C3a receptor blockade protects podocytes from injury in diabetic nephropathy

Morigi, Marina; Perico, Luca; Corna, Daniela; Locatelli, Monica; Cassis, Paola; Carminati, Claudia Elisa; Bolognini, Silvia; Zoja, Carla; Remuzzi, Giuseppe; Benigni, Ariela; Buelli, Simona

doi:10.1172/jci.insight.131849

Cited by 55 publications

(47 citation statements)

References 64 publications

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“…Here, we showed that C3aR1 and C5aR1 are expressed on podocytes and that their expression is induced during human pMN in vivo. Increased C3aR1 expression has also been recently reported in rodent models of diabetic nephropathy (37), suggesting that our observation might not be specific to pMN. Concurrent blockade of both receptors rescued a decrease in cAMP that we observed as a response to pMN serum and complement and ameliorated complement-induced podocyte injury.…”

Section: Discussionsupporting

confidence: 49%

Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1–associated membranous nephropathy

Haddad¹,

Lorenzen²,

Ma³

et al. 2021

Journal of Clinical Investigation

125

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Authorship note: GH and JML are co-first authors. Conflict of interest: LB, GL, and DJS are coinventors on the patent Diagnostics for Membranous Nephropathy (US 8,507,215 B2) with royalty income through Boston University (LB and DJS) and CNRS (GL). LB reports a grant from Sanofi Genzyme and advisory board fees from Visterra and receives author royalty and peer review payments from UpToDate, Inc. relating to topic cards on the subject of membranous nephropathy. DJS reports a grant from Sanofi Genzyme; consulting and advisory board fees from Advance Medical, Pfizer, and Visterra; and royalty payments from UpToDate, Inc. relating to topic cards on the subject of membranous nephropathy.

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Section: Discussionsupporting

confidence: 49%

Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1–associated membranous nephropathy

Haddad¹,

Lorenzen²,

Ma³

et al. 2021

Journal of Clinical Investigation

125

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“…57 On the other hand, previous studies demonstrated that the anaphylatoxins C3a and C5a through their GPRs may contribute to CKD by injuring podocytes, and that APC may inhibit podocyte apoptosis and kidney fibrosis via its endothelial protein C receptor and protease-activated receptor 1. 23,[58][59][60][61] Here, we found that rhTM inhibits the complement system and increases the generation of APC. Therefore, apart from the activation of the GPR15/Akt pathway, inhibition of complement factors and increased activation of protein C and its receptors may also explain the beneficial effects of rhTM in our TGFb1-associated kidney fibrosis model.…”

Section: Receptor Mediation In Rhtm Protective Activitymentioning

confidence: 73%

Thrombomodulin ameliorates transforming growth factor-β1–mediated chronic kidney disease via the G-protein coupled receptor 15/Akt signal pathway

Takeshita

Yasuma

Nishihama

et al. 2020

Kidney International

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Kidney fibrosis is the common consequence of chronic kidney diseases that inexorably progresses to end-stage kidney disease with organ failure treatable only with replacement therapy. Since transforming growth factor-b1 is the main player in the pathogenesis of kidney fibrosis, we posed the hypothesis that recombinant thrombomodulin can ameliorate transforming growth factor-b1-mediated progressive kidney fibrosis and failure. To interrogate our hypothesis, we generated a novel glomerulus-specific human transforming growth factor-b1 transgenic mouse to evaluate the therapeutic effect of recombinant thrombomodulin. This transgenic mouse developed progressive glomerular sclerosis and tubulointerstitial fibrosis with kidney failure. Therapy with recombinant thrombomodulin for four weeks significantly inhibited kidney fibrosis and improved organ function compared to untreated transgenic mice. Treatment with recombinant thrombomodulin significantly inhibited apoptosis and mesenchymal differentiation of podocytes by interacting with the G-protein coupled receptor 15 to activate the Akt signaling pathway and to upregulate the expression of anti-apoptotic proteins including survivin. Thus, our study strongly suggests the potential therapeutic efficacy of recombinant thrombomodulin for the treatment of chronic kidney disease and subsequent organ failure.

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“…The expression of Mn-SOD is reduced in several diabetic animal models, including STZ-induced type 1 diabetes ( Spencer et al, 2018 ; Li et al, 2019 ), a high-sugar/high-fat or cholesterol diet with STZ-induced diabetes ( Onozato et al, 2004 ; Chen P. et al, 2018 ; Zayed et al, 2018 ), Apo E –/– mice with STZ-induced diabetes ( Yi et al, 2011 ), db/db mice ( Lu et al, 2013 ; Hou et al, 2018 ), BTBR ob/ob mice ( Morigi et al, 2020 ), and diabetic spontaneously hypertensive rats (SHR) ( Tang et al, 1997 ). This has been associated with increased oxidative stress in kidney mitochondria.…”

Section: Physiological Significance Of Manganese Superoxide Dismutasementioning

confidence: 99%

Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease

Kitada

Ogura

et al. 2020

Front. Physiol.

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The mitochondria are a major source of reactive oxygen species (ROS). Superoxide anion (O 2 •– ) is produced by the process of oxidative phosphorylation associated with glucose, amino acid, and fatty acid metabolism, resulting in the production of adenosine triphosphate (ATP) in the mitochondria. Excess production of reactive oxidants in the mitochondria, including O 2 •– , and its by-product, peroxynitrite (ONOO – ), which is generated by a reaction between O 2 •– with nitric oxide (NO • ), alters cellular function via oxidative modification of proteins, lipids, and nucleic acids. Mitochondria maintain an antioxidant enzyme system that eliminates excess ROS; manganese superoxide dismutase (Mn-SOD) is one of the major components of this system, as it catalyzes the first step involved in scavenging ROS. Reduced expression and/or the activity of Mn-SOD results in diminished mitochondrial antioxidant capacity; this can impair the overall health of the cell by altering mitochondrial function and may lead to the development and progression of kidney disease. Targeted therapeutic agents may protect mitochondrial proteins, including Mn-SOD against oxidative stress-induced dysfunction, and this may consequently lead to the protection of renal function. Here, we describe the biological function and regulation of Mn-SOD and review the significance of mitochondrial oxidative stress concerning the pathogenesis of kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), with a focus on Mn-SOD dysfunction.

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C3a receptor blockade protects podocytes from injury in diabetic nephropathy

Cited by 55 publications

References 64 publications

Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1–associated membranous nephropathy

Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1–associated membranous nephropathy

Thrombomodulin ameliorates transforming growth factor-β1–mediated chronic kidney disease via the G-protein coupled receptor 15/Akt signal pathway

Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease

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