Using Drosophila Nephrocytes to Understand the Formation and Maintenance of the Podocyte Slit Diaphragm

Abstract

The podocyte slit diaphragm (SD) is an essential component of the glomerular filtration barrier and its disruption is a common cause of proteinuria and many types of kidney disease. Therefore, better understanding of the pathways and proteins that play key roles in SD formation and maintenance has been of great interest. Podocyte and SD biology have been mainly studied using mouse and other vertebrate models. However, vertebrates are limited by inherent properties and technically challenging in vivo access to the podocytes. Drosophila is a relatively new alternative model system but it has already made great strides. Past the initial obvious differences, mammalian podocytes and fly nephrocytes are remarkably similar at the genetic, molecular and functional levels. This review discusses SD formation and maintenance, and their dependence on cell polarity, the cytoskeleton, and endo- and exocytosis, as learned from studies in fly nephrocytes and mammalian podocytes. In addition, it reflects on the remaining gaps in our knowledge, the physiological implications for glomerular diseases and how we can leverage the advantages Drosophila has to offer to further our understanding.

JAK-STAT pathway activation compromises nephrocyte function in aDrosophilahigh-fat diet model of chronic kidney disease

“…Thus, given the HFD-induced dysfunctional uptake, we next tested whether the SD is affected by HFD. Therefore we looked at the distribution of polychaetoid (Pyd), the fly homolog of human tight junction protein 1 (TJP1, alias ZO-1) and a key component of the SD filtration unit (van de Leemput et al, 2022). Immunostaining with anti-Pyd antibody showed predominant membrane localization of Pyd in nephrocytes from NFD fed flies.…”

“…Nephrocytes share many characteristics with human podocytes, including genetics, molecular pathways, and function (Weavers et al, 2009; Zhang et al, 2013b, 2013a). Both cell types contain highly specialized filtration structures know as slit diaphragms that act in concert with the basement membrane; the fly lacuna channel is similar to the urinary space in the mammalian Bowman’s capsule; and, many key proteins for podocyte function are likewise essential for nephrocyte function (van de Leemput et al, 2022; Wang et al, 2021; Weavers et al, 2009; Zhuang et al, 2009). Indeed, fly in vivo nephrocyte models have been successfully used to study a variety of human kidney diseases, including forms of monogenic nephrotic syndrome and steroid-resistant nephrotic syndrome (SRNS) (Ashraf et al, 2013; Bierzynska et al, 2022; Fu et al, 2017; Gee et al, 2015, 2013; Gonçalves et al, 2018; Hermle et al, 2018, 2017; Milosavljevic et al, 2022; Odenthal et al, 2023; Paul et al, 2023; Zhao et al, 2019; Zhu et al, 2017).…”

Promoting mitochondrial dynamics by inhibiting the PINK1–PRKN pathway to relieve diabetic nephropathy

“…The slit diaphragm structure is essential for the nephrocyte filtration function ( van de Leemput et al, 2022 ; Wen et al, 2020 ). To examine its structural integrity in nephrocytes after high-sucrose treatment, we carried out immunochemistry for the slit diaphragm protein Polychaetoid (Pyd) (mammalian tight junction protein 1, TJP1, also known as ZO-1).…”

Podocyte injury and death: New insights into lupus nephritis pathogenesis and therapy

“…14 Compromised integrity of slit diaphragms and foot processes leads to proteinuria. 15,16 The integrity of the podocyte skeleton structure is also an important prerequisite for maintaining the normal morphology of podocytes and the mechanical stability of the glomerular filtration barrier. Recent findings show that polymorphisms in cytoskeleton genes, tubulin beta 2B class IIb (Tubb2b), 17 Alpha-actinin-4 gene (Actn4), 18 and CD2AP 19 disturb podocyte structure.…”

“…The negative surface charge present on foot processes and the slit diaphragm further aids in minimizing protein filtration 14 . Compromised integrity of slit diaphragms and foot processes leads to proteinuria 15,16 . The integrity of the podocyte skeleton structure is also an important prerequisite for maintaining the normal morphology of podocytes and the mechanical stability of the glomerular filtration barrier.…”