Accelerated Epithelial Cell Detachment in Progression of Kidney Disease

Chronic kidney disease (CKD) is a progressive condition that puts a substantial burden on individuals, families, and health care systems. CKD is already a leading cause of death world-wide, and the incidence and prevalence is expected to rise. CKD is about 34% more common in veterans than in the general population, and U.S. Department of Veterans Affairs cares for over 600,000 veterans with CKD. The VA spents approximately $18 billion for the care of patients with CKD without including costs for kidney replacement therapy (KRT). Research has established a multi-modular therapeutic approach that delays progression of CKD, but the residual risk remains unacceptably high. TGF beta (TGFβ) pathway is a key-mechanisms for progression of kidney disease, which has multiple cell-type specific divergent effects. Therefore, focusing on more specific downstream mediators within the pathway is a promising strategy for intervention. We identified TGF-beta1 (TGFβ1) signaling as the central upstream mediator of podocyte loss, a mechanism for progression of kidney disease, in kidney tissue of patients with early-stage kidney disease. Further analysis identified TGFβ-induced (TGFBI), a TGFβ1 downstream target gene and secreted protein that functions as anti-adhesive factor, as one of the top genes associated with podocyte depletion. Furthermore, we found that TGFBI is strongly up regulated in kidney biopsy tissue from patients with FSGS and diabetic kidney disease (DKD) and in Tgfβ-transgenic mice (Tgfβ-TG), a model of progressive glomerulosclerosis, in which podocyte loss is a prominent phenotype and mechanisms of disease progression. In cultured human podocytes, exogenous TGFBI treatment led to disruption of the cytoskeleton and podocyte detachment. Furthermore, we determined that increased urinary amounts of TGFBI were highly significant associated with progression in patients with kidney disease, in particular DKD. We hypothesize that TGFBI promotes podocyte loss by decreasing attachment of podocytes to GBM, thereby leading to glomerulosclerosis and progressive renal failure. We specifically aim to determine whether TGFBI mediates podocyte loss in mice that are either deficient for or overexpress Tgfbi and have diabetic kidney disease induced by streptozotin plus uni-nephrectomy mice (Aim 1). Furthermore, we propose to determine the molecular mechanisms underlying TGFBI-mediated podocyte loss by assessing podocyte attachment, cytoskeleton rearrangement, activation of cell-death signaling, binding of TGFBI to integrins and other ECM and cell membrane proteins in cultured human podocytes (Aim 2). In addition, we will assess whether urinary TGFBI (uTGFBI) is associated with intra-renal TGFβ/Smad signaling activity, renal pathologic changes and adverse clinical outcomes in patients with kidney disease in patients enrolled in observation clinical cohort of Clinical Phenotyping and Resource Biobank Core (C-PROBE) (Aim 3). If successful, these studies will justify future research developing interventions that target the TGFBI- induced podocyte detachment and potentially other detrimental effects on renal epithelial cells. Project Number: 1I01BX007185-01 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Markus Bitzer | Institution: VETERANS HEALTH ADMINISTRATION, ANN ARBOR, MI | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NEPH-N (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11181981