2019
DOI: 10.1073/pnas.1813580116
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Discovery of endoplasmic reticulum calcium stabilizers to rescue ER-stressed podocytes in nephrotic syndrome

Abstract: Emerging evidence has established primary nephrotic syndrome (NS), including focal segmental glomerulosclerosis (FSGS), as a primary podocytopathy. Despite the underlying importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of NS, no treatment currently targets the podocyte ER. In our monogenic podocyte ER stress-induced NS/FSGS mouse model, the podocyte type 2 ryanodine receptor (RyR2)/calcium release channel on the ER was phosphorylated, resulting in ER calcium leak and cytosolic calc… Show more

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Cited by 43 publications
(38 citation statements)
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References 53 publications
(70 reference statements)
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“…Moreover, calpeptin, a calpain inhibitor, markedly attenuates rat proteinuria induced by adriamycin administration in an experimental model for human FSGS (13). In podocytes, calpain has also been associated with endoplasmic reticulum stress-induced proteinuria (16), while urine samples from FSGS patients show a sharp increase in calpain activity compared with healthy controls (15). These findings concomitantly suggest that aberrantly increased calpain activity may drive kidney disease in rodent models and in humans by damaging the podocyte and disrupting glomerular filtration barrier integrity.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…Moreover, calpeptin, a calpain inhibitor, markedly attenuates rat proteinuria induced by adriamycin administration in an experimental model for human FSGS (13). In podocytes, calpain has also been associated with endoplasmic reticulum stress-induced proteinuria (16), while urine samples from FSGS patients show a sharp increase in calpain activity compared with healthy controls (15). These findings concomitantly suggest that aberrantly increased calpain activity may drive kidney disease in rodent models and in humans by damaging the podocyte and disrupting glomerular filtration barrier integrity.…”
Section: Discussionmentioning
confidence: 99%
“…Calpains have been shown to regulate cell behavior, actin cytoskeletal dynamics, cell motility, cell adhesion, endoplasmic reticulum stress, clathrin-dependent endocytosis, apoptosis, and inflammation upon interaction with their different substrates (12)(13)(14). We along with other groups have previously demonstrated that calpain activity is markedly increased in glomerular and urine samples from murine and human subjects with proteinuric kidney disease, while pursuant proteolysis of talin1, a critical protein linking the podocyte's actin cytoskeletal architecture to the glomerular basement membrane, has been observed in injured glomeruli (13,15,16). To determine whether mitigating calpain activation in Gak-KO mice would inhibit disease progression, we administered a calpain inhibitor that inhibits calpain-1/-2 activities and observed reduced albuminuria, kidney failure, and death in the Gak-KO mice.…”
Section: Introductionmentioning
confidence: 87%
“…NLRP3 inflammasome activation occurs in response to numerous damage-associated molecular patterns (DAMPs), including K + efflux, high levels of extracellular ATP, disruption of Ca 2+ homeostasis and generation of reactive oxygen species (ROS) [7,15,17]. These cellular and molecular events are also closely related to ERS, which suggests an interaction between the NLRP3 inflammasome and ERS [18][19][20][21][22][23]. On the one hand, ERS causes NLRP3 activation and exacerbates inflammation [25][26][27]; on the other hand, NLRP3 activation produces excessive ROS, which may further induce ERS [33][34][35].…”
Section: Discussionmentioning
confidence: 99%
“…The generation of reactive oxygen species (ROS), high levels of extracellular ATP and K + ions, intracellular Ca 2+ mobilization, hypoxia and acidosis can activate NLRP3 [7,[15][16][17]. Interestingly, the above factors and events underlie the generation and progression of endoplasmic reticulum stress (ERS) [18][19][20][21][22][23]. ERS is a condition in which accurate and appropriate endoplasmic reticulum (ER) structure and function are disordered.…”
Section: Introductionmentioning
confidence: 99%
“…Our structure is useful for thinking about MYDGF as a paracrine/autocrine survival factor with therapeutic potential after cardiac ischemia 7,32 . A number of ER proteins other than MYDGF have activities outside of the cell, including GRP78 (BiP) 34 , GRP94 35 , and mesencephalic astrocyte-derived neurotrophic factor (MANF) 36ā€“38 . Yet to be determined are the receptor for the survival function of extracellular MYDGF and when such a function arose during evolution.…”
Section: Discussionmentioning
confidence: 99%