ORCID Profile
0000-0001-9915-5376
Current Organisation
Icahn School of Medicine at Mount Sinai
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Publisher: Springer Science and Business Media LLC
Date: 19-12-2022
Publisher: Elsevier BV
Date: 10-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2013
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.KINT.2022.07.015
Abstract: Shahzad et al. examined the underlying mechanisms of sterile inflammation in diabetic kidney disease, specifically the role of NLRP3 inflammasome activation in podocytes. Using mouse models with gain-of-function and loss-of-function mutations in podocyte Nlrp3, or caspase-1 loss-of-function mutations in podocytes, they identified that Nlrp3 activation in these cells is central for development of diabetic kidney disease but not solely dependent on canonical mechanisms and caspase-1. These findings position podocyte-mediated immune cell-like functions as potential therapeutic targets for diabetic kidney disease.
Publisher: Society for Neuroscience
Date: 25-05-2023
DOI: 10.1523/JNEUROSCI.1828-22.2023
Abstract: The impact of tau pathology on sleep microarchitecture features, including slow oscillations, spindles, and their coupling, has been understudied, despite the proposed importance of these electrophysiological features toward learning and memory. Dual orexin receptor antagonists (DORAs) are known to promote sleep, but whether and how they affect sleep microarchitecture in the setting of tauopathy is unknown. In the PS19 mouse model of tauopathy MAPT (microtubule-associated protein tau) P301S (both male and female), young PS19 mice 2–3 months old show a sleep electrophysiology signature with markedly reduced spindle duration and power and elevated slow oscillation (SO) density compared with littermate controls, although there is no significant tau hyperphosphorylation, tangle formation, or neurodegeneration at this age. With aging, there is evidence for sleep disruption in PS19 mice, characterized by reduced REM duration, increased non-REM and REM fragmentation, and more frequent brief arousals at the macrolevel and reduced spindle density, SO density, and spindle-SO coupling at the microlevel. In ∼33% of aged PS19 mice, we unexpectedly observed abnormal goal-directed behaviors in REM, including mastication, paw grasp, and forelimb/hindlimb extension, seemingly consistent with REM behavior disorder (RBD). Oral administration of DORA-12 in aged PS19 mice increased non-REM and REM duration, albeit with shorter bout lengths, and increased spindle density, spindle duration, and SO density without change to spindle–SO coupling, power in either the SO or spindle bands, or the arousal index. We observed a significant effect of DORA-12 on objective measures of RBD, thereby encouraging future exploration of DORA effects on sleep-mediated cognition and RBD treatment. SIGNIFICANCE STATEMENT The specific effect of tauopathy on sleep macroarchitecture and microarchitecture throughout aging remains unknown. Our key findings include the following: (1) the identification of a sleep EEG signature constituting an early biomarker of impending tauopathy (2) sleep physiology deteriorates with aging that are also markers of off-line cognitive processing (3) the novel observation that dream enactment behaviors reminiscent of RBD occur, likely the first such observation in a tauopathy model and (4) a dual orexin receptor antagonist is capable of restoring several of the sleep macroarchitecture and microarchitecture abnormalities.
Publisher: Elsevier BV
Date: 05-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2015
Publisher: Herald Scholarly Open Access
Date: 08-06-2016
Publisher: Wiley
Date: 02-11-2011
DOI: 10.1016/J.FEBSLET.2011.10.040
Abstract: The anticancer and immunosuppressant thiopurines cause 6-thioguanine (6-TG) to accumulate in nuclear DNA. We report that 6-TG is also readily incorporated into mitochondrial DNA (mtDNA) where it is rapidly oxidized. The oxidized forms of mtDNA 6-TG inhibit replication by DNA Pol-γ. Accumulation of oxidized 6-TG is associated with reduced mtDNA transcription, a decline in mitochondrial protein levels, and loss of mitochondrial function. Ultraviolet A radiation (UVA) also oxidizes mtDNA 6-TG. Cells without mtDNA are less sensitive to killing by a combination of 6-TG and UVA than their mtDNA-containing counterparts, indicating that photochemical mtDNA 6-TG oxidation contributes to 6-TG-mediated UVA photosensitization.
