Cathepsin C is a novel mediator of podocyte and renal injury induced by hyperglycemia

Audzeyenka, Irena; Rachubik, Patrycja; Rogacka, Dorota; Typiak, Marlena; Kulesza, Tomasz; Angielski, S; Rychłowski, Michał; Wysocka, Magdalena; Gruba, Natalia; Lesner, Adam; Saleem, Moin A.; Piwkowska, Agnieszka

doi:10.1016/j.bbamcr.2020.118723

Cited by 15 publications

(9 citation statements)

References 53 publications

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“…Our research group previously found that HG conditions increase albumin permeability in rat glomeruli and cultured rat podocytes, accompanied by F-actin redistribution to cortical regions of podocytes [47][48][49]. However, to our knowledge, the present study is the first report of an analogous effect of hyperglycemia on human podocytes.…”

Section: Discussioncontrasting

confidence: 40%

“…Human immortalized podocytes (kind gift from Moin A. Saleem) were generated, as described previously [51]. The expression of podocyte markers and cell line purity were checked regularly [48]. Podocytes were grown in RPMI1640 medium (Thermo Fisher Scientific, Waltham, MA, USA) supplemented with heat-inactivated fetal bovine serum (Thermo Fisher Scientific) and antibiotics (penicillin/streptomycin, Sigma Aldrich, St. Louis, MO, USA).…”

Section: Human Podocyte Cell Culturementioning

confidence: 99%

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Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

Typiak

Kulesza

Rachubik

et al. 2021

IJMS

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Hyperglycemic conditions (HG), at early stages of diabetic nephropathy (DN), cause a decrease in podocyte numbers and an aberration of their function as key cells for glomerular plasma filtration. Klotho protein was shown to overcome some negative effects of hyperglycemia. Klotho is also a coreceptor for fibroblast growth factor receptors (FGFRs), the signaling of which, together with a proper rate of glycolysis in podocytes, is needed for a proper function of the glomerular filtration barrier. Therefore, we measured levels of Klotho in renal tissue, serum, and urine shortly after DN induction. We investigated whether it influences levels of FGFRs, rates of glycolysis in podocytes, and albumin permeability. During hyperglycemia, the level of membrane-bound Klotho in renal tissue decreased, with an increase in the shedding of soluble Klotho, its higher presence in serum, and lower urinary excretion. The addition of Klotho increased FGFR levels, especially FGFR1/FGFR2, after their HG-induced decrease. Klotho also increased levels of glycolytic parameters of podocytes, and decreased podocytic and glomerular albumin permeability in HG. Thus, we found that the decrease in the urinary excretion of Klotho might be an early biomarker of DN and that Klotho administration may have several beneficial effects on renal function in DN.

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Section: Discussioncontrasting

confidence: 40%

Section: Human Podocyte Cell Culturementioning

confidence: 99%

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

Typiak

Kulesza

Rachubik

et al. 2021

IJMS

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“…34 Structural and functional impairment of podocytes, which constitute the outer layer of the renal glomerular filtration barrier, will lead to proteinuria and in patients with diabetes mellitus, thus, play a pivotal role in the development of diabetic nephropathy. 35 Nephrin is an essential component of the slit diaphragms, which is necessary to maintain selective glomerular filtration. 36 Besides, podocin is also a glomerular slit diaphragm protein located between neighboring podocytes, and a critical component of glomerular filtration barrier, that plays a key role in maintaining the normal structure and function of podocytes.…”

Section: Discussionmentioning

confidence: 99%

“…36 Besides, podocin is also a glomerular slit diaphragm protein located between neighboring podocytes, and a critical component of glomerular filtration barrier, that plays a key role in maintaining the normal structure and function of podocytes. 35 Decreased expression of podocin and nephrin suggests that podocyte foot processes fuse, destroying the glomerular filtration barrier, resulting in production of albuminuria. 37 In this study, our data indicated that mefunidone was able to restore the expression of nephrin and podocin under diabetic condition.…”

Section: Discussionmentioning

confidence: 99%

“…Podocytes play a major role in preserving the integrity of glomerular function under normal conditions 34 . Structural and functional impairment of podocytes, which constitute the outer layer of the renal glomerular filtration barrier, will lead to proteinuria and in patients with diabetes mellitus, thus, play a pivotal role in the development of diabetic nephropathy 35 . Nephrin is an essential component of the slit diaphragms, which is necessary to maintain selective glomerular filtration 36 .…”

Section: Discussionmentioning

confidence: 99%

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Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

Jiang

Xie

et al. 2020

FASEB j.

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Diabetic kidney disease (DKD) a kind of microvascular complication, is a primary cause of end-stage renal disease (ESRD) worldwide. 1,2 Characteristic pathological features of DKD include glomerular basement membrane (GBM) thickening, mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis, owing to high expression of extracellular matrix (ECM), such as collagen, fibronectin, and so on. 3,4 Type 1 diabetes millitus (T1D) and type 2 diabetes millitus (T2D) are the most common cause of DKD. The incidence of DKD complicated by T1D and T2D is about 50%

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Hyperglycemic environment disrupts phosphate transporter function and promotes calcification processes in podocytes and isolated glomeruli

Kulesza

Typiak

Rachubik

et al. 2022

Journal Cellular Physiology

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Soft tissue calcification is a pathological phenomenon that often occurs in end-stage chronic kidney disease (CKD), which is caused by diabetic nephropathy, among other factors. Hyperphosphatemia present during course of CKD contributes to impairments in kidney function, particularly damages in the glomerular filtration barrier (GFB). Essential elements of the GFB include glomerular epithelial cells, called podocytes. In the present study, we found that human immortalized podocytes express messenger RNA and protein of phosphate transporters, including NaPi 2c (SLC34A3), Pit 1 (SLC20A1), and Pit 2 (SLC20A2), which are sodium-dependent and mediate intracellular phosphate (Pi) transport, and XPR1, which is responsible for extracellular Pi transport. We found that cells that were grown in a medium with a high glucose (HG) concentration (30 mM) expressed less Pit 1 and Pit 2 protein than podocytes that were cultured in a standard glucose medium (11 mM). We found that exposure of the analyzed transporters in the cell membrane of the podocyte is altered by HG conditions. We also found that the activity of tissue nonspecific alkaline phosphatase increased in HG, causing a rise in Pi generation. Additionally, HG led to a reduction of the amount of ectonucleotide pyrophosphatase/phosphodiesterase 1 in the cell membrane of podocytes. The extracellular concentration of pyrophosphate also decreased under HG conditions. These data suggest that a hyperglycemic environment enhances the production of Pi in podocytes and its retention in the extracellular space, which may induce glomerular calcification.

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Cathepsin C is a novel mediator of podocyte and renal injury induced by hyperglycemia

Cited by 15 publications

References 53 publications

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

Hyperglycemic environment disrupts phosphate transporter function and promotes calcification processes in podocytes and isolated glomeruli

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