Pnpla3 Polymorphism Causes Renal and Cardiac Dysfunction in Mice

Background: Pnpla3 (patatin-like phospholipid domain-containing protein 3) polymorphism, caused by methionine substitution for isoleucine at the 148 region (Pnpla3I148M) is linked to metabolic dysfunction-associated steatotic liver disease (MASLD). About 1/3 of the US population has Pnpla3I148M, while MASLD prevalence is 40%. Clinical studies also show that MASLD is associated with the development of heart and kidney disease; yet the mechanisms linking these diseases are unknown. The goal of this study was to determine the effect of Pnpla3I148M on renal and cardiac function using an endogenous Pnpla3I148M knock-in mouse model. Methods: 16 weeks male (M) and female (F) Pnpla3I148M mice and C57BL/6J (control) mice were either placed on a high sucrose diet (HSD) or kept on a normal sucrose diet (NSD) for 8 weeks (n=11- 13/group). GFR and echocardiography were measured at week 7 & 8, respectively, and blood pressure at week 8. Results: Pnpla3I148M mice showed several indices of altered cardiac function including: increased end-systolic volume (M NSD: 34.1±4.2 vs 51.0±5.5 µl, M HSD: 18.8±2.3 vs 41.9±2.8 µl p<0.05); (F NSD: 16.9±2.3 vs 31.6±4.3 µl, F HSD: 13.8±1.8 vs 27.7±3.1 µl p<0.05), left ventricular internal dimension at systole (M NSD: 2.9±0.1 vs 3.6±0.1 mm, M HSD: 2.3±0.1 vs 3.4±0.1 mm p<0.05); (F NSD: 2.1±0.2 vs 2.9±0.2 mm, F HSD: 1.8±0.2 vs 2.9±0.1 mm p<0.05), and decreased ejection fraction (M NSD: 51.2±2.7 vs 40.3±1.9 %, M HSD: 53.3±2.2 vs 36.3±1.4 % p<0.05); (F NSD: 59.1±3.7 vs 45.6±3.5 %, F HSD: 55.2±2.5 vs 43.5±2.9 % p<0.05). Pnpla3I148M mice exhibited hypertension (M NSD: 103.1±1.6 vs 124.1±1.7 µl, M HSD: 104.4±0.9 vs 117.3±2.5 µl p<0.05) (F HSD: 96.8±1.6 vs 106.4±1.8 % p<0.05). Pnpla3I148M mice exhibited renal hyperfiltration (M NSD: 919.6±32.5 vs 1281.9±49.2 µl/min/100gBW, M HSD: 931.2±80.8 vs 918±53.2 µl/min/100gBW p<0.05); (F NSD: 955.4±83.0 vs 1852.8±179.2 µl/min/100gBW, F HSD: 1033.7±74.6 vs 1583.0±139.1 µl/min/100gBW p<0.05). HSD-fed Pnpla3I148M mice also had increased albumin to creatinine ratio (M HSD: 0.3±0.1 vs 0.6±0.1 p<0.05; F HSD: 0.3±0.0 vs 0.5±0.1 p<0.05), indicative of renal injury. Conclusion: These findings demonstrate that Pnpla3I148M polymorphism leads to renal and cardiac dysfunction, which is exacerbated by high sucrose intake. This model can be used to determine the mechanisms by which the Pnpla3I148M polymorphism contributes to heart and kidney disease. Funding: NIDDK Support - NIDDK Support, NIDDK Support