Publisher: MyJove Corporation
Date: 13-09-2022
DOI: 10.3791/64147
Abstract: Glomerular endothelial cell (GEC) dysfunction can initiate and contribute to glomerular filtration barrier breakdown. Increased mitochondrial oxidative stress has been suggested as a mechanism resulting in GEC dysfunction in the pathogenesis of some glomerular diseases. Historically the isolation of GECs from in vivo models has been notoriously challenging due to difficulties in isolating pure cultures from glomeruli. GECs have complex growth requirements in vitro and a very limited lifespan. Here, we describe the procedure for isolating and culturing conditionally immortalized GECs with fluorescent mitochondria, enabling the tracking of mitochondrial fission and fusion events. GECs were isolated from the kidneys of a double transgenic mouse expressing the thermolabile SV40 TAg (from the Immortomouse), conditionally promoting proliferation and suppressing cell differentiation, and a photo-convertible fluorescent protein (Dendra2) in all mitochondria (from the photo-activatable mitochondria [PhAM
Publisher: Frontiers Media SA
Date: 02-06-2021
DOI: 10.3389/FPHYS.2021.689083
Abstract: The glomerulus is a compact cluster of capillaries responsible for blood filtration and initiating urine production in the renal nephrons. A trilaminar structure in the capillary wall forms the glomerular filtration barrier (GFB), composed of glycocalyx-enriched and fenestrated endothelial cells adhering to the glomerular basement membrane and specialized visceral epithelial cells, podocytes, forming the outermost layer with a molecular slit diaphragm between their interdigitating foot processes. The unique dynamic and selective nature of blood filtration to produce urine requires the functionality of each of the GFB components, and hence, mimicking the glomerular filter in vitro has been challenging, though critical for various research applications and drug screening. Research efforts in the past few years have transformed our understanding of the structure and multifaceted roles of the cells and their intricate crosstalk in development and disease pathogenesis. In this review, we present a new wave of technologies that include glomerulus-on-a-chip, three-dimensional microfluidic models, and organoids all promising to improve our understanding of glomerular biology and to enable the development of GFB-targeted therapies. Here, we also outline the challenges and the opportunities of these emerging biomimetic systems that aim to recapitulate the complex glomerular filter, and the evolving perspectives on the sophisticated repertoire of cellular signaling that comprise the glomerular milieu.
Publisher: American Association for Cancer Research (AACR)
Date: 15-03-2009
DOI: 10.1158/0008-5472.CAN-08-4264
Abstract: Azathioprine, a widely used immunosuppressant, is also used in the control of inflammatory disorders. These are characterized by the local accumulation of immune effector cells that produce reactive oxygen species (ROS). The DNA of azathioprine-treated patients contains 6-thioguanine (6-TG), a base analogue that is particularly susceptible to oxidation. Here, we show that 6-TG is vulnerable to ROS produced by chemical oxidants and that cells containing DNA 6-TG are hypersensitive to these oxidants. We also show that 6-TG incorporated into the DNA of macrophages sensitizes them to killing by endogenously produced ROS. ROS generated by macrophages are also a hazard for cocultured nonmacrophage cells containing DNA 6-TG. This bystander vulnerability of cells containing DNA 6-TG to oxidation by ROS generated by immune effector cells has implications for the long-term use of azathioprine in the management of inflammatory disorders. [Cancer Res 2009 (6):2393–9]
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2015
DOI: 10.2215/CJN.11541114
Publisher: Frontiers Media SA
Date: 23-03-2018
Publisher: MDPI AG
Date: 11-12-2020
DOI: 10.3390/IJMS21249456
Abstract: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), with prevalence increasing at an alarming rate worldwide and today, there are no known cures. The pathogenesis of DKD is complex, influenced by genetics and the environment. However, the underlying molecular mechanisms that contribute to DKD risk in about one-third of diabetics are still poorly understood. The early stage of DKD is characterized by glomerular hyperfiltration, hypertrophy, podocyte injury and depletion. Recent evidence of glomerular endothelial cell injury at the early stage of DKD has been suggested to be critical in the pathological process and has highlighted the importance of glomerular intercellular crosstalk. A potential mechanism may include reactive oxygen species (ROS), which play a direct role in diabetes and its complications. In this review, we discuss different cellular sources of ROS in diabetes and a new emerging paradigm of endothelial cell dysfunction as a key event in the pathogenesis of DKD.
