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

Abstract

Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of cysts and decline of renal function. The clinical feasibility of a number of potential disease-modifying drugs is limited by systemic, adverse effects. We hypothesize that megalin, a multi-ligand 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 analyzed by immunohistochemistry (IHC) of kidney sections from the ADPKD mouse model (PKD1RC/RC) at different postnatal 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 a partial expression of megalin, expression of AQP2 or no expression of 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.

Inhibiting centrosome clustering reduces cystogenesis and improves kidney function in autosomal dominant polycystic kidney disease

“…Quantification of centrosome number in 5-month-old Pkd1 RC/RC mice showed that between 5% and 15% of cystic epithelial cells contained excess centrosomes (Figure 2D and Supplemental Figure 1C; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.172047DS1), consistent with what we observed in human ADPKD samples. Overall, this mouse model effectively mimics the pathophysiological features of slow-onset progressive cystogenesis of human ADPKD, provides a large window of time to study the disease progression, and has been used extensively for preclinical testing of potential therapeutic compounds (26,43,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58).…”

Emerging roles of proximal tubular endocytosis in renal fibrosis

“…Endocytosis was further characterized as one of the shared gene pathways in ADPKD by the intra-species combined analysis ( Chatterjee et al, 2017 ). Endocytic uptake was evident in megalin-positive cysts but only in those that remained connected to the renal tubular system ( Nielsen et al, 2021 ). Altogether, many factors contributed to ADPKD induced renal fibrosis, and endocytic impairment occurred in ADPKD, leading to proteinuria, which may further partially orchestrate the development of renal fibrosis in ADPKD disease.…”