Novel therapeutic perspectives for crescentic glomerulonephritis through targeting parietal epithelial cell activation and proliferation

ABSTRACT

Introduction

Kidney injury is clinically classified as crescentic glomerulonephritis (CrGN) when ≥50% of the glomeruli in a biopsy sample contain crescentic lesions. However, current strategies, such as systemic immunosuppressive therapy and plasmapheresis for CrGN, are partially effective, and these drugs have considerable systemic side effects. Hence, targeted therapy to prevent glomerular crescent formation and expansion remains an unmet clinical need.

Areas covered

Hyperproliferative parietal epithelial cells (PECs) are the main constituent cells of the glomerular crescent with cell-tracing evidence. Crescents obstruct the flow of primary urine, pressure the capillaries, and degenerate the affected nephrons. We reviewed the markers of PEC activation and proliferation, potential therapeutic effects of thrombin and thrombin receptor inhibitors, and how podocytes cross-talk with PECs. These experiments may help identify potential early specific targets for the prevention and treatment of glomerular crescentic injury.

Expert opinion

Inhibiting PEC activation and proliferation in CrGN can alleviate glomerular crescent progression, which has been supported by preclinical studies with evidence of genetic deletion. Clarifying the outcome of PEC transformation to the podocyte phenotype and suppressing thrombin, thrombin receptors, and PEC hyperproliferation in early therapeutic strategies will be the research goals in the next ten years.

Plain Language Summary

It is clinically classified as crescentic glomerulonephritis (CrGN) when more than 50% of the glomeruli of the kidney in a biopsy sample contain crescentic lesions (crescent shaped injuries). However, current strategies, such as immunosuppressive therapy and plasmapheresis (the removal, treatment and returning of blood) for CrGN, are partially effective, and these drugs have considerable side effects. In order to seek targeted therapy for CrGN, we reviewed the current research evidences. First, the hyperproliferative parietal epithelial cells (PECs) are the main cells within the glomerular crescent seen with cell-tracing evidence. The activated PECs can express specific markers and altered biological characteristics, such as cell growth and multiplication, migration, and extracellular matrix production. CD44, CD74, CD9, and pERK-1/2 are specific markers for PEC activation, and also as the potential therapeutic targets with evidence of gene knockout and inhibitor. Second, during the formation of glomerular crescents, PECs grow and multiply also through cross-talking with podocyte cells by the AngII/SDF-1/CXCR4/ERK1/2, HB-EGF/EGFR/JAK/STAT3, and PDGF/PDGFR signaling pathways, suggesting that the intervention of key molecules in these disease processes may be promising therapeutic targets for CrGN. Third, thrombin and protease-activated receptors (PARs) participate in the excessive proliferation of PEC through activation of the coagulation cascade reaction, PAR-1 and PAR-2. Therefore, anticoagulation therapy, especially inhibition of PAR-1 and PAR-2, is expected to be an effective strategy for the early prevention and treatment of CrGN. The drug vorapaxar selectively antagonizes PAR-1 and is the most promising candidate. These findings will not only improve the outlook for CrGN treatment, but will also help in the treatment of other glomerular diseases with crescentic lesions.

KEYWORDS:

• Parietal epithelial cells
• glomerular crescent
• CD44
• CD74
• CD9

Article highlights

• CD44, CD74, CD9, and p-ERK1/2 are recognized as the specific markers for activated PECs, and also as the potential therapeutic targets in the early stage of PEC proliferation.

• Thrombin can participate in the excessive proliferation of PEC through activation of the coagulation cascade reaction, PAR-1 and PAR-2. The molecular weight of thrombin is 37.4 KDa, thus, it can freely enter the Bowman’s space through the glomerular basement membrane. Therefore, anticoagulation therapy, especially inhibition of PAR-1 and PAR-2, is expected to be an effective strategy for the early prevention and treatment of CrGN. Vorapaxar selectively antagonises PAR-1 and is the most promising candidate.

• During the formation of glomerular crescents, podocytes cross-talk with PECs mainly through the AngII/SDF-1/CXCR4/ERK1/2, HB-EGF/EGFR/JAK/STAT3, and PDGF/PDGFR signaling pathways, suggesting that the intervention of key molecules in these pathological processes may be promising therapeutic targets for CrGN.

• In addition to systemic immunosuppressive therapy and plasmapheresis, the suppression of excessive PEC proliferation may be beneficial for improving the efficacy of CrGN, especially in the early stages of glomerular crescent formation less than 50%.

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Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was funded by grants from the General Projects of The National Natural Science Foundation of China (No. 82174187), Leading Talent Project of Traditional Chinese Medicine in Henan Province (No. Yu Wei Zhong Yi Han [2021] No. 8), and the Henan Characteristic Backbone Discipline Construction Project of Traditional Chinese Medicine (No. STG-ZYXKY-2020008).