Publisher: Elsevier BV
Date: 05-2013
Publisher: Frontiers Media SA
Date: 13-10-2022
Publisher: Springer Science and Business Media LLC
Date: 08-07-2020
DOI: 10.1186/S12964-020-00605-X
Abstract: In the setting of diabetes mellitus, mitochondrial dysfunction and oxidative stress are important pathogenic mechanisms causing end organ damage, including diabetic kidney disease (DKD), but mechanistic understanding at a cellular level remains obscure. In mouse models of DKD, glomerular endothelial cell (GEC) dysfunction precedes albuminuria and contributes to neighboring podocyte dysfunction, implicating GECs in breakdown of the glomerular filtration barrier. In the following studies we wished to explore the cellular mechanisms by which GECs become dysfunctional in the diabetic milieu, and the impact to neighboring podocytes. Mouse GECs were exposed to high glucose media (HG) or 2.5% v/v serum from diabetic mice or serum from non-diabetic controls, and evaluated for mitochondrial function (oxygen consumption), structure (electron microscopy), morphology (mitotracker), mitochondrial superoxide (mitoSOX), as well as accumulation of oxidized products (DNA lesion frequency (8-oxoG, endo-G), double strand breaks (γ-H2AX), endothelial function (NOS activity), autophagy (LC3) and apoptotic cell death (Annexin/PI caspase 3). Supernatant transfer experiments from GECs to podocytes were performed to establish the effects on podocyte survival and transwell experiments were performed to determine the effects in co-culture. Diabetic serum specifically causes mitochondrial dysfunction and mitochondrial superoxide release in GECs. There is a rapid oxidation of mitochondrial DNA and loss of mitochondrial biogenesis without cell death. Many of these effects are blocked by mitoTEMPO a selective mitochondrial anti-oxidant. Secreted factors from dysfunctional GECs were sufficient to cause podocyte apoptosis in supernatant transfer experiments, or in co-culture but this did not occur when GECs had been previously treated with mitoTEMPO. Dissecting the impact of the diabetic environment on in idual cell-types from the kidney glomerulus indicates that GECs become dysfunctional and pathological to neighboring podocytes by increased levels of mitochondrial superoxide in GEC. These studies indicate that GEC-signaling to podocytes contributes to the loss of the glomerular filtration barrier in DKD.
Publisher: American Diabetes Association
Date: 29-11-2016
DOI: 10.2337/DB16-0695
Abstract: The molecular signaling mechanisms between glomerular cell types during initiation rogression of diabetic kidney disease (DKD) remain poorly understood. We compared the early transcriptome profile between DKD-resistant C57BL/6J and DKD-susceptible DBA/2J (D2) glomeruli and demonstrated a significant downregulation of essential mitochondrial genes in glomeruli from diabetic D2 mice, but not in C57BL/6J, with comparable hyperglycemia. Diabetic D2 mice manifested increased mitochondrial DNA lesions (8-oxoguanine) exclusively localized to glomerular endothelial cells after 3 weeks of diabetes, and these accumulated over time in addition to increased urine secretion of 8-oxo-deoxyguanosine. Detailed assessment of glomerular capillaries from diabetic D2 mice demonstrated early signs of endothelial injury and loss of fenestrae. Glomerular endothelial mitochondrial dysfunction was associated with increased glomerular endothelin-1 receptor type A (Ednra) expression and increased circulating endothelin-1 (Edn1). Selective Ednra blockade or mitochondrial-targeted reactive oxygen species scavenging prevented mitochondrial oxidative stress of endothelial cells and ameliorated diabetes-induced endothelial injury, podocyte loss, albuminuria, and glomerulosclerosis. In human DKD, increased urine 8-oxo-deoxyguanosine was associated with rapid DKD progression, and biopsies from patients with DKD showed increased mitochondrial DNA damage associated with glomerular endothelial EDNRA expression. Our studies show that DKD susceptibility was linked to mitochondrial dysfunction, mediated largely by Edn1–Ednra in glomerular endothelial cells representing an early event in DKD progression, and suggest that cross talk between glomerular endothelial injury and podocytes leads to defects and depletion, albuminuria, and glomerulosclerosis.
