The patatin-like phospholipase domain-containing protein 3 (Pnpla3) I148M polymorphism is an established genetic determinant of metabolic dysfunction-associated steatotic liver disease (MASLD). New evidence shows that Pnpla3(I148M) is also associated with an increased risk for chronic kidney disease (CKD) development independent of diseases like diabetes and MASLD, through an unknown mechanism. We hypothesized that Pnpla3(I148M) directly contributes to renal dysfunction and alterations in its physiology as a prelude to CKD. Hence, we assessed the effect of Pnpla3(I148M) on kidney function and disease using endogenous Pnpla3(I148M) knock-in mice. Male and female, 16-week-old Pnpla3(I148M) and C57BL/6 (CTL) mice were kept on a standard chow diet till 24 weeks of age (n=10-16 mice/group). Glomerular filtration rate (GFR) was measured by FITC-Sinistrin clearance at 22 weeks and plasma cystatin C at 24 weeks of age. Mice were placed in metabolic cages at 23 weeks for urine collection and assessment. At 24 weeks, blood pressure was measured by fluid-filled catheters. Kidney cortex was harvested for kinome profiling to assess signaling pathways. A second cohort of Pnpla3(I148M) and CTL mice was kept on chow diet for long-term GFR studies (n=4-12 mice/group), which was assessed at 20, 30, and 40 weeks of age. Urine and plasma were also collected at each time point. Kinome data were analyzed using Bionavigator (PamGene). A -Log10 (1.3) or above on protein activity fold change was considered statistically significant. All other data were analyzed with GraphPad Prism using two-way ANOVA combined with Tukey’s post-test. P values < 0.05 was considered statistically significant. Pnpla3(I148M) mice showed increased GFR at 22 weeks of age (M: 817±40 vs 1145±66, F: 1281±103 vs 1722±225 µl/min/100gBW, p< 0.05). This was recapitulated by plasma cystatin C, which was decreased (M: 0.51±0.02 vs 0.42±0.02, F: 0.42±0.03 vs 0.35±0.02 µg/ml, p< 0.05). At 24 weeks, Pnpla3(I148M) mice were hypertensive (M: 103.1±1.6 vs 124±1.7, F: 96.8±2.1 vs 104.8 ±1.8 mmHg, p< 0.05) but did not show any sign of albuminuria (M: 0.010±0.001 vs 0.01±0.001, F: 0.008±0.001 vs 0.010±0.001 µg/µg). In the second cohort of mice, GFR was elevated in Pnpla3(I148M) mice at 20 weeks (M: 1002±65 vs 1247±71, F: 878±106 vs 1292±163 µl/min/100gBW, p< 0.05) but dropped significantly by week 30 (M: 1027±73 vs 1016±74, F: 1094±115 vs 1032±156 µl/min/100gBW, p< 0.05). At week 40, GFR had further declined in Pnpla3(I148M) mice from week 30 and was also decreased in comparison to CTL mice (M: 1041±29 vs 859±60, F: 998±141 vs 742±47 µl/min/100gBW, p< 0.05). Albuminuria was elevated at week 30 (M: 0.009±0.001 vs 0.013±0.001, F: 0.008±0.001 vs 0.012±0.000 µg/µg, p< 0.05) and week 40 (M: 0.009±0.001 vs 0.011±0.001, F: 0.007±0.001 vs 0.010±0.001 µg/µg, p< 0.05). Renal kinome analysis showed sex-dependent alterations in the AKT/GSK3β pathway. While males showed inactivation of AKT and consequent activation of GSK3β, females showed activation of AKT. Our findings identify Pnpla3(I148M) as a systemic modifier of cardio-renal physiology, with sex-dependent signaling responses that precede and predict CKD development. Targeting Pnpla3 in the kidney or its downstream pathway could be an effective strategy to prevent CKD incidence and progression in patients with Pnpla3(I148M) polymorphsim, especially those with MASLD. This abstract was presented at the American Physiology Summit 2026 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.
Arthur et al. (Fri,) studied this question.