Heat Shock Protein 72 is a Druggable Target During Cold Storage to Improve Graft Outcome After Kidney Transplantation

Prolonged cold storage (CS) of donor kidneys results in poor outcomes after transplantation. We reported earlier that cold storage (CS) of rat kidneys for 18 hours (h) followed by transplantation (CS+Tx) reduces proteasome function, disrupts protein homeostasis, and compromises graft function. The goal of the present study was to define the contribution of specific heat shock proteins (Hsp) to CS-induced disruption of renal graft function and determine the benefit conferred by their pharmacological inhibition. We subjected kidneys isolated from donor Lewis rats to 18-h CS with or without pharmacological inhibition of heat-shock protein 72 (Hsp72), a stress-inducible member of the Hsp70 family. Subsequently, the donor kidneys were transplanted into Lewis rats (CS+Tx). Hsp72 was upregulated in kidney grafts after CS+Tx and this finding was coupled to a reciprocal loss of cognate Hsc70 and profound tubular injury. Knockdown of Hsc70 in renal cells increased Hsp72, compromised proteasome function, and increased mitochondrial oxidative stress. The addition of HS-72, a Hsp72-specific inhibitor, to the CS solution restored proteasome function and improved renal injury/function after transplantation. Our study shows that CS+Tx dysregulates heat shock proteins in the kidney and targeting a single disrupted protein, Hsp72, can improve graft function.