Glomerular Elasticity and Gene Expression Patterns Define Two Phases of Alport Nephropathy

Abstract

AbstractRationaleEarly steps in glomerular injury in collagen IV nephropathies are poorly understood.ObjectivesWe characterized structural, functional, and biophysical properties of glomerular capillaries and podocytes inCol4α3-/-mice and analyzed kidney cortex transcriptional profiles at various disease stages. We investigated the effects of TUDCA (suppresses ER stress) on these parameters and used human FSGS transcriptomic data to identify pathways rescued by TUDCA.FindingsInCol4α3-/-mice, podocyte injury develops by 3 months, with maximum glomerular capillary deformability and 40% podocyte loss at 4 months. This period is followed is followed by glomerular capillary stiffening, proteinuria, reduced renal function, inflammatory infiltrates, and fibrosis. Bulk RNA sequencing at sequential time points revealed progressive increases in inflammatory and injury gene expression, including activation of the TNF pathway. Mapping Podocyte-enriched genes from FSGS patients to mice showed that TUDCA, which mitigated renal injury suppressed molecular pathways associated with podocyte stress, hypertrophy and tubulo-interstitial injury.ConclusionsCol4α3-/-nephropathy progresses in two phases. The first is characterized by podocytopathy, increased glomerular capillary deformability and accelerated podocyte loss, and the second by increased capillary wall stiffening and renal inflammatory and profibrotic pathway activation. The response of podocytes to TUDCA treatment provides insights into signaling pathways in Alport and related nephropathies.