Podocyte endowment and the impact of adult body size on kidney health

Abstract

Low birth weight is a risk factor for chronic kidney disease (CKD), while adult podocyte depletion is a key event in the pathogenesis of glomerulosclerosis. However, whether low birth weight due to poor maternal nutrition is associated with low podocyte endowment and glomerulosclerosis in later life is not known. Female Sprague-Dawley rats were fed a normal (NPD, 20%) or low (LPD, 8%) protein diet from 3 weeks before mating until postnatal day 21 (PN21), when kidneys from some male offspring were taken for quantitation of podocyte number and density in whole glomeruli using immunolabeling, tissue clearing and confocal microscopy. Remaining offspring were fed a normal or high fat diet until 6 months to induce catch-up growth and excessive weight gain, respectively. At PN21, podocyte number per glomerulus was 15% lower in low birth weight (LPD) than normal birthweight (NPD) offspring, with this deficit greater in outer glomeruli. Surprisingly, podocyte number in LPD offspring increased in outer glomeruli between PN21 and 6 months, although an overall 9% podocyte deficit persisted. Postnatal fat feeding to LPD offspring did not alter podometric indices or result in glomerular pathology at 6 months, whereas fat feeding in NPD offspring was associated with far greater body and fat mass as well as podocyte loss, reduced podocyte density, albuminuria and glomerulosclerosis. This is the first report that maternal diet can influence podocyte endowment. Our findings provide new insights into the impact of low birth weight, podocyte endowment and postnatal weight on podometrics and renal health in adulthood.

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

“…Olivetti et al ( 1980 ) previously described a similar pattern between young, adult, and uninephrectomized rats. Interestingly, Cullen‐McEwen et al ( 2021 ) recently reported a similar postnatal increase in podocyte number in male rats fed a maternal low protein diet before birth and then switched to a normal diet. They found that between postnatal 3 weeks and 6 months of age, podocyte number per glomerulus increased by approximately 9% (12 podocytes per glomerulus), although podocyte number remained 9% lower than NPD control rats.…”

“…In contrast, hypoxia did not give rise to low podocyte endowment in female offspring (Goncalves et al, 2020 ). Cullen‐McEwen et al ( 2021 ) reported that a maternal low protein diet resulted in a podocyte deficit of 15% in male Sprague–Dawley rat offspring (female offspring were not studied) at 3 weeks of age. These findings of podocyte deficits in the present study and these two earlier studies in two species and two models of developmental programming suggest that other perturbations to the maternal environment likely result in a podocyte deficit.…”

“…In the last 30 years, a clear association between low birth weight/intrauterine growth restriction and increased risk of adult kidney disease (Hoy et al, 1999 ; Vikse et al, 2008 ; White et al, 2009 ) has resulted in a multitude of studies assessing the impact of the maternal environment on offspring nephron endowment (number of nephrons at the completion of nephrogenesis) and the resulting likelihood of kidney disease as an adult (Gray et al, 2010 ; Hoppe, Evans, Moritz, et al, 2007 ; Langley‐Evans et al, 1999 ; Singh et al, 2007 ; Villar‐Martini et al, 2009 ; Walton et al, 2017 ). While it is now well accepted that low birth weight/intrauterine growth restriction is associated with a permanent low nephron endowment we have recently shown that growth restriction, induced by low protein diet, also impacts podocyte endowment (Cullen‐McEwen et al, 2021 ).…”

Chorioamnionitis Causes Kidney Inflammation, Podocyte Damage, and Pro-fibrotic Changes in Fetal Lambs

“…The reduction of WT1-positive nuclei and synptopodin expression could indicate a reduced formation or a loss of podocytes, in which case the remaining podocytes have to compensate for the lower number by expanding in order to cover the glomerular surface area ( 22 ). Recently, a lower number of podocytes in a rat model of IUGR was indeed described ( 23 ). On the other hand, the lower number of WT1-positive nuclei can also be explained by podocytes undergoing phenotypic dysregulation, as described by Barisoni et al in collapsing focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy ( 24 ).…”

Low Nephron Number Induced by Maternal Protein Restriction Is Prevented by Nicotinamide Riboside Supplementation Depending on Sirtuin 3 Activation

“…In this setting, the offspring of mothers fed a low protein (LP) diet had a reduced number of nephrons and morphological and ultrastructural alterations in the glomerular architecture [ 20 ]. A recent paper showed that podocyte number can be developmentally programmed and was lower in rats born to mothers fed a LP diet [ 21 ]. Moreover, a LP diet during pregnancy induces significant changes in the gene expression of the developing kidney, the metanephroi [ 22 , 23 ].…”