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Human renal medullary interstitial cells and analgesic nephropathy
P H Whiting1, K Tisocki, G M Hawksworth
1School of Pharmacy and Pharmaceutical Sciences, De Montfort University, The Gateway, Leicester, England. pwhiting@DMU.ac.uk
Abstract:
The aim of this study was to investigate the effects of known papillotoxins using cultures of human renal interstital medullary cells (hRMIC). The culture of hMIC was based on the primary culture of human renal medullary explants, selective detachment of interstitial cells and selective overgrowth of these cells in a serum-rich medium after dilution cloning. The homogeneous population of cells obtained exhibited the characteristic morphological and functional characteristics of Type I interstitial cells, viz. stellate-shaped cells demonstrating numerous lipid droplets, abundant endoplasmic reticulum and mitochondria, fine filaments underlying the cell membrane and the production of extracellular matrix. Cytotoxicity studies using hMIC and known papillotoxins clearly demonstrated a reduction in cell viability that varied with bath exposure time and type of agent tested. While only phenylbutazone and mefenamic acid produced significant cytotoxicity after a 24 h incubation period, cell viability assessed using the MTT assay was only profoundly reduced by aspirin and paracetamol following sub-chronic exposure for 7 days. The rank order of cytotoxicity observed in hMIC was phenylbutazone > mefenamic acid > aspirin > paracetamol. The results demonstrate the potential of hMIC for investigating and defining the early cellular events in the pathogenesis of analgesic nephropathy.
Insights
This study explored how papillotoxins affect human renal interstitial medullary cells (hRMIC). Phenylbutazone and mefenamic acid showed acute toxicity, while aspirin and paracetamol exhibited chronic toxicity in hRMIC cultures.
Area of Science:
- Nephrology
- Toxicology
- Cell Biology
Background:
- Analgesic nephropathy is a significant cause of chronic kidney disease.
- The precise cellular mechanisms underlying analgesic nephropathy remain incompletely understood.
- Investigating the direct effects of analgesics on renal cells is crucial for understanding pathogenesis.
Purpose of the Study:
- To establish and characterize a human renal interstitial medullary cell (hRMIC) culture model.
- To evaluate the cytotoxic effects of known papillotoxins on hRMIC.
- To determine the potential of hRMIC for studying analgesic nephropathy.
Main Methods:
- Primary culture of human renal medullary explants.
- Selective isolation and expansion of interstitial cells.
- Morphological and functional characterization of hRMIC.
- Cytotoxicity assays (MTT) following acute (24h) and sub-chronic (7-day) exposure to papillotoxins.
Main Results:
- A homogeneous population of hRMIC was successfully cultured, exhibiting characteristics of Type I interstitial cells.
- Acute exposure (24h) showed significant cytotoxicity with phenylbutazone and mefenamic acid.
- Sub-chronic exposure (7-day) revealed profound cytotoxicity with aspirin and paracetamol.
- The rank order of cytotoxicity was phenylbutazone > mefenamic acid > aspirin > paracetamol.
Conclusions:
- Human renal interstitial medullary cells (hRMIC) provide a viable model for investigating drug-induced kidney injury.
- The study identified differential cytotoxic effects of various analgesics on hRMIC.
- hRMIC cultures hold promise for elucidating early cellular events in analgesic nephropathy pathogenesis.
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