Cathepsin K Deficiency Prevented Kidney Damage and Dysfunction in Response to 5/6 Nephrectomy Injury in Mice With or Without Chronic Stress

Abstract

Background: Chronic psychological stress is a risk factor for kidney disease, including kidney dysfunction and hypertension. Lysosomal CatK (cathepsin K) participates in various human pathobiologies. We investigated the role of CatK in kidney remodeling and hypertension in response to 5/6 nephrectomy injury in mice with or without chronic stress. Methods: Male 7-week-old WT (wild type; CatK +/+ ) and CatK-deficient (CatK −/− ) mice that were or were not subjected to chronic stress underwent 5/6 nephrectomy. At 8 weeks post-stress/surgery, the stress was observed to have accelerated injury-induced glomerulosclerosis, proteinuria, and blood pressure elevation. Results: Compared with the nonstressed mice, the stressed mice showed increased levels of TLR (Toll-like receptor)-2/4, p22 phox , gp91 phox , CatK, MMP (matrix metalloproteinase)-2/9, collagen type I and III genes, PPAR-γ (peroxisome proliferator-activated receptor-gamma), NLRP-3 (NOD-like receptor thermal protein domain associated protein 3), p21, p16, and cleaved caspase-8 proteins, podocyte foot process effacement, macrophage accumulation, apoptosis, and decreased levels of Bcl-2 (B cell lymphoma 2) and Sirt1, as well as decreased glomerular desmin expression in the kidneys. These harmful changes were retarded by the genetic or pharmacological inhibition of CatK. Consistently, CatK inhibition ameliorated 5/6 nephrectomy–related kidney injury and dysfunction. In mesangial cells, CatK silencing or overexpression, respectively, reduced or increased the PPAR-γ and cleaved caspase-8 protein levels, providing evidence and a mechanistic explanation of CatK’s involvement in PPAR-γ/caspase-8–mediated cell apoptosis in response to superoxide and stressed serum. Conclusions: These results demonstrate that CatK plays an essential role in kidney remodeling and hypertension in response to 5/6 nephrectomy or stress, possibly via a reduction of glomerular inflammation, apoptosis, and fibrosis, suggesting a novel therapeutic strategy for controlling kidney injury in mice under chronic psychological stress conditions.

Cathepsin S deficiency improves muscle mass loss and dysfunction via the modulation of protein metabolism in mice under pathological stress conditions

“…Recently, we demonstrated that chronic stress accelerated kidney injury and remodeling via the modulation of oxidative stress-induced CTSK expression and activity in mice that received kidney 5/6 nephrectomy surgery. 6 Collectively, these observations suggest that increased oxidative stress-mediated CTSS overexpression could also contribute to the mechanisms underlying stress-related skeletal muscle damage and atrophy in mice.…”

“…Skeletal muscle atrophy is often accompanied by an elevation in inflammatory cytokines and oxidative stress production, which induce harmful changes in the metabolism of proteins, carbohydrates, and lipids 2,4 . Emerging evidence suggests that biological oxidative and inflammatory stimulators increase the expression of several proteases, including members of the matrix metalloproteinases and cysteinyl cathepsins (i.e., CTSS and CTSK), which then modulate resident cell events (migration, invasion, apoptosis, and proliferation) and extracellular matrix remodeling in inflammatory and metabolic disorders 2,5,6,7,8,9 . Although it is well‐known that chronic stress causes inflammatory actions and oxidative stress production to promote cardiovascular disease initiation and progression in humans and animals under various pathological conditions, 5‐7 it remains largely uncertain CPS causes skeletal muscle atrophy and dysfunction.…”

Dipeptidyl peptidase‐4 disturbs adipocyte differentiation via the negative regulation of the glucagon‐like peptide‐1/adiponectin‐cathepsin K axis in mice under chronic stress conditions

“…The animal study protocols were approved by the Institutional Animal Care and Use Committees of Yanbian University and Nagoya University. Male DPP4 +/+ (C57BL/6J) and DPP4‐knockout (DPP4 −/− 30 ) mice, and male CTSK +/+ (C57BL/6J) and CTSK‐knockout (CTSK −/− 5 ) mice were used in the animal experiments; all mice were aged 8 weeks old and weighed 22–26 g. Both genotype‐matched pairs of mice were provided a growing diet and tap water ad libitum and housed three or four per cage under standard conditions (12 h light/dark cycle in a viral pathogen‐free facility) at the Animal Center of Yanbian University (for the former pair of genotype‐matched mice) and the Animal Center of Nagoya University Graduate School of Medicine (for the latter pair of genotype‐matched mice).…”

CTSS Modulates Stress-Related Carotid Artery Thrombosis in a Mouse FeCl 3 Model

“…Sliced carotid artery tissue was fixed immediately in 2% paraformaldehyde and 2.5% glutaraldehyde, dehydrated through graded ethanol and propylene oxide, and embedded in TAAB Epon 812 by standard procedures. 33 Ultrathin sections were stained with uranyl acetate for 10 min and subsequently in Reynolds lead citrate for 2 minutes. A JEM-1400EX transmission electron microscope (JEOL, Tokyo) was used to view all of the samples (at magnifications of ×6000 and ×60 000).…”