Topic Overview:

Chronic kidney disease (CKD) is a devastating pathology that culminates in renal failure and has exceptionally high mortality rates, especially among older people. It is estimated that, in the United States alone, around 30 million people are afflicted by chronic kidney disease, and its incidence is growing worldwide as the population ages. Identifying the pathomechanisms that drive CKD progression is critical for helping patients. A hallmark of CKD is renal tubular senescence, characterized by a decline in tubular epithelium regeneration and tubular cell G2/M arrest, which in turn promotes interstitial fibrosis and inflammation in the kidney. The questions of why tubular cells lose their ability to rejuvenate the kidney in CKD and how this loss is related to aging have remained largely unanswered.

Airik and colleagues have previously identified mutations in genes that cause early-onset CKD in children and adults in their 30s as part of nephronophthisis (NPHP), a premature renal aging syndrome. Molecular analysis of NPHP gene products using cell-culture techniques, proteomics assays, and orthologous mouse models revealed that their functions intersect with cell-cycle regulation, cellular metabolism, and DNA damage repair pathways. These observations engendered the hypothesis that perturbation of cell-cycle progression due to impaired DNA repair in the kidneys is an apical cause of cellular senescence and tubulointerstitial fibrosis in humans. In Airik’s talk, he will present evidence in support of this hypothesis and discuss the wider implications of his findings for the management of chronic kidney disease in humans.