Project Grant R01DK138101

TARGETING TUBULAR MITOCHONDRIAL SUPEROXIDE DISMUTATION IN CISPLATIN RENAL REPAIR - SUMMARY TREATMENT WITH THE CHEMOTHERAPY DRUG, CISPLATIN, FREQUENTLY RESULTS IN DEVELOPING AND/OR PROGRESSING CHRONIC KIDNEY DISEASE (CKD). CISPLATIN ACCUMULATES IN RENAL PROXIMAL TUBULAR CELLS, WHICH REABSORB NUTRIENTS AND METABOLIZE CISPLATIN TO REACTIVE THIOLS THAT CAUSE OXIDATIVE DAMAGE. INJURED TUBULAR CELLS THAT FAIL TO REPAIR ARE KNOWN DRIVERS OF PROGRESSIVELY DECLINING KIDNEY FUNCTION AND SHOW IMPAIRED MITOCHONDRIAL OXIDATIVE METABOLISM. WE HAVE SUPPORTIVE EVIDENCE DEMONSTRATING THAT GC4419, A MITOCHONDRIALLY TARGETED SUPEROXIDE (O2-) DISMUTASE (SOD) MIMETIC, PROTECTS THE KIDNEY AGAINST OXIDATIVE STRESS AND CISPLATIN-INDUCED CKD IN MICE AND HUMANS. GC4419 ALSO REVERSES ELECTRON TRANSPORT CHAIN (ETC) DISRUPTIONS AND IMPROVES MITOCHONDRIAL OXIDATIVE METABOLISM. BUILDING ON RECENT BREAKTHROUGHS FROM OUR GROUP, WE WILL TEST THE HYPOTHESIS THAT INCREASING MITOCHONDRIAL O2- DISMUTATION IN RENAL TUBULAR CELLS WILL REDUCE CISPLATIN-INDUCED RENAL INJURY AND PROMOTE RENAL REPAIR BY REVERSING MITOCHONDRIAL ETC DISRUPTIONS AND INCREASING NADPH REGENERATION BY THE PENTOSE PHOSPHATE PATHWAY. IN AIM 1, WE WILL DETERMINE HOW TUBULAR MITOCHONDRIAL O2- MEDIATED INTERACTIONS WITH ETC COMPLEX II DISRUPT MITOCHONDRIAL ETC FUNCTION IN CISPLATIN-INDUCED CKD. IN AIM 2, WE WILL ESTABLISH HOW O2- DISMUTATION IMPACTS RENAL NADPH METABOLISM IN CISPLATIN-INDUCED REPAIR. IN AIM 3, WE WILL DETERMINE RENAL BIOMARKERS THAT PREDICT THE BENEFICIAL EFFECTS OF GC4419 IN VIVO. THE OVERALL OBJECTIVE OF THIS PROPOSAL IS TO INCREASE OUR UNDERSTANDING OF HOW TUBULAR O2- DISMUTATION PROTECTS FROM CISPLATIN-INDUCED CKD AND TO DEVELOP TRANSLATIONAL TOOLS THAT WILL FACILITATE RISK STRATIFICATION STRATEGIES FOR FUTURE SOD-MIMETIC CLINICAL TRIAL DESIGN IN PATIENTS FIGHTING CANCER WITH CISPLATIN. TO THAT END, WE WILL INCORPORATE THE FOLLOWING INNOVATIVE METHODS USING 1) NEWLY DEVELOPED MOUSE MODEL TO DELETE MITOCHONDRIAL SOD IN TUBULAR CELLS FOR PRE-CLINICAL STUDIES, 2) NOVEL EXPERIMENTAL DESIGN TO INTERROGATE THE LINK BETWEEN RENAL METABOLOMIC ADAPTATIONS, OXIDANT FORMATION, AND ANTIOXIDANT RESPONSES IN CISPLATIN-INDUCED CKD MOUSE MODELS; 3) THE MITOCHONDRIALLY TARGETED SOD MIMETIC (GC4419) CURRENTLY PENDING APPROVAL BY THE US FDA IN PATIENTS UNDERGOING CISPLATIN TREATMENT, AND 4) EVALUATING TUBULOINTERSTITIAL INJURY BIOMARKERS TO FACILITATE RISK STRATIFICATION STRATEGIES FOR FUTURE CLINICAL TRIAL DESIGN. IF SUCCESSFUL, THIS PROPOSAL WILL TRANSLATE INTO NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES TO PROMOTE RENAL REPAIR IN CISPLATIN-INDUCED KIDNEY TOXICITY.