Publisher: Elsevier BV
Date: 07-2013
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.DNAREP.2011.05.010
Abstract: Patients taking the immunosuppressant and anticancer thiopurines 6-mercaptopurine, azathioprine or 6-thioguanine (6-TG), develop skin cancer at a very high frequency. Their DNA contains 6-TG which absorbs ultraviolet A (UVA) radiation, and their skin is UVA hypersensitive, consistent with the formation of DNA photodamage. Here we demonstrate that UVA irradiation of 6-TG-containing DNA causes DNA interstrand crosslinking. In synthetic duplex oligodeoxynucleotides, the interstrand crosslinks (ICLs) can form between closely opposed 6-TG bases and, in a less favoured reaction, between 6-TG and normal bases on the opposite strand. In vivo, UVA irradiation of cultured cells containing 6-TG-substituted DNA also causes ICL formation and induces the chromosome aberrations that are characteristically associated with this type of DNA lesion. 6-TG/UVA activates the Fanconi anemia (FA) pathway via monoubiquitination of the FANCD2 protein. Cells defective in the FA pathway or other factors involved in ICL processing, such as XPF and DNA Polζ, are all hypersensitive to killing by 6-TG/UVA-consistent with a significant contribution of photochemical ICLs to the cytotoxicity of this treatment. Our findings suggest that sunlight-exposed skin of thiopurine treated patients may experience chronic photochemical DNA damage that requires constant intervention of the FA pathway.
Publisher: American Society for Clinical Investigation
Date: 17-02-2015
DOI: 10.1172/JCI77084
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.KINT.2022.01.008
Abstract: Menon et al. report cell-specific transcriptional changes in podocytes and glomerular endothelial cells that indicate cell stress and increased bidirectional crosstalk among these cells in apparently healthy human allografts. They identified common and independent podocytes and glomerular endothelial cell-specific responses in nondiabetic and diabetic transplant recipients, as well as parallels in genes related to podocyte and glomerular endothelial cell stress in experimental focal segmental glomerular sclerosis. These findings could explain hypertrophy-associated glomerular disease progression associated with podocyte detachment after transplantation.
Publisher: Frontiers Media SA
Date: 26-04-2018
Publisher: figshare
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 05-06-2006
DOI: 10.1007/S10495-006-7960-3
Abstract: Apoptosis of keratinocytes is a key mechanism required for epidermal homeostasis and the renewal of damaged cells. Its dysregulation has been implicated in many skin diseases including cancer and hyperproliferative disorders. In the present study, the effect of sodium butyrate, a histone deacetylase inhibitor, on keratinocyte apoptosis was investigated using the HaCaT human keratinocyte cell line. Sodium butyrate induced morphological changes associated with apoptosis and nuclear fragmentation of HaCaTs. Annexin V staining demonstrated that sodium butyrate induced apoptosis in a dose and time-dependent manner with 50% of HaCaTs apoptotic after exposure to 0.8 mg/ml sodium butyrate for 24 h. Apoptosis was associated with upregulation of cell surface expression of the death receptor Fas and activation of the extrinsic caspase pathway, with induction of caspase 8 activity peaking after 8 h. Caspase 3 activity peaked after 24 h and was associated with cleavage of the caspase 3 substrate, poly (ADP-ribose) polymerase (PARP). The intrinsic caspase pathway was not activated as caspase 9 activity was not detected, and there was no change in the expression of terminal differentiation markers keratin 10 and involucrin following sodium butyrate treatment. Together these results indicate that sodium butyrate is a potent inducer of Fas associated apoptosis via caspase activation in HaCaT keratinocytes, an effect that is independent of the induction of terminal differentiation.
Publisher: Elsevier BV
Date: 10-2018
Publisher: Oxford University Press (OUP)
Date: 25-04-2016
Abstract: The clinical use of azathioprine and 6-mercaptopurine is limited by their delayed onset of action and potential side effects such as myelosuppression and hepatotoxicity. As these drugs specifically target the Vav1/Rac1 signalling pathway in T lamina propria lymphocytes via their metabolite 6-thio-GTP, we studied expression and optimised suppression of this pathway in inflammatory bowel diseases [IBD]. Rac1 and Vav1 expressions were analysed in mucosal immune cells in IBD patients. Targeted molecular modelling of the 6-thio-GTP molecule was performed to optimise Rac1 blockade 44 modified designer thiopurine-analogues were tested for apoptosis induction, potential toxicity, and immunosuppression. Activation of the Vav1/Rac1 pathway in lymphocytes was studied in IBD patients and in lamina propria immune cells in the presence or absence of thiopurine-analogues. Several thiopurine-analogues induced significantly higher T cell apoptosis than 6-mercaptopurine. We identified a compound, denoted B-0N, based on its capacity to mediate earlier and stronger induction of T cell apoptosis than 6-mercaptopurine. B-0N-treatment resulted in accelerated inhibition of Rac1 activity in primary peripheral blood T cells as well as in intestinal lamina propria immune cells. Compared with 6-thio-GTP and 6-mercaptopurine, B-0N-treatment was associated with decreased myelo- and hepatotoxicity. The Vav1/Rac1 pathway is activated in mucosal immune cells in IBD. The designer thiopurine-analogue B-0N induces immunosuppression more potently than 6-mercaptopurine.
