Functional megalin is expressed in renal cysts in a mouse model of adult polycystic kidney disease

Marlene L. Nielsen, Mia C. Mundt, Dorte L. Lildballe, Maria Rasmussen, Lone Sunde, Vicente E. Torres, Peter C. Harris, Henrik Birn

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of cysts and a decline of renal function. The clinical feasibility of the number of potential disease-modifying drugs is limited by systemic adverse effects. We hypothesize that megalin, a multiligand endocytic receptor expressed in the proximal tubule, may be used to facilitate drug uptake into cysts, thereby allowing for greater efficacy and fewer side effects. Methods: The cyst expression of various tubular markers, including megalin and aquaporin 2 (AQP2), was analysed by immunohistochemistry (IHC) of kidney sections from the ADPKD mouse model (PKD1RC/RC) at different post-natal ages. The endocytic function of megalin in cysts was examined by IHC of kidney tissue from mice injected with the megalin ligand aprotinin. Results: Cyst lining epithelial cells expressing megalin were observed at all ages; however, the proportion decreased with age. Concomitantly, an increasing proportion of cysts revealed expression of AQP2, partial expression of megalin and/or AQP2 or no expression of the examined markers. Endocytic uptake of aprotinin was evident in megalin-positive cysts, but only in those that remained connected to the renal tubular system. Conclusions: Megalin-expressing cysts were observed at all ages, but the proportion decreased with age, possibly due to a switch in tubular origin, a merging of cysts of different tubular origin and/or a change in the expression pattern of cyst lining cells. Megalin expressed in cysts was functional, suggesting that megalin-mediated endocytosis is a potential mechanism for drug targeting in ADPKD if initiated early in the disease.

Original languageEnglish (US)
Pages (from-to)2420-2427
Number of pages8
JournalClinical Kidney Journal
Volume14
Issue number11
DOIs
StatePublished - Nov 1 2021

Keywords

  • ADPKD
  • cystogenesis
  • immunohistochemistry
  • proximal tubule
  • targeted treatment

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

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