Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice

Bohnert, Bernhard N.; González-Menéndez, Irene; Dörffel, Thomas; Schneider, Jonas C; Xiao, Mengyun; Janessa, Andrea; Kalo, M. Zaher; Fehrenbacher, Birgit; Schaller, Martin; Casadei, Nicolas; Amann, Kerstin; Daniel, Christoph; Birkenfeld, Andreas L.; Grahammer, Florian; Izem, Lahoucine; Plow, Edward F.; Quintanilla-Martı́nez, Leticia; Artunc, Ferruh

doi:10.1242/dmm.049038

Cited by 4 publications

(6 citation statements)

References 35 publications

(23 reference statements)

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“…As CM inhibits these proteases, it is possible that other target serine proteases aside from plasmin may be involved. When it comes to podocyte injury, while a recent study demonstrated that plasmin is also involved in the podocyte injury in doxorubicin-induced nephropathy [18], a coagulation serine protease thrombin has been reported to injure podocytes in nephrotic rats and diabetic nephropathy rats by activating PAR-1 and PAR-4 [18,41]. Although we did not detect thrombin activity in urine or kidney tissue using specific substrates or DLF zymography (Boc-Val-Pro-Arg-MCA, No.…”

Section: Discussioncontrasting

confidence: 66%

“…This activation causes sodium retention and hypertension [4]. In addition, plasmin leakage induces podocyte injury through various mechanisms, including oxidative stress and apoptosis [6,7,18]. Our previous studies showed that DS rats loaded with an HS diet developed hypertension and proteinuria, accompanied by proteolytic activation of γENaC, and that treatment with CM attenuated hypertension and proteinuria [9,14].…”

Section: Discussionmentioning

confidence: 99%

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A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats

Iwata,

Deng,

Kakizoe

et al. 2023

IJMS

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In proteinuric renal diseases, the serine protease (SP) plasmin activates the epithelial sodium channel (ENaC) by cleaving its γ subunit. We previously demonstrated that a high-salt (HS) diet provoked hypertension and proteinuria in Dahl salt-sensitive (DS) rats, accompanied by γENaC activation, which were attenuated by camostat mesilate (CM), an SP inhibitor. However, the effects of CM on plasmin activity in DS rats remain unclear. In this study, we investigated the effects of CM on plasmin activity, ENaC activation, and podocyte injury in DS rats. The DS rats were divided into the control diet, HS diet (8.0% NaCl), and HS+CM diet (0.1% CM) groups. After weekly blood pressure measurement and 24-h urine collection, the rats were sacrificed at 5 weeks. The HS group exhibited hypertension, massive proteinuria, increased urinary plasmin, and γENaC activation; CM treatment suppressed these changes. CM prevented plasmin(ogen) attachment to podocytes and mitigated podocyte injury by reducing the number of apoptotic glomerular cells, inhibiting protease-activated receptor-1 activation, and suppressing inflammatory and fibrotic cytokine expression. Our findings highlight the detrimental role of urinary plasmin in the pathogenesis of salt-sensitive hypertension and glomerular injury. Targeting plasmin with SP inhibitors, such as CM, may be a promising therapeutic approach for these conditions.

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Section: Discussioncontrasting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats

Iwata,

Deng,

Kakizoe

et al. 2023

IJMS

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“…In susceptible mouse strains, doxorubicin causes glomerular injury involving first the glomerular endothelium and then the podocytes. Endothelial binding of plasminogen is a critical prerequisite for the progression of the damage to nephrotic‐range proteinuria 31 . In addition, deposits of the complement factor C3 are detectable soon after doxorubicin injection 39 .…”

Section: Induction Of Experimental Nephrotic Syndrome In Rodents By N...mentioning

confidence: 99%

“…30 DNA-PKcs play an essential role in the non-homologous end-joining (NHEJ) pathway that is critically involved in DNA repair after double-strand breaks as induced by doxorubicin. The authors found that the single nucleotide polymorphism (SNP) C6418T in exon 48 causes the amino acid substitution R2140C (Arg2140Cys), which can be genotyped using PCR 31 and is exclusively present in the susceptible BALB/c and 129S1/ SvImJ strains but not in B6 mice or rats. 30 Our group adopted the DIN model to 129S1/SvImJ mice and established proteinuria induction after a single injection of doxorubicin.…”

Section: Doxorubicin-induced Nephropathy In Micementioning

confidence: 99%

“…Endothelial binding of plasminogen is a critical prerequisite for the progression of the damage to nephrotic-range proteinuria. 31 In addition, deposits of the complement factor C3 are detectable soon after doxorubicin injection. 39 Still, there is no inflammatory infiltrate, and DIN represents a primarily non-immunological model.…”

Section: Doxorubicin-induced Nephropathy In Micementioning

confidence: 99%

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Rodent models to study sodium retention in experimental nephrotic syndrome

et al. 2022

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Sodium retention and edema are hallmarks of nephrotic syndrome (NS). Different experimental rodent models have been established for simulating NS, however, not all of them feature sodium retention which requires proteinuria to exceed a certain threshold. In rats, puromycin aminonucleoside nephrosis (PAN) is a classic NS model introduced in 1955 that was adopted as doxorubicin-induced nephropathy (DIN) in 129S1/SvImJ mice. In recent years, mice with inducible podocin deletion (Nphs2 Δipod ) or podocyte apoptosis (POD-ATTAC) have been developed. In these models, sodium retention is thought to be caused by activation of the epithelial sodium channel (ENaC) in the distal nephron through aberrantly filtered serine proteases or proteasuria. Strikingly, rodent NS models follow an identical chronological time course after the development of proteinuria featuring sodium retention within days and spontaneous reversal thereafter. In DIN and Nphs2 Δipod mice, inhibition of ENaC by amiloride or urinary serine protease activity by aprotinin prevents sodium retention, opening up new and promising therapeutic approaches that could be translated into the treatment of nephrotic patients. However, the essential serine protease(s) responsible for ENaC activation is (are) still unknown.With the use of nephrotic rodent models, there is the possibility that this (these) will be identified in the future. This review summarizes the various rodent models used to study experimental nephrotic syndrome and the insights gained from these models with regard to the pathophysiology of sodium retention.

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First person – Bernhard N. Bohnert

2021

Disease Models &Amp; Mechanisms

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First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Bernhard N. Bohnert is first author on ‘ Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice’, published in DMM. Bernhard is a physician/postdoc in the lab of Prof. Dr. med. Ferruh Artunc at the University Hospital Tübingen, Tübingen, Germany, investigating oedema formation in nephrotic syndrome.

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Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice

Cited by 4 publications

References 35 publications

A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats

A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats

Rodent models to study sodium retention in experimental nephrotic syndrome

First person – Bernhard N. Bohnert

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