Complement, a Therapeutic Target in Diabetic Kidney Disease

Budge, Kelly L.; Dellepiane, Sergio; Yu, Sherry H.; Cravedi, Paolo

doi:10.3389/fmed.2020.599236

Cited by 21 publications

(27 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, suppression of the complement system might be a novel therapy for DN 36 . Further study of the role of the complement system in DN might help to initiate new therapeutic approaches 37 .…”

Section: Discussionmentioning

confidence: 99%

Activation of complement C1q and C3 in glomeruli might accelerate the progression of diabetic nephropathy: Evidence from transcriptomic data and renal histopathology

Jiao

Jiang

Wang

et al. 2022

J of Diabetes Invest

View full text Add to dashboard Cite

Aims/Introduction It is not unclear whether the complement system is involved in the pathogenesis of diabetic nephropathy (DN). We explored the role of the complement system in glomeruli from patients with DN using integrated transcriptomic bioinformatics analysis and renal histopathology. Materials and Methods Four datasets (GSE30528, GSE104948, GSE96804 and GSE99339) from the Gene Expression Omnibus database were integrated. We used a protein–protein interaction network and the Molecular Complex Detection App to obtain hub genes. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were carried out to identify significant pathways. We also investigated the associations of C1q and C3 deposition on renal histopathology with clinical data, pathological parameters and renal survival in DN patients. Results We identified 47 up‐ and 48 downregulated genes associated with DN. C3, C1QB and C1QA were found to be complement‐related hub genes. The gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses identified complement activation and humoral immune response as the significant oncology terms, with C1QB and C3 positioned at the center of the pathway. Regarding renal histopathology, patients with both C1q and C3 deposition had more severe glomerular classes. Multivariate Cox proportional hazards regression showed that the deposition of glomerular C1q and C3 was an independent risk factor for kidney failure. Patients with high C1q, C3 or C4d expression in glomeruli were more likely to progress to kidney failure, whereas glomerular mannose‐binding lectin was rare. Conclusions Complement activation is involved in the development of DN, and activation of the classical complement pathway in glomeruli might accelerate disease progression.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of complement C1q and C3 in glomeruli might accelerate the progression of diabetic nephropathy: Evidence from transcriptomic data and renal histopathology

Jiao

Jiang

Wang

et al. 2022

J of Diabetes Invest

View full text Add to dashboard Cite

show abstract

“…Indeed previous research has shown that the activation of the alternative and lectin pathways may also be involved in the pathogenesis of DN ( 25 – 27 ). Given the role of the complement system in the pathogenesis of DN, inhibition of the specific components of the complement system may be an effective therapeutic strategy for DN ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Complement Deposition Predicts Worsening Kidney Function and Underlines the Clinical Significance of the 2010 Renal Pathology Society Classification of Diabetic Nephropathy

Jiang

Di²,

Jiao³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

ObjectivesConverging evidence points towards a role of the complement system in the pathogenesis of diabetic nephropathy (DN). The classification system of diabetic kidney lesions devised by the Renal Pathology Society (RPS) in 2010 are based on the pathogenic process of DN. Therefore, we investigated the correlation between glomerular C3 deposits and RPS DN classification and the combined deleterious effects thereof on kidney function.MethodsThe study analyzed data from 217 diabetic patients who underwent renal biopsy between 2010 and 2021 and were found to have DN as the only glomerular disease. C3 deposition was considered positive if the glomerular C3 immunofluorescence intensity was at the trace or ≥1+ level. We divided DN into five glomerular lesion classes and separately evaluated the degree of interstitial and vascular involvement. The primary outcome was the composite of a ≥50% decline from the initial estimated glomerular filtration rate, end-stage renal disease, and death.ResultsNone of the patients were classified into class I, and few were classified into classes IIa (7.8%) and IV (9.2%). Most patients were classified as IIb (30.9%) and III (52.1%). C3 deposition was detected in 53.9% of patients. Multivariate logistic regression analysis showed that DN class was significantly correlated with C3 deposits [odds ratio, 1.59; 95% confidence interval (CI), 1.08–2.36; p = 0.02). During a median follow-up of 22 months, 123 (56.7%) patients reached the composite outcome. The endpoints occurred more frequently in patients with C3 deposition (69.2 vs. 42%) compared with those without C3 deposition. Patients with C3 deposition in either class IIb [hazards ratio (HR), 3.9 (95% CI, 1.14–13.17) vs. 2.46 (95% CI, 0.68–8.89)] or III [HR, 4.98 (95% CI, 1.53–16.23) vs. 2.63 (95% CI, 0.77–9.0)] had a higher risk of adverse kidney outcomes than those without C3 deposition. The prognostic accuracy of the combination of DN class and C3 deposits at 1 and 3 years was higher than that for DN class only.ConclusionsComplement deposition together with DN class predicts more rapid deterioration of kidney function in DN, which underlines the clinical significance of the DN phenotype according to the RPS classification.

show abstract

“…Poor metabolic control in hyperglycemia and DKD activates complement mediated by lectin, by the glycation of pattern recognition molecules [ 57 ]. These changes lead to the dysregulated activation of the complement system.…”

Section: Complement Systemmentioning

confidence: 99%

Molecular Mechanisms of Diabetic Kidney Disease

Rico-Fontalvo

Aroca

Cabrales

et al. 2022

IJMS

View full text Add to dashboard Cite

The inflammatory component of diabetic kidney disease has become of great interest in recent years, with genetic and epigenetic variants playing a fundamental role in the initiation and progression of the disease. Cells of the innate immune system play a major role in the pathogenesis of diabetic kidney disease, with a lesser contribution from the adaptive immune cells. Other components such as the complement system also play a role, as well as specific cytokines and chemokines. The inflammatory component of diabetic kidney disease is of great interest and is an active research field, with the hope to find potential innovative therapeutic targets.

show abstract

Complement, a Therapeutic Target in Diabetic Kidney Disease

Cited by 21 publications

References 79 publications

Activation of complement C1q and C3 in glomeruli might accelerate the progression of diabetic nephropathy: Evidence from transcriptomic data and renal histopathology

Activation of complement C1q and C3 in glomeruli might accelerate the progression of diabetic nephropathy: Evidence from transcriptomic data and renal histopathology

Complement Deposition Predicts Worsening Kidney Function and Underlines the Clinical Significance of the 2010 Renal Pathology Society Classification of Diabetic Nephropathy

Molecular Mechanisms of Diabetic Kidney Disease

Contact Info

Product

Resources

About