In patients with
rhabdomyolysis, the overwhelming release of
myoglobin into the circulation is the primary cause of kidney injury.
Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and
acute kidney injury (AKI). The mechanisms that underlie
rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Studies have shown that
myoglobin stimulates
endothelin-1 (ET-1) production in glomerular mesangial cells. Circulating ET-1 is also increased in rats subjected to
glycerol-induced
rhabdomyolysis. However, the upstream mechanisms of ET-1 production and downstream effectors of ET-1 actions in
rhabdomyolysis-induced AKI remain unclear. Vasoactive ET-1 is generated by ET converting
enzyme 1 (ECE-1)-induced proteolytic processing of inactive big ET to biologically active
peptides. The downstream
ion channel effectors of ET-1-induced vasoregulation include the
transient receptor potential cation channel, subfamily C member 3 (TRPC3). This study demonstrates that
glycerol-induced
rhabdomyolysis in Wistar rats promotes ECE-1-dependent ET-1 production, RVR increase, GFR decrease, and AKI.
Rhabdomyolysis-induced increases in RVR and AKI in the rats were attenuated by post-injury pharmacological inhibition of ECE-1, ET receptors, and TRPC3 channels. CRISPR/Cas9-mediated knockout of TRPC3 channels attenuated ET-1-induced renal vascular reactivity and
rhabdomyolysis-induced AKI. These findings suggest that ECE-1-driven ET-1 production and downstream activation of TRPC3-dependent renal vasoconstriction contribute to
rhabdomyolysis-induced AKI. Hence, post-injury inhibition of ET-1-mediated renal vasoregulation may provide therapeutic targets for
rhabdomyolysis-induced AKI.