Publisher: figshare
Date: 2020
Publisher: Elsevier BV
Date: 08-2015
Publisher: Elsevier BV
Date: 05-2010
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000442051
Abstract: b i Background/Aims: /i /b In podocytes, the overexpression of TGFβ ligands and receptors during glomerulosclerosis could be a causal factor for injury induction and perpetuation in glomerular tufts. Mitochondrial dysfunction and oxidative stress are emerging as potential therapeutic targets in glomerular injury, and TGFβ has been shown to modulate mitochondrial metabolism in different cell types. This study aims at investigating the role of TGFβ in podocyte energy metabolism and cytoskeleton dynamics. b i Methods: /i /b Mitochondrial function and cytoskeleton dynamics were analyzed in TGFβ-treated WT and Smad2/3 double KO podocytes. b i Results: /i /b TGFβ treatment in podocytes induced a significant Smad-dependent increase of mitochondrial oxygen consumption rate (OCR). ATP content was unchanged and increased respiration was not associated with increased mitochondrial mass. Increased cellular reactive oxygen species induced by Smad-mediated TGFβ signaling were reverted by NADPH oxidase inhibitor apocynin. TGFβ treatment did not induce mitochondrial oxidative stress, and Smad2/3-dependent TGFβ signaling and increased mitochondrial OCR were found to be associated with actin cytoskeleton dynamics. The role of motor proteins myosin II and dynamin in TGFβ-induced actin polymerization was demonstrated by specific inhibition, resulting in actin stabilization and normalization of mitochondrial OCR. b i Conclusion: /i /b TGFβ-induced rearrangements of actin cytoskeleton are controlled by Smad2/3 signaling pathways and coupled with the activation of mitochondrial ATP synthesis as bioenergetic adaptation to ATP consumption by ATP- and GTP-dependent motor proteins, myosin II and dynamin.
Publisher: eLife Sciences Publications, Ltd
Date: 11-03-2022
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1046/J.1523-1755.2003.00080.X
Abstract: Hyperplasia is attributed to enhanced tubular cell proliferation with unbalanced cell death. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors induce apoptosis in a variety of cell lines, including proximal tubular cells. However, the mechanisms by which statins induce apoptosis in tubular cells have not been fully addressed. Apoptosis induced by simvastatin was measured in murine tubular cells with and without overexpressing Bcl-xL. Expression of genes implicated in cell death was studied by Northern and Western blot. The treatment of proliferating murine tubular cells (MCT) with simvastatin induced apoptosis in a time- and dose-dependent manner (0.1 to 1 micromol/L). Apoptosis was correlated with Bcl-xL mRNA and protein down-regulation. By contrast, the treatment with simvastatin did not modify the expression of the proapoptotic protein Bax. Simvastatin treatment was associated with cytochrome C release from the mitochondria to the cytosol. We also observed the presence of active caspase 9 and 3 during apoptosis induced by simvastatin. These effects were reversed by mevalonate, farnesylpyrophosphate (FPP), and geranylgeranylpyrophosphate (GGPP), suggesting the involvement of protein prenylation. Simvastatin appears to alter the balance between cell-life and death-promoting genes, as reflected by the decreased Bcl-xL/Bax ratio. Supporting this hypothesis, overexpression of Bcl-xL reduced the amount of apoptosis induced by simvastatin by 80% when compared with control vector-expressing cells. The overexpression of Bcl-xL also prevented the activation of caspase 9 and 3. Our results indicate that down-regulation of Bcl-xL expression mediates apoptosis induced by statins in tubular cells. These results may be relevant to the treatment of disorders characterized by altered tubular proliferation.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-09-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-05-2020
Publisher: Elsevier BV
Date: 07-2021
Publisher: Mary Ann Liebert Inc
Date: 12-2013
DOI: 10.1089/GEN.33.21.01
Publisher: Springer Science and Business Media LLC
Date: 14-07-2021
Publisher: American Society for Clinical Investigation
Date: 03-03-2014
DOI: 10.1172/JCI71195
Publisher: Elsevier BV
Date: 09-2022
Publisher: Wiley
Date: 12-03-2010
DOI: 10.1111/J.1600-0625.2009.00917.X
Abstract: The development of eczematous lesions is thought to be due in part to a breakdown in skin barrier function as a result of T lymphocytes (T cells) invading the skin causing epidermal keratinocyte apoptosis. In this study, we investigated the interaction of T cells and keratinocytes on apoptosis and terminal differentiation using an in vitro co-culture system. Experiments were performed using the HaCaT keratinocyte cell line or normal human epidermal keratinocytes. Activated human peripheral blood-derived T cells were found to induce Fas-dependent keratinocyte apoptosis by up to sixfold. Increased Fas was associated with increased IFN-gamma. The T-cell apoptotic signal was found to target preferentially keratinocytes in the very early stages of terminal differentiation, such as those with low levels of alpha 6-integrin expression, and result in subsequent increased caspase 3 activity. This observation was accompanied by a marked increase in keratinocyte ICAM-1 expression and its ligand LFA-1 on T cells. Our data suggest that T cells may initiate the onset of keratinocyte terminal differentiation making them more susceptible to Fas-dependent cell death signals delivered by the T cells.
