Abstract Body: Nearly 60% of heart failure (HF) patients develop a progressive decline in kidney function. Decompensated HF also causes edema, usually treated with loop diuretics, like furosemide, that inhibit the Na-K-2Cl cotransporter NKCC2 in the thick ascending limb (TAL). However, nearly 50% of HF patients do not respond adequately to loop diuretics and become resistant. The mechanisms causing loop diuretic resistance are unclear but may involve TAL-dependent and independent mechanisms. Few have used the mouse as a model of cardiorenal syndrome due to its resistance to renal damage. We hypothesize that mice develop loop diuretic resistance and lower GFR after chronic HF induced by myocardial infarction (MI). MI was induced in C57Bl6J mice through ligation of the left anterior descending coronary artery and compared to a sham surgery group. We assessed heart function by echocardiography and GFR (FITC inulin) in conscious mice. The response to diuretics was studied in metabolic cages. MI mice had a 50% reduction in ejection fraction (EF) one month after MI (MI: 29.94 ± 1.94, Sham: 67.02 ± 1.14%, n= 8, p<0.05). EF was still lower 3 and 6 months after MI. The MI group showed decreased GFR, 6 months after MI (MI: 0.50 ± 0.06, Sham: 0.75±0.05 µl/min, n= 5, p<0.05). Urinary albumin was similar in both groups (n=8). In metabolic cages, a saturating dose of the NKCC2 inhibitor bumetanide (20 mg/Kg), induced diuresis and natriuresis in sham mice (Delta UV: 1.96 ± 0.27 ml/4h, Delta UNa: 117.2 ± 11.02µmols/4h, n= 6) but had an attenuated response in MI mice (Delta UV: 0.88 ± 0.23 ml/4h, Delta UNa: 65.00 ± 4.53 µmols/4h, n= 4, p<0.05 vs sham). To study the distal convoluted tubule (DCT) we measured the response to hydrochlorothiazide (HCTZ). HCTZ (100 mg/Kg) induced a natriuretic response in sham mice (Delta UNa: 75.24±11.18µmols/4h, n= 10) and a higher response in the MI group (Delta UNa: 129.54±11.59µmols/4h, n= 12, p<0.05 vs sham). RNAseq in isolated mTALs from MI and sham mice identified 85 up- and 160 down-regulated genes (n=5, p<0.025). Up-regulated genes involved those in the sphingosine pathway, protein trafficking, PKA signaling (PDE4B, PRKD2) and cell growth/tubule differentiation (FREM2, WFDC1). mRNA expression of TAL NaCl transporters was not affected. We conclude that HF decreases GFR, induces loop diuretic resistance and affects mTAL signaling in mice. Loop diuretic resistance may involve enhanced DCT NaCl reabsorption.