Injury-induced actin cytoskeleton reorganization in podocytes revealed by super-resolution microscopy

Suleiman, Hani; Roth, Robyn; Jain, Sanjay; Heuser, John E.; Shaw, Andréy S.; Miner, Jeffrey H.

doi:10.1172/jci.insight.94137

Cited by 67 publications

(99 citation statements)

References 60 publications

(63 reference statements)

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“…In contrast to STED, another SRM technique allowing an optical resolution down to even 35 nm, 3D-SIM can be directly applied on standard biopsy sections used in pathology routine without any time-consuming optical clearing. Recently, Suleiman and colleagues used Airyscan microscopy to image podocytes of whole murine isolated glomeruli in situ stained for synaptopodin ( 2 ). As an alternative to SIM, Airyscan has a resolution of 120 nm in the xy-plane and 350 nm in the z-direction, a resolution between that of CLSM and 3D-SIM ( 14 ).…”

Section: Discussionmentioning

confidence: 99%

“…In the past another SRM technique, (d)STORM, was used to study details of podocyte foot process morphology and podocyte-associated proteins ( 2 ). However, only cryosections and specific dyes that can be transferred in a so-called dark state can be used.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been demonstrated that super-resolution microscopy (SRM) overcomes the optical resolution limit of 200 nm formulated by Ernst Abbe. Therefore, different research groups have focused their attention on the visualization of podocyte foot processes by SRM ( 2 , 3 ). The term SRM summarizes a variety of different techniques like photo-activated localization microscopy (PALM), (direct) stochastic optical reconstruction microscopy [(d)STORM], stimulated emission depletion (STED) and structured illumination microscopy (SIM).…”

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of Podocyte Foot Process Morphology in Three Species by 3D Super-Resolution Microscopy

et al. 2018

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Since the size selectivity of the filtration barrier and kidney function are highly dependent on podocyte foot process morphology, visualization of foot processes is important. However, the size of foot processes is below the optical resolution of light microscopy. Therefore, electron microcopy has been indispensable to detect changes in foot process morphology so far, but it is a sophisticated and time-consuming technique. Recently, our group has shown that 3D structured illumination microscopy (3D-SIM), a super-resolution microscopy (SRM) technique, can visualize individual foot processes in human biopsies. Moreover, we have developed a software-based approach to directly quantify the structure of podocyte foot processes named Podocyte Exact Morphology Measurement Procedure (PEMP). As shown in patients suffering from minimal change disease (MCD), PEMP allows the quantification of changes of the foot process morphology by measuring the filtration slit density (FSD). Since rodents are frequently used in basic research, we have applied PEMP to quantify foot processes of mice and rats. Comparative analysis of nephrin-stained kidneys from humans, rats, and mice showed significant differences of the FSD. The highest FSD was measured in mice (3.83 ± 0.37 μm−1; mean ± SD) followed by rats (3.36 ± 0.42 μm−1) and humans (3.11 ± 0.26 μm−1). To demonstrate that PEMP can be used to determine foot process morphology also in affected animals, we measured the FSD in palladin-knockout mice on a 129S1 genetic background compared to wild-type littermates. Taken together, we established a method for the quick and exact quantification of podocyte foot process morphology which can be applied to diagnosis and basic research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of Podocyte Foot Process Morphology in Three Species by 3D Super-Resolution Microscopy

et al. 2018

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“…This observation suggests that mitochondrial dynamics might also play important roles in maintaining the shape and function of podocytes because podocytes, like neurons (Imasawa & Rossignol, 2013), require a proper supply and high amount of energy to maintain their foot processes. In addition, as the foot process has rich microfilaments, these interactions might also participate in podocyte homeostasis (Greka & Mundel, 2012, Suleiman, Roth et al, 2017). Moreover, these cytoskeletal defects in ADCK4 KO podocytes were also consistent with the iTRAQ analysis data, which elucidated that cytoskeleton-related proteins were down-regulated in ADCK4 KO podocytes compared to those in control podocytes.…”

Section: Discussionmentioning

confidence: 99%

ADCK4 deficiency destabilizes the coenzyme Q complex, which is rescued by 2,4-dihydroxybenzoic acid treatment

Widmeier

Nag³

et al. 2019

Preprint

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AbstractADCK4 mutations usually manifest as steroid-resistant nephrotic syndrome, and cause coenzyme Q10 (CoQ10) deficiency. However, the function of ADCK4 remains obscure. We investigated ADCK4 function using mouse and cell models. Podocyte-specific Adck4 deletion in mice significantly reduced survival and caused severe focal segmental glomerular sclerosis with extensive interstitial fibrosis and tubular atrophy, which were prevented by treatment with 2,4-dihydroxybenzoic acid (2,4-diHB), an analog of CoQ10 precursor molecule. ADCK4 knockout podocytes exhibited significantly decreased CoQ10 level, respiratory chain activity, mitochondrial potential, and dysmorphic mitochondria with loss of cristae formation, which were rescued by 2,4-diHB treatment, thus attributing these phenotypes to decreased CoQ10 levels. ADCK4 interacted with mitochondrial proteins including COQ5, and also cytoplasmic proteins including myosin and heat shock proteins. ADCK4 knockout decreased COQ complex levels, and the COQ5 level was rescued by ADCK4 overexpression in ADCK4 knockout podocytes. Overall, ADCK4 is required for CoQ10 biosynthesis and mitochondrial function in podocytes.

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“…Super-resolution imaging reveals a network of myosin IIA-containing contractile actin cables within podocyte cell bodies and major processes, which are also rich in intermediate filaments and microtubules. Conversely, myosin IIA-negative, non-contractile actin fibers populate podocyte FP ( 9 ), which are largely devoid of other cytoskeletal components.…”

Section: The Unique Ultrastructure Of the Podocytementioning

confidence: 99%

Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond

2018

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Podocytes are a major component of the glomerular blood filtration barrier, and alterations to the morphology of their unique actin-based foot processes (FP) are a common feature of kidney disease. Adjacent FP are connected by a specialized intercellular junction known as the slit diaphragm (SD), which serves as the ultimate barrier to regulate passage of macromolecules from the blood. While the link between SD dysfunction and reduced filtration selectivity has been recognized for nearly 50 years, our understanding of the underlying molecular circuitry began only 20 years ago, sparked by the identification of NPHS1, encoding the transmembrane protein nephrin. Nephrin not only functions as the core component of the extracellular SD filtration network but also as a signaling scaffold via interactions at its short intracellular region. Phospho-regulation of several conserved tyrosine residues in this region influences signal transduction pathways which control podocyte cell adhesion, shape, and survival, and emerging studies highlight roles for nephrin phospho-dynamics in mechanotransduction and endocytosis. The following review aims to summarize the last 5 years of advancement in our knowledge of how signaling centered at nephrin directs SD barrier formation and function. We further provide insight on promising frontiers in podocyte biology, which have implications for SD signaling in the healthy and diseased kidney.

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Injury-induced actin cytoskeleton reorganization in podocytes revealed by super-resolution microscopy

Cited by 67 publications

References 60 publications

Comparative Analysis of Podocyte Foot Process Morphology in Three Species by 3D Super-Resolution Microscopy

Comparative Analysis of Podocyte Foot Process Morphology in Three Species by 3D Super-Resolution Microscopy

ADCK4 deficiency destabilizes the coenzyme Q complex, which is rescued by 2,4-dihydroxybenzoic acid treatment

Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond

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