DHHC21 deficiency attenuates renal dysfunction during septic injury

Area of Science:

• Biomedical Science
• Renal Physiology
• Molecular Biology

Background:

• Sepsis frequently causes kidney dysfunction, often linked to renal vascular issues.
• Protein palmitoylation is a key regulator of vascular function.
• The role of palmitoyl acyltransferase (PAT)-DHHC21 in sepsis-induced renal dysfunction is unclear.

Purpose of the Study:

• To investigate if PAT-DHHC21 contributes to septic injury-induced renal dysfunction by affecting renal hemodynamics.
• To explore the mechanism by which DHHC21 influences renal vascular function during sepsis.

Main Methods:

• Cecal ligation and puncture (CLP) model of septic injury in wild-type and DHHC21-deficient mice.
• Multispectral optoacoustic imaging to assess renal excretion and perfusion.
• Histological analysis of renal pathology and measurement of circulating injury markers.
• Western blotting to detect protein palmitoylation and ERK activation.
• In vitro vasoreactivity studies on isolated renal arteries and human kidney arteries.

Main Results:

• CLP-induced septic injury impaired renal excretion, which was improved in DHHC21-deficient mice.
• DHHC21 deficiency attenuated renal pathology, preserved renal perfusion, and improved oxygen saturation post-CLP.
• CLP increased vascular α1-adrenergic receptor (α1AR) palmitoylation and ERK activation, effects blunted in DHHC21-deficient mice.
• Renal arteries from DHHC21-deficient mice showed reduced constriction to phenylephrine.
• Inhibition of PATs reduced vasoconstriction response to phenylephrine in human kidney arteries.

Conclusions:

• DHHC21 plays a significant role in sepsis-induced renal dysfunction.
• DHHC21 promotes renal vasoconstriction during sepsis by enhancing α1AR palmitoylation.
• Targeting DHHC21 may offer a therapeutic strategy to preserve renal function during septic injury.