Gene Expression as a Guide to the Development of Novel Therapies in Primary Glomerular Diseases.

Panagiotis Garantziotis,Eleni Frangou,Ioannis Boletis,Stavros A P Doumas

doi:10.3390/jcm10112262

Abstract

Despite improvements in understanding the pathogenic mechanisms of primary glomerular diseases, therapy still remains nonspecific. We sought to identify novel therapies targeting kidney-intrinsic injury of distinct primary glomerulonephritides through computational systems biology approaches. We defined the unique transcriptional landscape within kidneys from patients with focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN) and thin basement membrane nephropathy (TBMN). Differentially expressed genes were functionally annotated with enrichment analysis, and distinct biological processes and pathways implicated in each primary glomerular disease were uncovered. Finally, we identified novel drugs and small-molecule compounds that may reverse each glomerulonephritis phenotype, suggesting they should be further tested as precise therapy in primary glomerular diseases.

Highlights

Primary glomerulonephritides encompass a heterogeneous group of glomerular diseases characterized by abnormal activation of innate and/or adaptive immune responses due to kidney-intrinsic factors [1]
Functional enrichment analysis of differentially expressed genes identified distinct biological processes and pathways implicated in each primary glomerular disease
By the use of computational systems biology resources, we revealed novel, not previously identified, drugs and small-molecule compounds that may reverse the phenotype of primary glomerular diseases in a glomerulonephritis-specific manner

Summary

Introduction

Primary glomerulonephritides encompass a heterogeneous group of glomerular diseases characterized by abnormal activation of innate and/or adaptive immune responses due to kidney-intrinsic factors [1]. Relatively rare, they represent the most common cause of end-stage renal disease in young adults and are associated with increased morbidity, mortality and healthcare costs [2]. Despite improvements in understanding the underlying pathogenic mechanism of each glomerular disease, therapy still remains nonspecific and includes general supportive measures coupled with immunosuppression [3,4]. Recent advances in omics technologies have provided insights into the molecular mechanisms underlying complex traits, such as glomerular diseases. Gene expression represents the intermediate phenotype between genetic variation and disease phenotypic variation and may inform about genetic and environmental effects on cells and tissues

Methods

Results

Conclusion