Elevated Cathepsin S Linked to Increased Risk of IgA Nephropathy

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Findings suggest greater CTSS levels are associated with an elevated risk of IgAN and highlight the enzyme’s potential as a diagnostic biomarker.

Shaojie Fu | Credit: Loop

Shaojie Fu

Credit: Loop

Greater levels of cathepsin S (CTSS) may be associated with an increased risk of IgA nephropathy (IgAN), according to findings from a recent study.1

Results highlight a significant upregulation of CTSS in the serum and renal tissues of patients with IgAN, suggesting CTSS may serve as a viable diagnostic and prognostic biomarker and could present a promising pathway for developing effective IgAN therapies.1

“The intricate pathophysiology of IgAN remains largely elusive, resulting in limited effective treatments and reliable biomarkers for disease progression,” Shaojie Fu, a student and intern in the department of nephrology at the First Hospital of Jilin University in China, and colleagues wrote.1 “Consequently, an urgent need exists to identify specific biomarkers and potential therapeutic targets for IgAN.”

Mainly found in acidic endo/lysosomal compartments, cathepsins are the most abundant lysosomal proteases and play a vital role in intracellular protein degradation, energy metabolism, and immune responses. Acknowledging the differential expression of cathepsins in pathological conditions, much research is focused on their use as diagnostic markers and therapeutic targets. Although the role of cathepsins in certain kidney diseases is well explored, less is known about their viability in IgAN.2

To explore the potential causal relationship between cathepsins and IgAN, investigators conducted a bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data. They collected genetic instruments evaluating the levels of various cathepsins from the INTERVAL study and sourced GWAS data for IgAN from the UK Biobank and FinnGen datasets, ultimately analyzing approximately 25 million genetic variants.1

Investigators used the inverse variance weighting method to estimate the overall effect size, and to validate the robustness of our MR results, they also employed MR-Egger and Weighted Median. Additionally, immunohistochemical staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of patients with IgAN.1

Univariate MR analyses demonstrated a significant link between increased CTSS levels and a greater risk of IgAN, evidenced by an odds ratio (OR) of 1.041 (95% CI, 1.009–1.073; P = .012) estimated using inverse variance weighting. Complementary tests, including Weighted Median and MR-Egger methods, supported this result, with Weighted Median yielding an OR of 1.054 (95% CI, 1.007–1.103; P = .025) and MR-Egger yielding an OR of 1.059 (95% CI, 1.005–1.115; P = .043). Of note, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins.1

In multivariable MR analysis, even after accounting for the presence of other cathepsin types, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P = .020; OR, 1.037; 95% CI, 1.006–1.069). However, investigators did not observe any statistically significant causal relationships between other cathepsin types and the risk of IgAN.1

In immunohistochemical analysis, compared to normal controls, the expression of CTSS was significantly greater in the tubulointerstitial region in IgAN patients, and this high expression was unique to IgAN compared with several other primary kidney diseases. Similarly, ELISA results indicated patients with IgAN had notably increased levels of serum CTSS compared to healthy controls, and this high expression was also unique to IgAN versus other primary kidney diseases such as membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis.1

Further investigation into immune cell infiltration, gene set enrichment analysis, and gene set variation analysis highlighted the role of CTSS expression in the immune dysregulation observed in IgAN, implying CTSS may play a role in the development of IgAN by influencing immune-related processes and metabolic pathways.1

Finally, molecular docking and virtual screening based on a combination of Glide XP scores, MM-GBSA scores, and clustering analysis pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS.1

Investigators outlined notable limitations to these findings, including their limited generalizability due to participants being exclusively of European descent; the lack of exploration of the relationship between CTSS and IgAN prognosis; and the lack of experimental validations for these candidates while identifying potential drugs targeting CTSS.1

“This study represents a groundbreaking MR analysis exploring the causal relationships between various cathepsins and IgAN,” investigators concluded.1 “Through integrating results from both univariable and multivariable analyses, we have identified CTSS as a significant risk factor for IgAN, with no evidence of reverse causality for CTSS observed.”

References

  1. Fu S, Wu M, Cheng Y, et al. Cathepsin S (CTSS) in IgA nephropathy: an exploratory study on its role as a potential diagnostic biomarker and therapeutic target. Front. Immunol. 15:1390821. doi: 10.3389/fimmu.2024.1390821
  2. Yadati T, Houben T, Bitorina A, Shiri-Sverdlov R. The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management. Cells. 2020;9(7):1679. Published 2020 Jul 13. doi:10.3390/cells9071679
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