Pnpla3^I148MMutation Causes Cardiovascular and Renal Disease in Mice

Polymorphism in the patatin-like phospholipid domain-containing protein 3 ( Pnpla3 ) is linked to metabolic dysfunction-associated steatotic liver disease (MASLD). In the US, >30% of MASLD patients have the most common type of Pnpla3 polymorphism in which methionine is substituted for isoleucine at the 148 region ( Pnpla3 I148M ). Also, in MASLD patients, cardiovascular disease (CVD) is the leading cause of death. Since Pnpla3 is mainly expressed in the liver and kidney, clinical studies have shown that Pnpla3 I148M polymorphism increases the incidence of chronic kidney disease (CKD) independent of MASLD or any other co-morbidities. Thus the goal of our study was to determine the effect of Pnpla3 I148M polymorphism in mice on renal and cardiovascular function using an endogenous Pnpla3 I148M knock-in mouse model. Male (M) and female (F) Pnpla3 I148M and C57BL6/J (control) mice at 16 weeks of age were either switched to a high sucrose diet (HSD) or left on a normal sucrose diet (NSD) for 8 extra weeks (n=6-11/group). Glomerular filtration rate (GFR) studies were performed at week 6 of diet using transdermal GFR probe and echocardiography at week 8 using Vevo Sonics imaging system. Pnpla3 I148M polymorphism increased liver triglyceride in HSD-fed (M: 0.3±0.0 vs 0.5±0.2 mM, F: 0.4±0.0 vs 0.5±0.0 mM p<0.05) but not in NSD-fed mice (M: 0.2±0.0 vs 0.2±0.0 mM, F: 0.2±0.0 vs 0.3±0.0 mM). Pnpla3 I148M polymorphism also 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) and end-systolic diameter (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). Ejection fraction was decreased in Pnpla3 I148M mice (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) along with fractional shortening (M NSD: 26.2±1.7 vs 16.3±1.3 %, M HSD: 20.3±0.9 vs 14.7±1.4 % p<0.05); (F NSD: 28.9±2.5 vs 19.5±1.8 %, F HSD: 23.7±1.9 vs 18.2±1.7 % p<0.05). A high sucrose diet caused further alterations in cardiovascular morphology and function in Pnpla3 I148M mice, namely end-diastolic volume, end-diastolic diameter, cardiac output, left carotid and abdominal aorta resistive index. Assessment of renal function and injury showed that NSD-fed and female HSD-fed Pnpla3 I148M mice exhibit 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). Yet, both male and female HSD-fed Pnpla3 I148M mice had increased albumin to creatinine ratio (M NSD: 0.2±0.0 vs 0.2±0.0 %, M HSD: 0.3±0.1 vs 0.6±0.1 p<0.05); (F NSD: 0.2±0.0 vs 0.2±0.0 %, F HSD: 0.3±0.0 vs 0.5±0.1 p<0.05). These findings show that Pnpla3 I148M polymorphism can lead to renal and cardiac dysfunction, which exacerbate on a high sucrose diet, and that understanding the mechanism of dysfunction can provide novel targets for MASLD, CVD in MASLD and CKD patients with Pnpla3 I148M polymorphism. Ongoing studies will investigate the mechanism of hyperfiltration and its effect on blood pressure regulation in Pnpla3 I148M mice. This work was supported by the NIDDK 1R01DK121748-01A1 (DES) and the NIGMS P20GM104357-02 P30GM149404 and P20GM144041 awards This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.