Cathepsin S Deficiency Prevents Chronic Stress-Related Renal Remodeling and Dysfunction in a Mouse 5/6 Nephrectomy Injury Model.

Chronic psychological stress exacerbates chronic kidney disease (CKD). Given that lysosome cathepsins participate in human pathobiology, we investigated the roles of cathepsin S (CatS) in chronic stress-related renal damage and dysfunction in mice subjected to a 5/6 nephrectomy surgery. A mouse model combining 5/6 nephrectomy (5/6Nx) surgery and chronic restrain stress (CRS) was applied to wild-type (CatS+/+) and CatS knockout (CatS-/-) mice. The CRS exacerbated the 5/6Nx-induced renal injury, blood-pressure elevation, glomerulosclerosis, fibrosis, podocyte damage, and inflammatory macrophage infiltration while simultaneously increasing the renal CatS expression. Compared to the CatS+/+ mice, the CatS-/- mice exhibited attenuated CRS-induced renal injury exacerbation manifested by improved renal function (urinary albumin) and blood pressure, reduced microstructure alterations, and lowered levels of renal inflammation (interleukin-1β, tumor necrosis factor-α, galectin-3, angiotensin II type 1 receptor, monocyte chemoattractant protein-1, and Toll-like receptor-2), oxidative stress (gp91phox, p22phox)-related and apoptosis [cleaved caspase-3 (C-caspase-3), cytochrome c, and Bcl-2]-related, extracellular remodeling (CatS, matrix metalloproteinase-9, and collagen types I and III)-related molecular proteins and/or genes. Pharmacological inhibition of CatS yielded the same conclusions. In mesangial cells, CatS overexpression and silencing, respectively, elevated or lowered C-caspase-3 and cytochrome c levels, providing evidence that a mechanistic explanation of CatS-caspase-3/cytochrome-mediated cell apoptosis in response to 5% stressed serum and oxidative stress. CatS inhibition appeared to ameliorate CRS-related renal injury and hypertension development in mice that underwent 5/6 nephrectomy surgery, possibly by lowering renal oxidative stress, inflammation, proteolysis, and apoptosis. CatS might thus become a potential therapeutic target for CRS-related renal remodeling and hypertension in animals with CKD.