Cathepsins are known to regulate an exquisite range of biological functions, and the dysregulation of cathepsin activity contributes to the development of inflammatory and metabolic diseases in humans 32,33 . Therefore, we sought to examine the effect of pharmacological inhibition of lysosomal cathepsins on the mannose-mediated upregulation of tight junction proteins. ...
... However, the exact mechanisms governing the functional crosstalk between mitochondria and lysosomes remain to be elucidated. Several lysosomal proteases, such as cathepsins, are released into the cytosol of target cells as a result of lysosomal disruption 32,33 . Among all cathepsins, cathepsin B is one of the most abundant cysteine proteases in lysosomes and has been associated with mitochondrial damage 54 . ...
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... In the cytosol, cathepsins regulate apoptosis by both activating apoptotic proteases and degrading antiapoptotic proteins [2,8,46,47], and mediate inflammatory responses by activating inflammasome [32][33][34][35]. Loss of function or inactivation of cathepsins in the cytosol have been associated with pathological conditions such as neurodegenerative diseases, atherosclerosis [48,49], type 2 diabetes [50,51] kidney diseases [52,53], and ischemia [54][55][56]. In the nucleus, cathepsins are involved in processing transcription factors that regulate the cell cycle, cell proliferation, and differentiation, and therefore, dysregulation of nuclear cathepsins may contribute to the transformed phenotype of cancer cells [57]. ...
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Cathepsins encompass a family of lysosomal proteases that mediate protein degradation and turnover. Although mainly localized in the endolysosomal compartment, cathepsins are also found in the cytoplasm, nucleus, and extracellular space, where they are involved in cell signaling, extracellular matrix assembly/disassembly, and protein processing and trafficking through the plasma and nuclear membrane and between intracellular organelles. Ubiquitously expressed in the body, cathepsins play regulatory roles in a wide range of physiological processes including coagulation, hormone secretion, immune responses, and others. A dysregulation of cathepsin expression and/or activity has been associated with many human diseases, including cancer, diabetes, obesity, cardiovascular and inflammatory diseases, kidney dysfunctions, and neurodegenerative disorders, as well as infectious diseases. In viral infections, cathepsins may promote (1) activation of the viral attachment glycoproteins and entry of the virus into target cells; (2) antigen processing and presentation, enabling the virus to replicate in infected cells; (3) up-regulation and processing of heparanase that facilitates the release of viral progeny and the spread of infection; and (4) activation of cell death that may either favor viral clearance or assist viral propagation. In this review, we report the most relevant findings on the molecular mechanisms underlying cathepsin involvement in viral infection physiopathology, and we discuss the potential of cathepsin inhibitors for therapeutical applications in viral infectious diseases.
... Different proteases, such as calpain, cathepsin, and matrix metalloproteinases, are reportedly dysregulated in CKD [19][20][21]. The gelatinases, MMP2 and MMP9, mediate fibrosis in CKD, such as in diabetes mellitus [21]. ...
... The kidney is the organ with the highest lysosome content; the integration of lysosome membrane protein and soluble lysosome hydrolase mediates lysosome activity. New evidence shows that lysosome protease cathepsin (CTSS) plays an essential role in the pathogenesis and progress of kidney diseases [19,41]. The main physiological function of CTSS is beyond lysosomes, and it participates in the degradation of extracellular matrix proteins [19]. ...
... New evidence shows that lysosome protease cathepsin (CTSS) plays an essential role in the pathogenesis and progress of kidney diseases [19,41]. The main physiological function of CTSS is beyond lysosomes, and it participates in the degradation of extracellular matrix proteins [19]. ...
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... Increased or decreased a2-M has no apparent adverse effects on the physiological functions, [42] but a2-M can inactivate various proteinases and bind many cytokines or growth factors, such as platelet-derived growth factor, insulin, and transforming growth factor-b. Cathepsin D is an aspartic endoprotease ubiquitously distributed in lysosomes [43,44] that can regulate extracellular matrix homeostasis, glomerular permeability, endothelial function, and inflammation in kidney diseases [45]. CD324 (AKA Ecadherin) is a cellecell adhesion protein increased during microalbuminuria progression after diabetes [46]. ...
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... This sarcopenia-related protein degradation may be explained by several systems, such as the ubiquitin-proteasome system, where multiple ubiquitin molecules attach to specific proteins marking them for rapid degradation following enzymatic activation, with these polyubiquitinated proteins being subsequently degraded by the proteasome [71]. Another mechanism of sarcopenia-related protein degradation is lysosomal proteolysis, which despite the low presence of lysosomes in adult skeletal muscle, these organelles have been observed to be stimulated in a variety of pathological conditions, specifically through the action of the protease cathepsin known to regulate extracellular matrix homeostasis, autophagy, apoptosis, glomerular permeability, and inflammation in CKD [72]. More recently, the role of autophagosomes in muscle pathology, doublemembrane vesicles formed from intracellular lysosomal degradation, has also been described [73]. ...
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Chronic kidney disease (CKD) is a prevalent worldwide public burden that increasingly compromises overall health as the disease progresses. Two of the most negatively affected tissues are bone and skeletal muscle, with CKD negatively impacting their structure, function and activity, impairing the quality of life of these patients and contributing to morbidity and mortality. Whereas skeletal health in this population has conventionally been associated with bone and mineral disorders, sarcopenia has been observed to impact skeletal muscle health in CKD. Indeed, bone and muscle tissues are linked anatomically and physiologically, and together regulate functional and metabolic mechanisms. With the initial crosstalk between the skeleton and muscle proposed to explain bone formation through muscle contraction, it is now understood that this communication occurs through the interaction of myokines and osteokines, with the skeletal muscle secretome playing a pivotal role in the regulation of bone activity. Regular exercise has been reported to be beneficial to overall health. Also, the positive regulatory effect that exercise has been proposed to have on bone and muscle anatomical, functional, and metabolic activity has led to the proposal of regular physical exercise as a therapeutic strategy for muscle and bone-related disorders. The detection of bone- and muscle-derived cytokine secretion following physical exercise has strengthened the idea of a cross communication between these organs. Hence, this review presents an overview of the impact of CKD in bone and skeletal muscle, and narrates how these tissues intrinsically communicate with each other, with focus on the potential effect of exercise in the modulation of this intercommunication.
... The cathepsin family of lysosomal proteases is a super-family of proteolytic enzymes with 15 members to date. Cathepsins are usually classified into cysteine (B, C, F, H, K, L, O, S, V, Z/X and W), serine (A and G) and aspartic (D and E) proteases, depending on the catalytic site residue and can be further subdivided in endo-peptidases (S, K, V, F, L) and both endo and exo-peptidases (B, C, H, Z/X), based on their proteolytic activity [173,174]. ...
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