PFAS, Renal Hemodynamics, and Kidney Disease - Per- and polyfluoroalkyl substances (PFAS) are a large group of highly stable chemicals used in the production of water-, grease-, and stain-repellent properties. PFAS are recognized as persistent organic pollutants, detected in food and drinking sources, and can bioaccumulate in humans. Epidemiological data indicate that PFAS are associated with a variety of negative health effects including chronic kidney disease (CKD) and hypertension. Moreover, the deleterious effects of PFAS may be exacerbated in individuals already at risk for CKD and hypertension. Yet, the direct effects of PFAS on kidney function and disease remain poorly understood, especially in susceptible populations. The goals of this proposal are to investigate the direct effects of PFAS on renal hemodynamics and mechanisms of renal injury in rat strains (Sprague-Dawley (SD) and Dahl Salt-Sensitive (SS)) with large differences in susceptibility of developing CKD and hypertension. Our overarching hypothesis is that PFAS cause proximal tubule injury, renal vasoconstriction, hypertension, and ultimately ischemia-induced acute kidney injury (AKI), which is a major cause of CKD. As a corollary to our central hypothesis, we propose that the deleterious effects of PFAS will be exacerbated in Dahl SS rats, which are susceptible to developing CKD and hypertension. Aim 1 will test the hypothesis that PFAS cause renal vasoconstriction and AKI over time. The direct effects of PFAS on arterial blood pressure, renal blood flow, and glomerular filtration rate will be assessed in conscious, chronically instrumented rats. Serum and urine concentrations of PFAS will be measured by mass spectrometry to assess renal handling of PFAS and body burden levels. In addition to renal pathology, the off-target pathological effects of PFAS will be assessed in liver, heart, and spleen tissue. Aim 2 will test the hypothesis that pathogenic signaling and renal pathology will evolve over time during the transition from initial proximal tubule injury to the subsequent development of AKI. We will use an unbiased mass spectrometry/proteomics approach to identify PFAS-induced pathogenic signaling pathways associated with the initiation of proximal tubule injury, independent of changes in renal hemodynamics, and the subsequent development of ischemia-induced AKI. Renal hemodynamics, proximal tubule injury, renal pathology, and proteomics-based signaling pathways will be assessed at the same time points to assess relationships between pathophysiology, pathology, and molecular mechanisms. Preliminary data show that our experimental model is well-suited to address these questions and that the experiments are feasible. Our approach involves an investigative team with expertise in renal hemodynamics (Dr.'s Polichnowski and Griffin), AKI (Dr.'s Polichnowski and O'Connor), PFAS and proteomics (Ms. Grindstaff and Dr. Lau), and renal pathology (Dr. Youngberg), which will provide novel insights regarding the pathophysiologic and molecular mechanisms mediating PFAS-induced kidney disease and bioaccumulation.
