The Complement C3a and C3a Receptor Pathway in Kidney Diseases

Gao, Shuang; Cui, Zhao; Zhao, Ming‐Hui

doi:10.3389/fimmu.2020.01875

Cited by 34 publications

(22 citation statements)

References 67 publications

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“…IHC staining and quantitative analysis showed the upregulated expression of nephrin and WT1 in Crp −/− DKD rats in comparison with wt and huCRP tg DKD rats (Figure 5A,C), which demonstrated the negative effects of CRP on podocyte survival and function. Furthermore, owing to the intense deposition of C3a in glomeruli (Figure 3C) and many studies reporting the expression of C3aR on podocytes, 40,41 we speculated that the C3a/C3aR axis is activated in podocyte autophagy. Then we found that C3aR expression was remarkably increased in Crp −/− DKD rats compared with wt and huCRP tg DKD rats (Figure 5B,D), which implied that CRP might regulate C3aR expression on podocytes.…”

Section: Resultsmentioning

confidence: 85%

C‐reactive protein inhibits C3a/C3aR‐dependent podocyte autophagy in favor of diabetic kidney disease

Zhang

Gong

et al. 2022

The FASEB Journal

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Numerous studies have reported the pathogenic roles of C‐reactive protein (CRP) and complement activation in diabetic kidney disease (DKD) individually. However, considering the potent regulatory effect of CRP on complement activation, it remains unclear whether CRP participates in DKD pathogenesis by regulating complement activation. Moreover, this work focuses on complement activation in rats, which aims at settling the dispute that whether rat CRP can activate the complement system. To address this question, the complement effectors C3a, C5a, and C5b‐9 were examined in human patients with diabetic nephropathy (DN) and wt, Crp−/−, and huCRPtg rats with STZ‐diabetic DKD. The Crp−/− rats showed more C3a accumulation in blood and glomeruli than wt and huCRPtg rats. The balance between autophagy and apoptosis was evaluated in DKD rats, and Crp−/− rats showed increased podocyte autophagy compared with wt and huCRPtg rats. Meanwhile, stable CRP‐overexpression and CRP‐knockout cell lines were established and used to demonstrate that CRP suppresses C3a‐induced podocyte autophagy under high‐glucose conditions. We further verified that the inhibition of C3a‐induced podocyte autophagy by CRP was dependent on C3aR expression and that this effect could be reversed with a C3aR antagonist and agonist. Therefore, our findings provide evidence that CRP suppresses podocyte autophagy to accelerate the development of DKD by inhibiting C3a/C3aR axis signaling, which may help in the development of a new therapeutic strategy for the management of podocyte autophagy and DKD. In addition, rat CRP has been shown to be identical to human CRP in the activation of autologous complement and interspecific complement.

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Section: Resultsmentioning

confidence: 85%

C‐reactive protein inhibits C3a/C3aR‐dependent podocyte autophagy in favor of diabetic kidney disease

Zhang

Gong

et al. 2022

The FASEB Journal

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“…Despite the large number of clinical trials targeting C5, C5a and C5aR1 trials targeting C3, C3a and C3aR are less. Protective effects of C3aR deficiency or antagonism have been reported in membranous nephropathy, diabetic nephropathy, focal segmental glomerulosclerosis, ischemia reperfusion injury and other renal diseases (Morigi et al ., 2020, Gao et al ., 2022 and review in Gao et al ., 2020). However, in the present study, C3aR deficiency clearly did not protect the kidney from hypertensive injury.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of complement C3a and C5a receptors does not prevent angiotensin II–induced hypertension and hypertensive end-organ damage

