Cathepsin S As an Inhibitor of Cardiovascular Inflammation and Calcification in Chronic Kidney Disease

Abstract

Cardiovascular disease (CVD) is responsible for the majority of deaths in the developed world. Particularly, in patients with chronic kidney disease (CKD), the imbalance of calcium and phosphate may lead to the acceleration of both vascular and valve inflammation and calcification. One in two patients with CKD are reported as dying from cardiovascular causes due to the resulting acceleration in the development of atherosclerosis plaques. In addition, CKD patients on hemodialysis are prone to aortic valve calcification and often need valve replacement before kidney transplantation. The lysosomal proteases, cathepsins, are composed of 11 cysteine members (cathepsin B, C, F, H, K, L, O, S, V, W, and Z), as well as serine proteases cathepsin A and G, which cleave peptide bonds with serine as the amino acid, and aspartyl proteases D and E, which use an activated water molecule bound to aspartate to break peptide substrate. Cysteine proteases, also known as thiol proteases, degrade protein via the deprotonation of a thiol and have been found to play a significant role in autoimmune disease, atherosclerosis, aortic valve calcification, cardiac repair, and cardiomyopathy, operating within extracellular spaces. This review sought to evaluate recent findings in this field, highlighting how among cathepsins, the inhibition of cathepsin S in particular, could play a significant role in diminishing the effects of CVD, especially for patients with CKD.

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

“…A recent study showed that NR3C2 is downregulated in stable and chronic rejection (CR) patients compared with kidneytransplant recipients with "operational tolerance" [47]. CTSS, also known as cathepsin S, is a lysosomal cysteine proteinase that may participate in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules; in addition, circulating cathepsin S levels are associated with GFR decline in mice and humans [48], and specific inhibition of cathepsin S could diminish the effects of cardiovascular disease (CVD), especially in patients with CKD [49]. Still, only few co.DEGs have been reported in association with CKD to date, especially for their roles in podocyte damage.…”

Lysosomes as a therapeutic target

“…Selective inhibition of cathepsin S with a potent active site inhibitor known as RO5461111 (Roche) mitigated disease in MRL/lpr lupus prone mice, by reducing prim ing of T and B cells by dendritic cells, and plasma cell generation 262 . Promising data have also been generated in murine models, in the context of diabetic nephrop athy and cardiovascular diseases 295 . Further studies based on cathepsin S inhibitors should evaluate the clinical safety and utility of treating patients affected by autoimmune and inflammatory diseases 295 .…”

“…Promising data have also been generated in murine models, in the context of diabetic nephrop athy and cardiovascular diseases 295 . Further studies based on cathepsin S inhibitors should evaluate the clinical safety and utility of treating patients affected by autoimmune and inflammatory diseases 295 . Cathepsin K, which is highly expressed by osteoclasts and very effi ciently degrades type I collagen, the major component of the organic bone matrix, is also a potential target for modulating lysosomal dysfunction in some of the dis orders discussed above, such as SLE 96 .…”

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…The inhibition of CTSs has been widely explored over the last decades in the field of chronic inflammatory diseases [27,37,204,205], cardiovascular diseases [10,19,181], osteoporosis [70][71][72][73], arthritis [28,206], kidney diseases [30][31][32]84], pancreatitis [207], obesity [208][209][210], cancer [25,34,48,74,82,211], neurodegenerative diseases [39,41,184,185,212,213], and many other pathological states. Multiple inhibitors are currently available, ranging from reversible covalent inhibitors to irreversible inhibitors [214][215][216][217][218] (Table 4).…”

“…However, molecular modeling-assisted design of CTSS inhibitors has provided novel scaffolds for improved CTSS inhibition [217]. Experimental evidences suggest that inhibition of CTSS attenuates the progression of atherosclerosis during chronic kidney disease [84], improves sugar levels during type2 diabetes [208], and prevents autoantigen presentation and autoimmunity [229]. CTSK inhibitors have been proved successful improving osteoporosis [72,73,230]; however, concerns emerged over off-target effects of the inhibitors against other CTSs and CTSK inhibition at nonbone sites (i.e., skin, and cardiovascular and cerebrovascular sites).…”