Accelerated podocyte detachment and progressive podocyte loss from glomeruli with age in Alport Syndrome

Abstract

Podocyte depletion is a common mechanism driving progression in glomerular diseases. Alport Syndrome glomerulopathy, caused by defective α3α4α5 (IV) collagen heterotrimer production by podocytes, is associated with an increased rate of podocyte detachment detectable in urine and reduced glomerular podocyte number suggesting that defective podocyte adherence to the glomerular basement membrane might play a role in driving progression. Here a genetically phenotyped Alport Syndrome cohort of 95 individuals [urine study] and 41 archived biopsies [biopsy study] were used to test this hypothesis. Podocyte detachment rate (measured by podocin mRNA in urine pellets expressed either per creatinine or 24 hour excretion) was significantly increased 11-fold above control, and prior to a detectably increased proteinuria or microalbuminuria. In parallel, Alport Syndrome glomeruli lose an average 26 podocytes per year versus control glomeruli that lose 2.3 podocytes per year, an 11-fold difference corresponding to the increased urine podocyte detachment rate. Podocyte number per glomerulus in Alport Syndrome biopsies is projected to be normal at birth (558/glomerulus) but accelerated podocyte loss was projected to cause end stage kidney disease by about 22 years. Biopsy data from two independent cohorts showed a similar estimated glomerular podocyte loss rate comparable to the measured 11-fold increase in podocyte detachment rate. Reduction in podocyte number and density in biopsies correlated with proteinuria, glomerulosclerosis and reduced renal function. Thus, the podocyte detachment rate appears to be increased from birth in Alport Syndrome, drives the progression process, and could potentially help predict time to end stage kidney disease and response to treatment.

Targeting STAT3 signaling in kidney disease

“…Alport syndrome is a hereditary disease affecting collagen type IV, which leads to an altered composition of the glomer- ular basement membrane and consequential podocyte loss because of detachment (20). Glomerular dysfunction and resulting albuminuria further stimulates proximal tubule damage and eventual fibrosis, which progresses to renal failure (72).…”

Oestrogen inhibits PTPRO to prevent the apoptosis of renal podocytes

“…In a study of patients with Alzheimer's disease, podocyte exfoliation from the glomerulus was accelerated with increasing age and the number of podocytes decreased with age (2). The reduction of podocyte number and density induced diseases, including proteinuria, glomerulosclerosis and renal dysfunction (3). Oestrogen affects a variety of physiological and pathological functions of the kidney, including the regulation of haemodynamics, mesangial cells, the mesangial matrix, collagen metabolism, cytokines, the release of inflammatory mediators and glomerular filtration (4,5).…”

Urinary podocyte mRNAs precede microalbuminuria as a progression risk marker in human type 2 diabetic nephropathy

“…Alternatively, in order to compare events happening in the glomerulus to events happening in the down-stream tubular compartment we have used the podocin to aquaporin 2 mRNA ratio, where aquaporin 2 is a marker of the distal tubule/collecting duct. We now have extensive experience with this approach in both model systems and man that has proven to be informative 30,31,35,[42][43][44][45][46][47][48] .…”