The Human PNPLA3^I148M Polymorphism Alters the Renal Kinome and Transporters to Cause Hyperfiltration and Hypertension

The patatin-like phospholipase domain-containing protein 3 (Pnpla3) I148M polymorphism is a well-established genetic determinant of metabolic dysfunction-associated steatotic liver disease (MASLD), and emerging evidence links it to chronic kidney disease (CKD) and cardiovascular disease (CVD). However, the mechanisms underlying this relationship remain unclear. The goal of this study was to investigate the role of the Pnpla3^I148M polymorphism on kidney function, blood pressure, and cardiac function in a mouse model carrying the identical human polymorphism. Male and female Pnpla3^I148M knock-in and control C57BL/6 mice were fed either a normal sucrose diet (NSD) or a high sucrose diet (HSD) for 8 weeks. Glomerular filtration rate (GFR), blood pressure, cardiac, and vascular function were measured in each group. Renal cortical protein expression and kinome profiles were analyzed to identify pathways associated with hyperfiltration and renal injury. Pnpla3^I148M mice exhibited increased renal sodium transporter levels and hyperfiltration, which was compounded by albuminuria in HSD mice. Pnpla3^I148M mice were also hypertensive and exhibited impaired systolic function, consistent with pressure-overload-induced cardiac remodeling. Renal kinome profiling revealed sex- and diet-dependent alterations in serine/threonine kinases, primarily involving isoforms of protein kinase C (PKC), protein kinase A (PKA), cGMP-dependent protein kinase (PRKG), and calcium/calmodulin-dependent protein kinase (CaMK). Our findings suggest that Pnpla3^I148M acts as a systemic cardio-renal risk allele that links metabolic dysregulation to progressive end-organ damage via renal kinase remodeling in a sex- and diet-dependent manner.