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Podocyte Pathogenic Bone Morphogenetic Protein-2 Pathway and Immune Cell Behaviors in Primary Membranous Nephropathy
Anxiang Cai1, Yiwei Meng2,3, Hang Zhou1
1Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
Abstract:
Primary membranous nephropathy (PMN) is one of the leading causes of end-stage renal disease, and the most frequent cause of massive proteinuria in nondiabetic adults, resulting in fatal complications. However, the underlying pathomechanisms of PMN remain largely unclear. Here, single-cell RNA sequencing is employed to analyze kidney biopsies from eleven PMN patients and seven healthy subjects. Profiling 44 060 cells from patients allowed us to characterize the cellular composition and cell-type-specific gene expression in the PMN kidney. The complement-induced BMP2/pSMAD1/COL4 pathway is identified as the pathogenic pathway in podocytes, bridging two key events, i.e., complement system activation and glomerular basement membrane thickening in PMN. Augmented infiltration and activation of myeloid leukocytes and B lymphocytes are found, profiling delicate crosstalk of immune cells in PMN kidneys. Overall, these results provide valuable insights into the roles of podocytes and immune cells in PMN, and comprehensive resources toward the complete understanding of PMN pathophysiology.
Insights
Primary membranous nephropathy (PMN) involves complement activation and glomerular basement membrane thickening. This study reveals a key pathway in podocytes and immune cell interactions, offering insights into PMN pathophysiology.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Primary membranous nephropathy (PMN) is a major cause of end-stage renal disease and proteinuria in adults.
- The precise molecular mechanisms driving PMN pathogenesis are not fully understood.
Purpose of the Study:
- To elucidate the cellular and molecular underpinnings of primary membranous nephropathy.
- To identify key pathways and cellular players involved in PMN development.
Main Methods:
- Single-cell RNA sequencing was performed on kidney biopsies from PMN patients and healthy controls.
- Analysis included characterization of cellular composition and cell-type-specific gene expression.
Main Results:
- A complement-induced BMP2/pSMAD1/COL4 pathway in podocytes was identified as central to PMN.
- This pathway links complement activation to glomerular basement membrane thickening.
- Increased infiltration and activation of myeloid leukocytes and B lymphocytes were observed, indicating immune cell crosstalk.
Conclusions:
- The study provides novel insights into the roles of podocytes and immune cells in PMN pathogenesis.
- Identified pathways and cellular interactions offer targets for understanding and potentially treating PMN.
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