Megalin and transition from AKI to CKD
VA Merit Award BX002006 (funding extended through 2031): The prevalence of chronic kidney disease (CKD) in the US is increasing, linked with the aging population and conditions like hypertension and diabetes. As CKD progresses, it worsens cardiovascular outcomes, increases mortality, and may lead to end-stage kidney disease (ESKD). The progression from acute kidney injury (AKI) to CKD and the involved pathways are not well understood. Mitochondrial dysfunction is key to many diseases. We recent showed that megalin is a mitochondrial protein, interacting with stanniocalcin-1 (STC1) and SIRT3, consistent with its engagement in antioxidant defenses. Megalin is essential for glycolysis and mitochondrial respiration and serves as a shittle for hormones such as stanniocalcin-1, angiotensin II and TGF-β from the cell surface to the mitochondria. We demonstrate that tubular epithelium-specific knockout of megalin worsens AKI following ischemia/reperfusion, upregulates TGF-β signaling, inflammation and fibrosis, and accelerates the progression to CKD. On the other hand, tubular epithelium-specific overexpression of megalin protects from ischemic kidney injury. We are currently characterizing pathways of injury and/or protection in the settings of megalin deletion and/or overexpression, respectively.
Mesoamerican nephropathy (MeN)
Also known as chronic kidney disease of uncertain etiology (CKDu) or chronic interstitial nephritis in agricultural communities (CINAC), MeN is a devastating disease impacting agricultural communities worldwide. Our survey of migrants with end-stage renal disease (ESRD) identified an association between chronic or intermittent exposure to agrochemicals, especially paraquat, and the development of MeN-ESRD. We carried these observations to the bench; mice treated with sub-toxic doses of paraquat developed kidney failure similar to MeN, characterized by tubulointerstitial inflammation, increased organic cation transporter 2 (OCT2) and decreased multidrug and toxin extrusion protein 1 (MATE1) levels. These transporters move cationic substances such as paraquat and heavy metals through the proximal tubule (PT), where OCT2 serves as entry pathway from the blood to PTs, and MATE1 serves as an exit pathway from the cell to the urine. Similar OCT2 and MATE1 phenotype is observed in kidney biopsies of Nicaraguan MeN patients. Paraquat-treated kidney cells show an arrest in the clearance of damaged mitochondria and reduced activity of Transcription Factor EB (TFEB), the key regulator of mitophagy and lysosomal biogenesis. Our findings align with observations that CINAC is a toxic tubulopathy marked by dysmorphic lysosomes. Paraquat is an example of many compounds encountered in agricultural work that generate reactive oxygen species (ROS), potentially contributing to CKD. This is supported by high exposure levels to nickel, cadmium, lead, and arsenic in Mesoamerican and Sri Lankan agricultural communities. Thus, we established an animal model for the study of MeN/CKDu/CINAC, and identified potential therapeutic targets for the disease.
Comparative effectiveness of Asymptomatic vs. Symptomatic initiation of dialysis
PCORI grant submission titled “Comparative effectiveness of Asymptomatic vs. Symptomatic initiation of dialysis.” Chronic kidney disease (CKD), a major global public health problem, emerged as one of the leading causes of death, affecting over 800 million individuals worldwide, with significant burden to patients and their caregivers, and may lead to end-stage kidney disease (ESKD). The decision on optimal initiation of chronic dialysis is a common problem faced by nephrologists, patients, and caregivers. Determining the ideal time to initiate maintenance dialysis for individuals struggling with ESKD has remained a puzzle. Currently, there is no consensus among guidelines as to the best time to initiate dialysis, and discrepancies in guidelines stem from lack of adequate data. This project examines QOL, morbidity and mortality in ESRD patients initiated on dialysis at eGFR of 12 mL/min (without symptoms), or upon developing symptoms (not medically manageable) at any eGFR below 12 mL/min.
Ongoing funded projects
VA Merit Award BX002006
Oct. 1, 2023 - Sept. 30, 2017 (with extension through 2031)
Title: Megalin, and transition from AKI to CKD
Role: PI
Pending Project
PCORI
July 1, 2026 - June 30, 2031
Title: Comparative effectiveness of Asymptomatic vs. Symptomatic initiation of dialysis.
Role: MPI