Cellular senescence links severe Leptospira infection to chronic kidney disease progression.

AIMS: Leptospirosis, a re-emerging zoonotic disease caused by pathogenic Leptospira species, poses an increasing public health risk, particularly in the context of climate change. Severe leptospirosis has been associated with a heightened risk of chronic kidney disease (CKD), suggesting potential long-term renal consequences. However, the underlying mechanisms remain unclear. This study investigates the impact of severe acute Leptospira infection on kidney function, focusing on cellular senescence and its role in disease progression.

MATERIALS AND

METHODS

A hamster model of severe leptospirosis was established to assess renal function and injury biomarkers. Bulk RNA-seq was used to analyze differential gene expression and identify upregulated signaling pathways. Cellular senescence was evaluated through senescence-associated β-galactosidase (SA-β-gal) activity and the expression of senescence markers p16Ink4a (P16) and p21Cip1 (P21) in renal tubular cells via confocal microscopy. Kidney fibrosis was analyzed histologically, while SASP expression was quantified using qPCR. The roles of ROS and inflammation in driving senescence were further examined in cellular models.

KEY FINDINGS: Leptospira infected hamsters developed marked renal dysfunction accompanied by increased SA-β-gal activity and elevated P16 and P21 expression, indicating cellular senescence. Enhanced fibrosis and upregulation of SASP factors were also detected. Mechanistic analyses identified ROS generation and inflammation as major inducers of senescence.

SIGNIFICANCE: Severe Leptospira infection drives maladaptive kidney repair through senescence and fibrosis, promoting CKD progression. Targeting cellular senescence may represent a promising strategy to prevent chronic renal damage after leptospirosis.