Related Experiment Video
Updated: Jun 28, 2025
Intrarenal Injection of Escherichia coli in a Rat Model of Pyelonephritis
Published on: July 18, 2017
The NLRP3 Inflammasome Is a Major Cause of Acute Renal Failure Induced by Polypeptide Antibiotics
Tomohiro Kagi1, Aya Inoue1, Takuya Noguchi1
1Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Abstract:
Drug-induced acute renal failure (ARF) is a public health concern that hinders optimal drug therapy. However, pathological mechanisms of drug-induced ARF remain to be elucidated. Here, we show that a pathological process of drug-induced ARF is mediated by proinflammatory cross-talk between kidney tubular cells and macrophages. Both polymyxin B and colistin, polypeptide antibiotics, frequently cause ARF, stimulated the ERK and NF-κB pathways in kidney tubular cells, and thereby upregulated M-CSF and MCP-1, leading to infiltration of macrophages into the kidneys. Thereafter, the kidney-infiltrated macrophages were exposed to polypeptide antibiotics, which initiated activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. Interestingly, blockade of the NLRP3 activation clearly ameliorated the pathology of ARF induced by polypeptide antibiotics, suggesting that a combination of the distinct cellular responses to polypeptide antibiotics in kidney tubular cells and macrophages plays a key role in the pathogenesis of colistin-induced ARF. Thus, our results provide a concrete example of how drugs initiate ARF, which may give insight into the underlying pathological process of drug-induced ARF.
Insights
Drug-induced acute renal failure (ARF) involves kidney cells and macrophages. Blocking NLRP3 inflammasome activation in macrophages ameliorates ARF caused by polypeptide antibiotics like colistin.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Drug-induced acute renal failure (ARF) is a significant clinical issue.
- The precise pathological mechanisms underlying drug-induced ARF require further elucidation.
Purpose of the Study:
- To investigate the pathological mechanisms of drug-induced ARF.
- To explore the role of kidney tubular cells and macrophages in ARF induced by polypeptide antibiotics.
Main Methods:
- Examined the effects of polymyxin B and colistin on kidney tubular cells and macrophages.
- Investigated the activation of ERK, NF-κB, and NLRP3 inflammasome pathways.
- Assessed the impact of NLRP3 activation blockade on ARF pathology.
Main Results:
- Polypeptide antibiotics stimulated ERK and NF-κB pathways in kidney tubular cells, upregulating M-CSF and MCP-1.
- This led to macrophage infiltration into the kidneys.
- Macrophage activation of the NLRP3 inflammasome was observed.
- Blocking NLRP3 activation ameliorated ARF pathology.
Conclusions:
- Drug-induced ARF pathogenesis involves proinflammatory cross-talk between kidney tubular cells and macrophages.
- The activation of the NLRP3 inflammasome in macrophages is a critical step in colistin-induced ARF.
- Targeting NLRP3 activation may offer a therapeutic strategy for drug-induced ARF.
More Related Videos
Related Concept Videos
01:10Nephrons
01:20Renal Corpuscle
Glomerulus: Structure and Function
The glomerulus is a tiny, intricate network of capillaries located at the beginning of the nephron. It's enveloped by the Bowman's capsule and receives its blood supply from an afferent arteriole, which divides into numerous...
01:27Dialysis
Acute kidney injury develops suddenly and can be caused by pre-renal causes (e.g., hypovolemia, shock), intrinsic renal causes (e.g., acute tubular necrosis), or post-renal causes (e.g., urinary obstruction). In contrast, chronic renal failure progresses gradually over time and is often...