Dual Therapeutic Strategy Against Leptospira-Induced Renal Pathology: Antibiotics and Senolytics

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Dual Therapeutic Strategy Against Leptospira-Induced Renal Pathology: Antibiotics and Senolytics

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Co-author 1

Shen-Hsing Hsu d938208@gmail.com Kidney research center Chang Gung Memorial Hospital Taoyuan Taiwan *

Co-author 2

Yi-Chun Liu happy14jass@gmail.com Kidney research center Chang Gung Memorial Hospital Taoyuan Taiwan -

Co-author 3

Ming-Yang Chang mingyc@adm.cgmh.org.tw Kidney research center Chang Gung Memorial Hospital Taoyuan Taiwan -

Co-author 4

Li-Fang Chou d928209@gmail.com Kidney research center Chang Gung Memorial Hospital Taoyuan Taiwan -

Co-author 5

Ya-Chung Tian dryctian@cgmh.org.tw Kidney research center Chang Gung Memorial Hospital Taoyuan Taiwan -

Co-author 6

Chien Li zxcv6985@gmail.com Kidney research center Chang Gung Memorial Hospital Taoyuan Taiwan -

Co-author 7

Chih-Wei Yang cwyang00@gmail.com Kidney research center Chang Gung Memorial Hospital Taoyuan Taiwan -

Co-author 8

Co-author 9

Co-author 10

Co-author 11

Co-author 12

Co-author 13

Co-author 14

Co-author 15

Introduction

Leptospirosis, a globally neglected zoonotic disease, primarily affects the kidney, where Leptospira colonization in renal tubules triggers severe pathological alterations, especially the acute kidney injury (AKI). The infection induces excessive production of reactive oxygen species (ROS) and inflammatory activation, resulting in tubular injury and driving epithelial cells toward a senescent phenotype. Persistent senescence, characterized by upregulation of p16 and p21 and secretion of senescence-associated secretory phenotype (SASP) factors, sustains inflammation and contributes to renal fibrosis. The timing of therapeutic intervention plays a pivotal role in determining disease outcome.

Methods

To investigate the role of cellular senescence and therapeutic timing in leptospiral infection, a hamster model of Leptospira interrogans infection was established. Early antibiotic therapy (EAT) and delayed antibiotic therapy (DAT) were administered to evaluate treatment efficacy. Molecular and histopathological analyses were conducted using quantitative PCR (qPCR) for p16, p21, and SASP genes expression, Masson’s trichrome staining for collagen and fibronectin deposition, and immunofluorescence (IF) for senescence and fibrosis markers. Reactive oxygen species (ROS) generation was assessed by DHE staining, while renal function was evaluated by BUN and creatinine measurements. To assess the therapeutic potential of senolytic intervention, ABT-263 was administered following DAT, and its effects on senescent cell clearance and renal repair were examined using morphological, molecular, and biochemical analyses.

Results

EAT effectively eradicated Leptospira and prevented tubular damage, preserving renal function. In contrast, DAT resulted in persistent cellular senescence, as evidenced by elevated p16 and p21 expression and increased SASP factor production, leading to progressive fibrosis despite bacterial clearance. Treatment with the senolytic drug ABT-263 selectively eliminated senescent renal cells, reduced SASP burden, mitigated fibrotic remodeling, and significantly improved renal recovery in the DAT group.

Conclusion

These findings demonstrate that unresolved cellular senescence is a key driver of fibrosis and chronic kidney disease (CKD) following leptospiral infection. A dual therapeutic strategy combining timely antibiotic administration to eradicate Leptospira with senolytic therapy to remove senescent cells, offers a promising approach to prevent CKD progression. This study highlights the importance of targeting both infection and host cellular responses in the comprehensive management of leptospirosis.

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