The genetic basis of kidney ageing
Chronic kidney disease is often treated via dialysis and in severe cases kidney transplantation, but patient outcomes and quality of life remain poor. Novel solutions are urgently needed to resolve age-associated organ damage and chronic loss of renal function. Recent studies have found that lost podocytes cannot be regenerated or replaced. Podocytes are highly specialised kidney cells that form the filtration barrier. They are degenerated in ageing kidneys and in patients with chronic kidney disease. The RENAL EPIGENETICS (Epigenetic modifications in glomerular nephropathy and renal aging) initiative is investigating the mechanisms of renal ageing with a focus on post-mitotic podocytes. These cells are sensitive to reactive oxygen species and growth factors, which could alter gene expression and cell behaviour. The researchers also aim to elucidate the role of mTOR and autophagy-dependent epigenetic modifications in kidney ageing using suitable mouse models. Some key discoveries were made during the first project period. Scientists identified that autophagic cell repair plays a major role in cellular ageing for long-lived glomerular podocytes. In particular, the mTOR-regulated phophoinositolkinase class 3, Vps34, was found to be a key player in endocytotic and autophagic vesicle maturation. A first, project researchers analysed podocyte-specific knockouts of epigenetic regulators in kidney ageing to obtain better insight into the poorly understood mTOR-signalling pathway. Studies revealed that transcriptional silencing of the Ras-GTP suppressor RASAL1 and aberrant promoter CpG island methylation leads to chronic kidney disease. Already, the RENAL EPIGENETICS study has identified factors involved in renal ageing and provided biomarkers that are potential targets for therapy as well as monitoring disease progression. Other potential applications from the ongoing study include risk prediction and prevention of diabetic nephropathy.
Keywords
Kidney ageing, kidney disease, epigenetic, podocytes, nephropathy, renal ageing
