Related Experiment Video
Updated: Oct 30, 2025
A Mouse 5/6th Nephrectomy Model That Induces Experimental Uremic Cardiomyopathy
Published on: November 7, 2017
Catalytic iron mediated renal stress responses during experimental cardiorenal syndrome 1 ("CRS-1")
Ali Cm Johnson1, Richard A Zager2
1The Fred Hutchinson Cancer Research Center, Seattle, Washington.
Insights
Isoproterenol-induced acute heart failure in mice models cardiorenal syndrome type 1, showing iron-dependent kidney stress and inflammation. These reversible changes suggest direct tubular toxicity contributes to renal dysfunction.
Area of Science:
- Nephrology
- Cardiology
- Toxicology
Background:
- Cardiorenal syndrome type 1 (CRS-1) involves acute kidney injury secondary to acute heart failure (AHF).
- Isoproterenol (Iso) is a common agent for modeling AHF due to its potent chronotropic and inotropic effects, leading to hemodynamic compromise.
Purpose of the Study:
- To investigate the renal manifestations and underlying mechanisms of CRS-1 using an Iso-induced AHF mouse model.
- To determine the role of iron-mediated oxidative stress and direct tubular toxicity in Iso-induced renal dysfunction.
Main Methods:
- Mice were administered Isoproterenol (50 mg/kg) to induce AHF, followed by assessments of renal function and cortical tissue over 4 hours.
- Renal function was evaluated by blood urea nitrogen (BUN), plasma creatinine, and para-amino-hippurate (PAH) clearance.
- Renal cortical stress markers (NGAL, HO-1, IL-6, MCP-1), oxidative stress indicators (glutathione, malondialdehyde), and proximal tubule cell integrity (MTT assay) were assessed.
- The effect of the iron chelator desferrioxamine (DFO) and direct Iso exposure on cultured HK-2 cells were investigated.
Main Results:
- Iso administration induced acute azotemia and reduced renal plasma flow in mice, indicative of acute kidney injury.
- No significant morphologic tubular injury was observed, but renal cortex showed increased stress markers and oxidative stress.
- These renal changes were significantly attenuated by desferrioxamine, indicating a dependence on catalytic iron.
- In vitro studies showed Iso induced iron-dependent proximal tubule cell injury and iron-independent increases in HO-1/IL-6 mRNA.
Conclusions:
- Isoproterenol-induced AHF serves as a valuable and reversible model for studying CRS-1.
- Renal dysfunction in this model involves iron-mediated oxidative stress and inflammation, partly due to direct tubular cell toxicity from Iso.
- Iso-triggered renal cytokine production may contribute to inter-organ communication and systemic inflammation.
Abstract:
Cardiorenal syndrome I (CRS-1) denotes a state in which acute kidney injury occurs in the setting of acute heart failure (AHF). Isoproterenol (Iso) administration is widly used as an AHF model by transiently inducing extreme tachycardia, hypotension, and myocyte apoptosis and/or necrosis. To gain potential insights into renal manifestations of CRS-1, mice were subjected to the Iso-AHF model (50 mg Iso/kg), followed by renal functional and renal cortical assessments over 4 hours Iso induced acute azotemia (doubling of BUN, plasma creatinine) and significantly reduced renal plasma flow (prolonged plasma para-amino-hippurate clearance). Although no morphologic tubular injury was identified, marked increases in renal cortical 'stress markers' (NGAL, HO-1, IL-6, MCP-1 mRNAs) and oxidant stress (decreased glutathione, increased malondialdehyde) were observed. These changes were catalytic Fe dependent, given that the iron chelator desferrioxamine (DFO) significantly blunted, or completely reversed, these renal cortical abnormalities. Despite these acute changes, no lasting renal injury was observed (assessed over 3 days). To determine whether Iso directly impacts tubular cell integrity, cultured proximal tubule (HK-2) cells were exposed to Iso. Substantial Fe dependent cell injury (decreased MTT uptake), and Fe independent increases in HO-1/IL-6 mRNA expression were observed. We conclude that Iso-induced AHF is a useful reversible model of CRS-1. Despite its largely hemodynamic ('pre-renal') nature, Fe-mediated oxidative stress and pro-inflammatory reactions are induced. These arise, at least in part, from direct Iso- induced tubular cell toxicity, rather than simply being secondary to Iso-mediated hemodynamic events. Finally, Iso-triggered renal cytokine production can potentially contribute to 'organ cross talk' and a systemic pro-inflammatory state.
Related Concept Videos
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:29Renal Regulation of Acid-Base Balance
In the kidneys, cells within the proximal convoluted tubules (PCT) and the collecting ducts secrete hydrogen ions (H+) into the tubular fluid. Specifically, in the PCT, Na+/H+ antiporters secrete H+ while reabsorbing Na+.
However, the intercalated cells in...
01:29Acute Kidney Injury II: Pathophysiology
01:29Heart Failure II: Pathophysiology
01:29Hypertension II: Pathophysiology
01:22Acute Kidney Injury I: Introduction