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Acute renal failure and proximal tubule lesions after trichosanthin injection in rats
Abstract:
The structural basis of the recently recognized renal impairment after infusion of trichosanthin (TCS), a type I ribosome inactivating protein, is uncertain, but functionally it appears to be related to a lesion in the renal tubules. In this study, renal dysfunction in experimental rats was induced by a single dose of TCS. Creatinine clearance and tubular proteinuria were used to assess renal function. Light microscopy and ultrastructure of the kidneys were examined and apoptosis in proximal tubules was evaluated by the in situ TdT-mediated nick end labeling technique. TCS-treated rats demonstrated a significant dose-dependent decrease in creatinine clearance together with a mild degree of low-molecular-weight proteinuria. The proximal convoluted tubule was the site of lesions showing individual tubular cell death, which was more abundant in rats receiving high doses of TCS. Apoptotic cell death, together with heterophagosomes and large residual bodies, was observed. DNA fragmentation was confirmed by the in situ technique. There was also a dose-dependent density of apoptotic cells. Other portions of the nephron were spared, and it was not accompanied by any inflammatory infiltrate. In conclusion, these findings are consistent with TCS-induced proximal tubular toxicity resulting in reduction of glomerular filtration rate and tubular proteinuria. The extent of injury is dosage dependent. Both necrotic cell death and apoptosis participated in the loss of cells from the proximal tubules. Such toxicity may be mediated through intracellular events induced by trichosanthin.
Insights
Trichosanthin (TCS) causes dose-dependent kidney damage, specifically affecting proximal tubules. This toxicity, involving cell death and apoptosis, reduces kidney function and increases proteinuria.
Area of Science:
- Nephrology
- Toxicology
- Molecular Biology
Background:
- Renal impairment following trichosanthin (TCS) infusion is recognized but its structural basis remains unclear.
- Functional studies suggest lesions in renal tubules are involved in TCS-induced nephrotoxicity.
Purpose of the Study:
- To investigate the structural and functional renal changes induced by trichosanthin (TCS) in experimental rats.
- To evaluate the role of proximal tubular cell death, including apoptosis, in TCS nephrotoxicity.
Main Methods:
- Experimental rats received single doses of TCS to induce renal dysfunction.
- Renal function was assessed via creatinine clearance and tubular proteinuria.
- Kidney histology (light and ultrastructure) and proximal tubule apoptosis (TUNEL assay) were examined.
Main Results:
- TCS administration caused a dose-dependent decrease in creatinine clearance and mild low-molecular-weight proteinuria.
- Lesions were localized to proximal convoluted tubules, showing individual cell death, including apoptosis and necrosis.
- Apoptotic cells and DNA fragmentation increased with higher TCS doses; other nephron segments were unaffected.
Conclusions:
- Trichosanthin (TCS) induces dose-dependent proximal tubular toxicity, leading to reduced glomerular filtration rate and proteinuria.
- Both necrotic and apoptotic cell death contribute to proximal tubular injury.
- Intracellular events triggered by TCS likely mediate this observed toxicity.