Investigation of the Effects of Fosfomycin in Kidney Damage Caused by CLP-Induced Sepsis

Abstract

Sepsis, a life-threatening condition characterized by dysregulated host responses to infection, often leads to multi-organ dysfunction, including kidney injury. Kidney damage in sepsis can have severe consequences and is associated with high mortality rates. This study aimed to investigate the potential therapeutic effects of fosfomycin (FOS), a broad-spectrum antibiotic with immunomodulatory properties, on kidney damage induced by cecal ligation and puncture (CLP)-induced sepsis in a rodent model. In total, 24 rats were randomly divided into three groups. Group 1 (n = 8), the healthy control group (C), received a single dose of 0.9% NaCl (saline) solution via an intraperitoneal (i.p.) route. To group 2 (n = 8), the CLP group, CLP-induced sepsis was applied without medication, and a single dose of 0.9% NaCl (saline) solution was applied i.p. before induction. To group 3 (n = 8), the CLP + FOS (500 mg/kg) group, a single dose of 500 mg/kg FOS was administered i.p. before sepsis induction. The effects of fosfomycin on kidney function, histopathological changes, inflammatory markers, oxidative stress, and apoptosis were assessed. In the fosfomycin-treated group, the histological analysis results demonstrated reduction in kidney tissue damage and inflammation. Additionally, fosfomycin attenuated the upregulation of pro-inflammatory cytokines and reduced oxidative stress markers in kidney tissue. Furthermore, fosfomycin treatment was associated with a decrease in apoptotic cell death in the kidney. These findings suggest that fosfomycin may have a protective effect on kidney damage caused by CLP-induced sepsis. The potential mechanisms underlying this protection include the modulation of inflammation, reduction of oxidative stress, and inhibition of apoptosis.

Keywords: CLP; fosfomycin; inflammation; kidney; rat; sepsis.

Figure 1

Representative light microscopic image of kidney tissue sections stained with hematoxylin and eosin. A(x20)-B(x40): When the sections of the control group are examined under a light microscope, renal corpuscles and renal tubules containing normal glomeruli are observed. It was noteworthy that the brush border structure in the proximal tubules (p) was typical (arrow) (KHDS: 0 (0–0)). C(x20)-D(x40): In the CLP application group, degenerative renal corpuscles (drc) and intraluminal necrotic cellular debris accumulation in diffuse necrotic tubules (spiral arrow) are observed (arrowhead). There was loss of brush border structures in the necrotic epithelial cells of the proximal tubule. Excessive protein exudation (arrowhead) and vascular congestions (c) are observed in intertubular areas (KHDS: 9 (9–10)). E(x20)-F(x40): It is observed that degenerative renal corpuscles, widespread necrotic tubules and intraluminal necrotic cellular debris accumulation decreased in the FOS treatment group. In addition, glomerular and renal tubular epithelial cells with typical structures are observed here and there (KHDS: 4.5 (4–6)). Glomerulus (g), proximal tubule (p), distal tubule (d), brush border (arrow).

Figure 2

Representative light microscopic screenshot of sections of kidney tissue incubated with cleaved caspase-3 primary antibody. A(x20)-B(x40): In the sections of the control group, normal proximal and distal tubule epithelial cells are observed (arrow) (cleaved caspase-3 positivity score: 0 (0–1)). C(x20)-D(x40): Apoptotic proximal and distal tubule epithelial cells showing intense cleaved caspase-3 positivity are observed in the kidney tissue sections of the CLP application group (tailed arrow) (cleaved caspase-3 positivity score: 2 (2–3)). E(x20)-F(x40): In the kidney tissue sections of the FOS treatment group, apoptotic proximal and distal tubule epithelial cells showing cleaved caspase-3 positivity are observed to decrease (arrow) (cleaved caspase-3 positivity score: 0 (0–1)). Glomerulus (g), proximal tubule (p), distal tubule (d).

Figure 3

Representative light microscopic screenshot of kidney tissue sections incubated with 8-OHdG primary antibody. A(x20)-B(x40): Normally structured proximal and distal tubule epithelial cells are observed in the sections of the control group (arrow) (8-OHdG positivity score: 0 (0–0)). C(x20)-D(x40): In the kidney tissue sections of the CLP application group, proximal and distal tubule epithelial cells showing intense 8-OHdG positivity are observed (tailed arrow) (8-OHdG positivity score: 3(2–3)). E(x20)-F(x40): In the kidney tissue sections of the FOS treatment group, apoptotic proximal and distal tubule epithelial cells showing 8-OHdG positivity are observed to decrease (arrow) (8-OHdG positivity score: 0.5 (0–1)). Glomerulus (g), proximal tubule (p), distal tubule (d).