Bode

Herrnstadt

Dreher

et al. 2023

Preprint

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Complement activation may drive the pathology of hypertension through its effects on innate and adaptive immune responses, aside from direct effects on tissue integrity. Recently it was suggested that hypertension is a disease characterized by a decreased number of forkhead box protein 3 (Foxp3)+ regulatory T cells (Tregs) and that combined deficiency of the anaphylatoxin receptors C3aR (complement component 3a receptor) and C5aR1 (complement component 5a receptor) upregulates Tregs and heals hypertension and hypertensive end-organ damage. Using data from the European Renal cDNA Bank, renal single cell sequencing data and immunohistochemistry we found increased expression of C3aR, C5aR1 and Foxp3 in kidney biopsies of patients with hypertensive nephropathy. Expression of C3aR and C5aR1 was mainly found in myeloid cells and almost absent in lymphocytes. Next we aimed to determine whether C3aR or C3aR/C5aR1 double deficiency decreases blood pressure and hypertensive injury in Ang II infused mice. However, no difference was found for blood pressure, renal injury (albuminuria, glomerular and tubulointerstitial injury, inflammation) and cardiac injury (cardiac fibrosis, heart weight, gene expression) between C3aR KO and WT mice as well as C3aR/C5aR1 double KO respectively. Ang II as well as DOCA salt induced hypertension resulted in an increased number of Tregs in the kidney. This was valid in mice of the Balb/c and C57black strain. In summary, hypertensive nephropathy in patients is characterized by an increased expression of anaphylatoxin receptors and Tregs. However, deficiency of C3aR alone or C3aR and C5aR1 combined does not influence blood pressure or hypertensive end-organ damage in Ang II induced hypertension. Targeting the anaphylatoxin receptors C3aR alone or in combination with C5aR1 is not useful to treat cardiovascular disease in hypertension.

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“…Among these core genes, some have been shown to play an important role in the pathogenesis of DN, C3 ( 52 , 53 ), ALB ( 54 – 56 ), EGF ( 57 ), EGR1 ( 58 – 61 ), COL1A2 ( 62 ), FN1 ( 63 , 64 ), CD44 ( 65 , 66 ), FOS ( 67 ), PLG ( 68 , 69 ), and DUSP1 ( 70 ). It is well-known that inflammation and fibrosis play an important role in the pathogenesis of the DN glomerulus ( 71 ).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Reveals Crosstalk Among Platelets, Immune Cells, and the Glomerulus That May Play an Important Role in the Development of Diabetic Nephropathy

et al. 2021

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Diabetic nephropathy (DN) is the main cause of end stage renal disease (ESRD). Glomerulus damage is one of the primary pathological changes in DN. To reveal the gene expression alteration in the glomerulus involved in DN development, we screened the Gene Expression Omnibus (GEO) database up to December 2020. Eleven gene expression datasets about gene expression of the human DN glomerulus and its control were downloaded for further bioinformatics analysis. By using R language, all expression data were extracted and were further cross-platform normalized by Shambhala. Differentially expressed genes (DEGs) were identified by Student's t-test coupled with false discovery rate (FDR) (P < 0.05) and fold change (FC) ≥1.5. DEGs were further analyzed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID) to enrich the Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. We further constructed a protein-protein interaction (PPI) network of DEGs to identify the core genes. We used digital cytometry software CIBERSORTx to analyze the infiltration of immune cells in DN. A total of 578 genes were identified as DEGs in this study. Thirteen were identified as core genes, in which LYZ, LUM, and THBS2 were seldom linked with DN. Based on the result of GO, KEGG enrichment, and CIBERSORTx immune cells infiltration analysis, we hypothesize that positive feedback may form among the glomerulus, platelets, and immune cells. This vicious cycle may damage the glomerulus persistently even after the initial high glucose damage was removed. Studying the genes and pathway reported in this study may shed light on new knowledge of DN pathogenesis.

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The Complement C3a and C3a Receptor Pathway in Kidney Diseases

Cited by 34 publications

References 67 publications

C‐reactive protein inhibits C3a/C3aR‐dependent podocyte autophagy in favor of diabetic kidney disease

C‐reactive protein inhibits C3a/C3aR‐dependent podocyte autophagy in favor of diabetic kidney disease

Deficiency of complement C3a and C5a receptors does not prevent angiotensin II–induced hypertension and hypertensive end-organ damage

Bioinformatics Analysis Reveals Crosstalk Among Platelets, Immune Cells, and the Glomerulus That May Play an Important Role in the Development of Diabetic Nephropathy

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