Publisher: figshare
Date: 2020
Publisher: American Physiological Society
Date: 08-2023
DOI: 10.1152/AJPRENAL.00047.2023
Abstract: Diabetic kidney disease (DKD) is one of the most devastating complications of diabetes mellitus, where currently there is no cure available. Several important mechanisms contribute to the pathogenesis of this complication, with oxidative stress being one of the key factors. The past decades have seen a large number of publications with various aspects of this topic however, the specific details of redox regulation in DKD are still unclear. This is partly because redox biology is very complex, coupled with a complex and heterogeneous organ with numerous cell types. Furthermore, often times terms such as “oxidative stress” or reactive oxygen species are used as a general term to cover a wide and rich variety of reactive species and their differing reactions. However, no reactive species are the same, and not all of them are capable of biologically relevant reactions or “redox signaling.” The goal of this review is to provide a biochemical background for an array of specific reactive oxygen species types with varying reactivity and specificity in the kidney as well as highlight some of the advances in redox biology that are paving the way to a better understanding of DKD development and risk.
Publisher: Elsevier BV
Date: 10-2019
Publisher: figshare
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 06-04-2023
Publisher: Elsevier BV
Date: 03-2004
Publisher: Elsevier BV
Date: 05-2014
Publisher: American Physiological Society
Date: 06-2014
DOI: 10.1152/AJPRENAL.00608.2013
Abstract: Mitochondrial dysfunction is increasingly recognized as contributing to glomerular diseases, including those secondary to mitochondrial DNA (mtDNA) mutations and deletions. Mitochondria maintain cellular redox and energy homeostasis and are a major source of intracellular reactive oxygen species (ROS) production. Mitochondrial ROS accumulation may contribute to stress-induced mitochondrial dysfunction and apoptosis and thereby to glomerulosclerosis. In mice, deletion of the gene encoding Mpv17 is associated with glomerulosclerosis, but the underlying mechanism remains poorly defined. Here we report that Mpv17 localizes to mitochondria of podocytes and its expression is reduced in several glomerular injury models and in human focal segmental glomerulosclerosis (FSGS) but not in minimal change disease. Using models of mild or severe nephrotoxic serum nephritis (NTSN) in Mpv17 +/+ wild-type (WT) and Mpv17 −/− knockout mice, we found that Mpv17 deficiency resulted in increased proteinuria (mild NTSN) and renal insufficiency (severe NTSN) compared with WT. These lesions were associated with increased mitochondrial ROS generation and mitochondrial injury such as oxidative DNA damage. In vitro, podocytes with loss of Mpv17 function were characterized by increased susceptibility to apoptosis and ROS injury including decreased mitochondrial function, loss of mtDNA content, and change in mitochondrial configuration. In summary, the inner mitochondrial membrane protein Mpv17 in podocytes is essential for the maintenance of mitochondrial homeostasis and protects podocytes against oxidative stress-induced injury both in vitro and in vivo.
Location: United States of America
Start Date: 2013
End Date: 2019
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2020
End Date: 2023
Funder: Congressionally Directed Medical Research Programs
View Funded Activity