Postinjury Inhibition of Endothelin-1 Dependent Renal Vasoregulation Mitigates Rhabdomyolysis-Induced Acute Kidney Injury.

Rhabdomyolysis is a life-threatening condition resulting from the breakdown of skeletal muscle fibers leading to the release of myoglobin into the blood. Increased circulating myoglobin can cause kidney damage, and acute kidney injury (AKI) occurs in 33-50% of patients with myoglobinuria. Persistent constriction of the renal microvessels, which reduces renal blood flow (RBF) and glomerular filtration rate (GFR), contributes to rhabdomyolysis-induced AKI. Since activation of G-protein-coupled receptors (GPCR) and ion channels regulate renal vascular resistance (RVR), rhabdomyolysis may likely modulate RVR via GPCR and vascular ion channel mechanisms. Pretreatment of rats with an endothelin receptor antagonist has been shown to alleviate rhabdomyolysis-induced AKI. However, the downstream and upstream links between rhabdomyolysis and increased ET-1 synthesis are unknown. The downstream effectors of ET-1-induced vasoconstriction are smooth muscle cell (SMC) Ca -permeable ion channels. Yet, the ion channel mechanisms that trigger renal vasoconstriction in rhabdomyolysis-induced AKI remain unknown. Also, most cases of rhabdomyolysis-induced AKI cannot be predicted. Whether post-injury inhibition of the vascular mechanisms of ET-1 ameliorates, rhabdomyolysis-induced AKI is unknown. This study investigates post-injury renal production and vascular regulation of the ET system in rhabdomyolysis-induced AKI. Six h of rhabdomyolysis increased peptidase endothelin converting enzyme (ECE-1)-dependent biosynthesis of ET-1 in the kidneys. Rhabdomyolysis-induced AKI was not sex-dependent. At 24 h, rhabdomyolysis also increased renal reactive oxygen species (ROS), ECE-1, and ET-1 levels. Furthermore, ET-1 activated rat renal vascular smooth muscle cell TRPC3 leading to a reduction in RBF and increased RVR. Protein expression levels of the ET receptors (ETA and ETB) and TRPC3 channels in renal microvessels were unaltered. However, postinjury inhibition of ECE1, ET Receptors, and TRPC3 mitigated rhabdomyolysis-induced GFR impairment, renal hypoperfusion, AKI biomarker elevation, and morphological kidney damage. To further explore the role of TRPC3 ion channels in rhabdomyolysis-induced AKI, we subjected TRPC3 knock-out (KO) rats to rhabdomyolysis. Compared to their wild-type counterparts, KO rats show protection against rhabdomyolysis-induced AKI. Our findings suggest that ECE-driven proteolytic ET-1 production contributes to rhabdomyolysis-induced AKI. Downstream, ET-derived DAG activates renal vascular smooth muscle cell TRPC3 channels leading to extracellular calcium entry, vasoconstriction, increased RVR, and reduced GFR.