Current update on theranostic roles of cyclophilin A in kidney diseases

Abstract

Cyclophilin A (CyPA) or peptidylprolyl isomerase A (PPIA), an immunophilin with peptidyl-prolyl cis/trans isomerase (PPIase) activity, is an abundant cellular protein widely expressed across various cell types and tissues, including the kidney. Expression of CyPA in the kidney is relatively higher in proximal tubular epithelial cells than others along the nephron. Alterations in expression and secretion of CyPA play important roles in physiological processes and pathophysiology of several diseases affecting the kidney. Herein, we provide a brief overview of CyPA structural biology and present the current update on its theranostic roles in various kidney diseases, including diabetic nephropathy, acute kidney injury, chronic kidney disease, renal fibrosis, and nephrotoxicity associated with organ transplantation. Notably, the diagnostic/prognostic role for urinary CyPA in several of these kidney diseases is promising. Finally, future perspectives on the CyPA research, especially targeting CyPA for therapeutics, are discussed. A comprehensive understanding of the theranostic roles of CyPA in kidney diseases is expected to provide novel insights into the design of new therapeutic interventions and prevention strategies.

Keywords: AKI; Biomarker; CKD; Diabetic nephropathy; Nephrotoxicity; PPIA; Renal fibrosis; Therapeutics.

Figure 1

Human cyclophilins. Amino acid sequences, protein name, and/or description of human cyclophilins were obtained from The UniProt Knowledgebase (UniProtKB) database (https://www.uniprot.org/). (A): Alignment of human cyclophilins together with the PPIase cyclophilin-type domain in each cyclophilin. (B): The 3D structure of individual cyclophilins generated using SWISS-MODEL template library (https://swissmodel.expasy.org/templates/), including PPIA:PDB (4n1s), PPIB:PDB (1cyn), PPIC:PDB (2esl), PPID:PDB (1ihg), PPIE:PDB (2r99), and PPIF:PDB (5ccs). Their β-sheet and α-helix are labelled with green and greyish purple, respectively. Note that the unique structure of the cyclophilin protein family consists of 8 β-strands and 2 α-helices.

Figure 2

General structural biology of CyPA. (A): Mapping of location of PPIA gene on chromosome 7 at location 7p13 (NC_000007.14: 44,795,960-44,803,117) as indicated in the red box. (B): Amino acid sequence of CyPA. The residues that form the secondary structure (β-strand and α-helix) are labeled. (C): The 3D structure of CyPA with 8 β-strands and 2 α-helices. (D): The key amino acids, R55 and K82, that play crucial role in CyPA-mediated cis/trans isomerization (adopted from Ref. that is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution, and reproduction in any medium or format).

Figure 3

Flow chart representing inclusion and exclusion literature search criteria to retrieve the articles for this review. From a total of 182 articles initially retrieved using the well-defined keywords, 17 relevant articles were included for discussion in this review. Main findings reported in these articles are summarized in Table 1.

Figure 4

Proposed pathogenic mechanisms of CyPA in kidney diseases. During cellular injury, CyPA expression and secretion are induced by various stimuli, e.g., oxidative stress, hypoxia, infection, inflammation, hyperglycemia and mechanical stretch, via the Rho-dependent pathway. The downstream cascade is associated with Rho kinase and actin remodeling mediators. Intracellular CyPA (iCyPA) can be secreted (eCyPA) from the cells into the extracellular compartment and performs paracrine and autocrine functions. For the autocrine function, the binding of eCyPA to CD147 activates MAPK pathway via p38, ERK1/2 and NF-κB, leading to cell proliferation, migration and inflammatory cascade. For the paracrine function, eCyPA secreted from the injured cells promotes accumulation and activation of leukocytes, such as neutrophils, monocytes and T-cells, which subsequently mediate tubular cell necrosis, interstitial inflammation, fibrogenesis and impaired kidney function. Finally, the increase in circulating eCyPA and uCyPA serves as a promising biomarker for many kidney diseases.