Abstract Our long-term objective is to fill the unmet need for treatments for chronic kidney disease (CKD). Caveolin-1 is a promising therapeutic target in fibrotic diseases. The profibrotic effects of caveolin-1 deficiency in cells and in mouse models is suppressed by a peptide equivalent to its active site (caveolin-1 scaffolding domain, CSD). We demonstrated the beneficial effects of CSD using model systems for lung, skin, heart, and kidney fibrosis. CSD almost completely suppressed the dramatic increases in fibrosis, vascular leakage, and inflammatory cell infiltration and the deficits in organ function occuring in these models. Similar aging-associated pathological changes also occur in the heart and kidneys of otherwise untreated 18-month-old mice and were reversed by CSD. Thus, CSD reverses pathological changes even when they are established prior to treatment initiation. However, CSD lacks key pharmacologic properties for drug development. Therefore, we undertook a rational series of steps (devising CSD fragments, making the fragments water soluble, comparing fragment efficacy) to select a Lead Compound (W94-101). These studies were performed by s.c. delivery; however, we recently determined that oral delivery can be just as beneficial. Our Lead Compound selection and demonstration of oral efficacy puts us in a strong position to successfully perform these logical next steps in developing our Lead Compound as a CKD treatment. 1) Determine the Therapeutic Index of the Lead Compound (toxic dose to therapeutic dose ratio). We will determine the dose-dependence of the beneficial effects of daily oral delivery of the Lead Compound in angiotensin II (AngII)-induced kidney disease and the dose-dependence of the toxicity (if any) associated with treating healthy mice with Lead Compound daily at high doses. Success will be defined as a Therapeutic Index >25. Readouts in the beneficial effect studies both in Aims 1 & 2 will be kidney function (albuminuria, BUN, creatinine, glomerular filtration rate), fibrosis/tissue morphology (analyzed by Western blot and IHC), and vascular leakage. 2) Further Validate the Lead Compound: Second Model System, Scrambled Lead Compound, Comparison to Drug Used to Treat Kidney Fibrosis, Less Frequent Dosing, Therapeutic Protocol. Two mouse model systems will be used: AngII Infusion and unilateral ureteral obstruction (UUO) surgery. These models are complementary because in the AngII model glomeruli are most affected, while in the UUO model the tubulo-interstitium is most affected. In each model we will compare daily oral administration of the Lead Compound with daily oral administration of scrambled Lead; daily oral administration of the drug finerenone; and less frequent Lead Compound administration. We will also determine whether the Lead Compound is efficacious when its administration is initiated only after AngII-induced disease is already well- established (Therapeutic Protocol). We will consider these studies to...