Renal Dysfunction Exacerbates Ischemic Muscle Injury in Mice Subjected to Hindlimb Ischemia

Abstract

Patients with critical limb ischemia (CLI) have multiple concomitant comorbidities which are associated with poorer overall health outcomes. CLI patients with impaired kidney function and/or diabetes are at greater risk for limb amputation and death. While the negative impacts of renal dysfunction and diabetes on CLI outcomes are known clinically, the underlying biologic mechanism(s) responsible are poorly understood. Thus, we sought to evaluate the impact of impaired renal function and diabetes on the skeletal muscle pathology in mice following unilateral hindlimb ischemia (HLI). Renal dysfunction (RD) was induced by dietary administration of adenine which causes renal tubular injury, while diabetes was induced by streptozocin injection. HLI was induced by ligation and excision of the femoral artery, while the contralateral hindlimb was utilized as a control (no surgery). Three groups (n = 15; 5 per group) of C57BL/6J mice were analyzed: control, RD, and RD+ diabetes. Skeletal muscle ischemic injury was assessed using histological measurements of myofiber centralized nuclei, myofiber cross‐sectional area, ischemic lesion areas, and vascular density. High‐resolution O2 consumption was used to examine mitochondrial function in permeablized myofibers. Mice with RD, regardless of diabetes, exhibited greater ischemic lesions within the tibialis anterior muscle (Con = 2.53 ± 0.51% vs. RD = 60.554 ± 24.15% vs. RD+STZ = 79.99 ± 19.99%; P < 0.0001) despite similar capillary density (Con = 466.36 ± 44.98 vs. RD = 455.20 ± 79.55 vs. RD+STZ = 578.20 ± 87.16 capillaries/field; P = 0.9011). Mice with RD exhibited a ~45% decrease in mitochondrial respiratory capacity across numerous substrates, whereas control mice had normal respiration in the ischemic limb muscle seven days post‐HLI. These observations demonstrate that impaired kidney function exacerbates ischemic muscle injury in mice. Future studies are needed to uncover the molecular mechanisms by which RD negatively impacts skeletal muscle.Support or Funding InformationSupported by AHA Grant 18CDA34110044 to TER.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.