The Role of Megalin Expression in Diet-Induced Kidney Injury

Elynna Youm - Final Dissertation Defense - HUGEN PhD Candidate Department of Human Genetics Doctoral Candidate, Elynna Youm, will defend the following dissertation on “The Role of Megalin Expression in Diet-Induced Kidney Injury” COMMITTEE CHAIR: Ora A. Weisz, PhD Committee Members: Brenda Diergaarde, PhDF. Yesim Demirci, MDCary Boyd-Shiwarski, MD, PhD ABSTRACT: The kidney proximal tubule (PT) is responsible for maintaining protein-free urine through receptor-mediated endocytosis of proteins that escape the glomerular filtration barrier. Megalin, a multiligand receptor highly expressed on the PT apical membrane, is necessary for this process. Beyond its role in endocytosis, megalin also regulates PT transcription and metabolism. While crucial for maintaining baseline kidney function, megalin’s role in the progression of kidney disease is unclear. Our lab has previously shown that knocking out megalin (megKO) in opossum kidney (OK) PT cells leads to significant changes in transcription and metabolism that are not seen in knockout cells of its endocytic adaptor protein, Dab2. Of these changes, we observed a dramatic decrease in transcription of SLC5A2, which encodes sodium-glucose co-transporter 2 (SGLT2). SGLT2 is primarily expressed in the S1 segment of the PT and is responsible for the reabsorption of ~90% of filtered glucose. To investigate whether megKO would be protective against WD-induced hyperglycemia, we utilized a Cre-EMX recombinase megKO mouse model. Following WD, we found that both male and female megKO mice have increased glucose tolerance, as well as virtually no fat fain. Surprisingly, male megKO mice fed a WD also exhibited extensive kidney injury, while females did not. When aged to 14-16 months, we found that both female and male megKO mice die rapidly on WD (45% mortality within 2 weeks). Of the mice that survived, both male and female megKO mice both exhibited extensive kidney injury. Because a high-fat only diet