Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis

Abstract

Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-β signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

“…3,28 A transgenic mouse model has shown that mitochondrial dysfunction in podocytes induced by TGF-b signaling preceded the manifestation of segmental glomerulosclerosis. 29 In addition, diabetic mouse models and in vitro studies have demonstrated that hyperglycemia induced mitochondrial fragmentation in podocytes, endothelial cells, and renal tubular cells. 7,30 Finally, WBCs are involved in the kidney's response to injury as evidenced by leukocyte infiltration in kidney tissues of patients with CKD and in experimental models.…”

Comparison of Glomerular and Podocyte mRNA Profiles in Streptozotocin-Induced Diabetes

“…8-OxoG staining on formaldehydeperfused frozen sections was done as previously described 16 using anti-8-oxoG monoclonal antibody (N45.1; Japan Institute for the Control of Aging). Sections were also stained with rabbit anti-podocin antibody (a gift from Dr. Peter Mundel) and antibodies for CD31 (MEC 7.46; Abcam, Inc.), E-cadherin (4065; Cell Signaling Technology), Alpha SMA (5694; Abcam, Inc.), and Cleaved caspase3 (9664; Cell Signaling Technology).…”

“…8-Oxoguanine (8-oxoG) immunostaining further confirmed that the oxidative stress in the diabetic kidney is increased mostly in glomerular endothelial cells rather than in podocytes (Supplemental Figure 11, A-C), which is consistent with a recently published study. 16 These findings raise an important question as Figure 1. Heat map and PCA analysis between glomeruli and sorted podocytes from control and diabetic mice.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Although their regenerative potential is much higher than that of podocytes, chronic exposure of these cells to injurious stimuli in transplantation, for example, immunologic, hypertensive or toxic, likely contributes to glomerulosclerosis (113,114). In vivo imaging studies revealed a novel concept of glomerular inflammation in which leukocytes are retained on the glomerular endothelium for longer periods compared to other vascular beds but do not extravasate (115).…”