The ability of remaining glomerular podocytes to adapt to the loss of their neighbours decreases with age

Abstract

Progressive podocyte loss is a feature of healthy ageing. While previous studies have reported age-related changes in podocyte number, density and size and associations with proteinuria and glomerulosclerosis, few studies have examined how the response of remaining podocytes to podocyte depletion changes with age. Mild podocyte depletion was induced in PodCreiDTR mice aged 1, 6, 12 and 18 months via intraperitoneal administration of diphtheria toxin. Control mice received intraperitoneal vehicle. Podometrics, proteinuria and glomerular pathology were assessed, together with podocyte expression of p-rp-S6, a phosphorylation target that represents activity of the mammalian target of rapamycin (mTOR). Podocyte number per glomerulus did not change in control mice in the 18-month time period examined. However, control mice at 18 months had the largest podocytes and the lowest podocyte density. Podocyte depletion at 1, 6 and 12 months resulted in mild albuminuria but no glomerulosclerosis, whereas similar levels of podocyte depletion at 18 months resulted in both albuminuria and glomerulosclerosis. Following podocyte depletion at 6 and 12 months, the number of p-rp-S6 positive podocytes increased significantly, and this was associated with an adaptive increase in podocyte volume. However, at 18 months of age, remaining podocytes were unable to further elevate mTOR expression or undergo hypertrophic adaptation in response to mild podocyte depletion, resulting in marked glomerular pathology. These findings demonstrate the importance of mTORC1-mediated podocyte hypertrophy in both physiological (ageing) and adaptive settings, highlighting a functional limit to podocyte hypertrophy reached under physiological conditions.

Nephron deficit and low podocyte density increase risk of albuminuria and glomerulosclerosis in a model of diabetes

“…It is well established that a range of perturbations to the maternal environment including low protein diet (Hoppe, Evans, Bertram, et al, 2007 ; Langley‐Evans et al, 1999 ; Zimanyi et al, 2004 ), hypoxia (Walton et al, 2017 ), alcohol exposure (Gray et al, 2008 , 2010 ; Kenna et al, 2012 ), gestational diabetes (Hokke et al, 2016 ), and glucocorticoid exposure (Dickinson et al, 2007 ; Singh et al, 2007 ; Wintour et al, 2003 ) result in a nephron deficit and this may well be the case also for podocyte endowment. Given the association between podocyte depletion and glomerular pathology (Puelles et al, 2019 ; Puelles, van der Wolde, et al, 2016 ; van der Wolde et al, 2022 ; Wharram et al, 2005 ; Wiggins et al, 2005 ) further studies on the regulation of podocyte endowment are warranted. Indeed, low podocyte endowment may be an important factor leading to the increased risk of CKD for patients born small or early (Luyckx et al, 2013 , 2017 ; White et al, 2009 ).…”

Nephrons, podocytes and chronic kidney disease: Strategic antihypertensive therapy for renoprotection

“…Podocyte hypertrophy (increased podocyte volume) can occur in response to various stimuli. This process is also considered to function as a method of compensation to maintain the coverage area of the glomerular capillaries under conditions of podocyte depletion [ 48 , 49 ]. Fukuda et al observed that the glomerular tuft volume exponentially increased with body weight gain in nephrectomized rats.…”