INPP5D/SHIP1-mediated immunometabolic remodeling of renal monocytes in idiopathic membranous nephropathy

Idiopathic membranous nephropathy (IMN) is an antibody-mediated glomerulopathy in which podocyte-directed autoimmunity is well characterized, whereas the immunometabolic programs of innate immune cells within the renal microenvironment remain poorly defined. Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1, encoded by INPP5D) is a key negative regulator of PI3K signaling in myeloid cells and an emerging immunopharmacologic target, but its role in IMN is unknown.

Bulk and single-cell RNA-seq analyses were performed using public human IMN datasets, and the passive Heymann nephritis (PHN) rat model was used specifically for in vivo validation of key histopathological and signaling readouts to dissect INPP5D/SHIP1-centered immunometabolic pathways in IMN. Public glomerular transcriptomes from IMN and control kidneys were deconvoluted using CIBERSORT and ESTIMATE to quantify immune/stromal components and infer infiltrating leukocyte subsets. Differentially expressed genes were intersected with curated immune- and metabolism-related gene sets to identify immunometabolic hubs. Single-cell RNA-sequencing datasets were used to localize INPP5D and related pathways to specific renal cell populations, reconstruct monocyte differentiation trajectories and metabolic states, and infer ligand-receptor communication with podocytes. Key findings were validated in PHN rats by assessing proteinuria, renal histopathology, immune cell markers, podocyte proteins and SHIP1-related signaling molecules.

IMN kidneys exhibited elevated immune and stromal scores, with increased infiltration of monocytes and naïve B cells and a relative depletion of regulatory T cells. Cross-differential analyses identified five overlapping immune-metabolic genes (INPP5D, PLCG1, KL, ACO1, ARG2), among which INPP5D was significantly upregulated and predominantly expressed in monocytes. Single-cell analyses revealed that renal monocytes in IMN displayed enhanced steroid biosynthesis, a skewed trajectory toward an M1-like state and strengthened SPP1-mediated communication with podocytes. In PHN rats, we recapitulated key clinical and histological features of IMN, accompanied by increased monocyte/macrophage infiltration, altered podocyte markers, and upregulation of SHIP1 and downstream PI3K/Akt signaling.

These data delineate an INPP5D/SHIP1-centered immunometabolic program in renal monocytes as a potential regulatory factor of pathological monocyte-podocyte crosstalk in IMN. Targeting SHIP1-related PI3K/Akt pathways and monocyte immunometabolism may offer novel immunomodulatory strategies for risk stratification and disease modification in membranous nephropathy.