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

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ABSTRACT 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 (gp91 phox , p22 phox )‐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.

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