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Dual blockade of DPP-4 and CXCL12/CXCR4 axes synergistically protects podocytes in lupus nephritis
Hui-Miao Hu1,2, Yong-Chun Li2,3,4, Yang-Ming Zhang2,3,4
1Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Background:
Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), is characterized by podocyte injury that contributes to disease progression. Dipeptidyl peptidase-4 (DPP-4) inhibitors, though developed for diabetes, have shown renoprotective potential. However, DPP-4 inhibition may elevate CXCL12/CXCR4 signaling, a pathway implicated in LN pathogenesis. This study aimed to determine whether dual DPP-4 and CXCL12/CXCR4 blockade confers enhanced renal protection in LN.
Methods:
MRL/lpr lupus-prone mice were treated with the DPP-4 inhibitor linagliptin, either alone or in combination with the CXCL12/CXCR4 axis antagonist AMD3100. We evaluated renal function, histopathology, podocyte structure, and markers of oxidative stress, fibrosis, and inflammation. In vitro assays using DPP4-knockout podocytes were also performed to elucidate underlying mechanisms.
Results:
DPP4-deficient podocytes exhibited elevated CXCL12/CXCR4 expression and modest nephrin upregulation. Co-treatment with AMD3100 further increased nephrin expression compared to linagliptin alone. In vivo, linagliptin monotherapy reduced proteinuria and serum creatinine but also increased CXCL12/CXCR4 expression. Combined therapy significantly decreased proteinuria, serum creatinine, anti-dsDNA, and ANA titers. Histological analysis showed reduced mesangial proliferation and interstitial inflammation. Transmission electron microscopy and immunostaining demonstrated improved podocyte foot process integrity and upregulation of nephrin and podocin. Dual blockade also reduced renal oxidative stress (DHE, NOX4), fibrosis markers (α-SMA, fibronectin), and inflammatory mediators (NF-κB p65, NLRP3).
Conclusion:
Combined DPP-4 and CXCL12/CXCR4 axis inhibition synergistically enhanced podocyte protection and attenuated renal inflammation, fibrosis, and oxidative stress in lupus nephritis. These findings support dual blockade as a promising therapeutic strategy for LN.
Insights
Dual blockade of Dipeptidyl peptidase-4 (DPP-4) and CXCL12/CXCR4 signaling synergistically protects kidneys in lupus nephritis (LN). This combined therapy reduces inflammation, fibrosis, and oxidative stress, offering a promising new treatment strategy for LN.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Lupus nephritis (LN) involves podocyte injury, a key driver of systemic lupus erythematosus (SLE) progression.
- Dipeptidyl peptidase-4 (DPP-4) inhibitors show renoprotective effects but may increase CXCL12/CXCR4 signaling, implicated in LN.
- This study investigates the therapeutic potential of combined DPP-4 and CXCL12/CXCR4 blockade in LN.
Purpose of the Study:
- To evaluate the efficacy of dual DPP-4 and CXCL12/CXCR4 axis inhibition in a lupus nephritis mouse model.
- To determine if combined blockade offers enhanced renal protection compared to monotherapy.
- To elucidate the underlying mechanisms of renoprotection, including effects on podocyte integrity, inflammation, fibrosis, and oxidative stress.
Main Methods:
- MRL/lpr mice with lupus nephritis were treated with linagliptin (DPP-4 inhibitor) alone or with AMD3100 (CXCL12/CXCR4 antagonist).
- Renal function, histopathology, podocyte structure, and molecular markers of stress, fibrosis, and inflammation were assessed.
- In vitro studies using DPP4-knockout podocytes were conducted to explore mechanistic insights.
Main Results:
- Linagliptin monotherapy improved renal function but increased CXCL12/CXCR4 expression.
- Combined therapy significantly reduced proteinuria, serum creatinine, and autoantibody titers (anti-dsDNA, ANA).
- Dual blockade enhanced podocyte integrity, reduced mesangial proliferation, interstitial inflammation, oxidative stress, and fibrosis.
Conclusions:
- Combined DPP-4 and CXCL12/CXCR4 axis inhibition demonstrates synergistic renoprotective effects in lupus nephritis.
- This dual blockade strategy effectively attenuates renal inflammation, fibrosis, and oxidative stress.
- Dual inhibition represents a promising therapeutic approach for managing lupus nephritis.
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