Title:
Megalin-targeted translational research on kidney diseases

 

Speaker:
Akihiko Saito, MD, PhD
Department of Applied Molecular Medicine, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences

 

Abstract:
Megalin is an endocytic receptor expressed at the apical membrane of proximal tubule epithelial cells (PTECs) (1). It mediates the reabsorption and metabolism of various glomerular-filtered substances such as proteins and drugs. In a high-fat diet-induced model of diabetic kidney disease (DKD), we found that megalin plays a critical role in the development of kidney injury (2). Hence, in diabetes, adequate suppression of megalin hyperfunction in PTECs may be a therapeutic option. Indeed, bardoxolone methyl, an Nrf2 activator, is known to suppress renal megalin expression, which may be related to the renoprotective action of this drug in DKD.
Megalin also mediates acute kidney injury by taking up nephrotoxic drugs, such as gentamicin, colistin, vancomycin, and cisplatin, into PTECs. We found that cilastatin, as a megalin antagonist, competes with these drugs to bind to megalin and suppresses experimental renal injury caused by these drugs (3). Megalin thus acts as a “gateway” for the entry of nephrotoxic substances into the kidney to cause both chronic kidney disease and acute kidney injury.
Moreover, we established sandwich enzyme-linked immunosorbent assays to measure the ectodomain (A-megalin) and full-length (C-megalin) forms of urinary megalin using specific monoclonal antibodies against the amino- and carboxyl-terminals of megalin, respectively (4). Urinary C-megalin excretion increases along with the development and progression of DKD. Protein metabolic load via megalin on residual nephrons is a mechanism underlying increased urinary C-megalin excretion, which is mediated by exocytosis (5). Urinary A-megalin excretion may be increased in association with accelerated megalin recycling and has distinct clinical relevance.
In conclusion, megalin is a promising target for the development of novel diagnostic and therapeutic strategies for kidney diseases.

 

References:
1.Saito A, Pietromonaco S, Loo AKC, Farquhar MG: Complete cloning and sequencing of rat gp330/”megalin,” a distinctive member of the low density lipoprotein receptor gene family. Proc Natl Acad Sci USA, 91: 9725-9729, 1994.
2.Kuwahara S, Hosojima M, Kaneko R, Aoki H, Nakano D, Sasagawa T, Kabasawa H, Kaseda R，Yasukawa R, Ishikawa T, Suzuki A, Sato H, Kageyama S, Tanaka T, Kitamura N, Narita I，Komatsu M, Nishiyama A, Saito A: Megalin-Mediated Tubuloglomerular Alterations in High-Fat Diet-Induced Kidney Disease. J Am Soc Nephrol, 27: 1996-2008, 2016.
3.Hori Y, Aoki N, Kuwahara S, Hosojima M, Kaseda R, Goto S, Iida T, De S, Kabasawa H, Kaneko R, Aoki H, Tanabe Y, Kagamu H, Narita I, Kikuchi T, Saito A: Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity. J Am Soc Nephrol, 28: 1783-1791, 2017.
4.Ogasawara S, Hosojima M, Kaseda R, Kabasawa H, Yamamoto-Kabasawa K, Kurosawa H, Sato H, Iino N, Takeda T, Suzuki Y, Narita I, Yamagata K, Tomino Y, Gejyo F, Hirayama Y, Sekine S, Saito A: Significance of urinary full-length and ectodomain forms of megalin in patients with type 2 diabetes. Diabetes Care, 35: 1112-1118, 2012.
5.De S, Kuwahara S, Hosojima M, Ishikawa T, Kaseda R, Sarkar P, Yoshioka Y, Kabasawa H, Iida T, Goto S, Toba K, Higuchi Y, Suzuki Y, Hara M, Kurosawa H, Narita I, Hirayama Y, Ochiya T, Saito A: Exocytosis-Mediated Urinary Full-Length Megalin Excretion Is Linked With the Pathogenesis of Diabetic Nephropathy. Diabetes, 66: 1391-1404, 2017.