The phenotypes of podocytes and parietal epithelial cells may overlap in diabetic nephropathy

Abstract

Reversal of diabetic nephropathy (DN) has been achieved in humans and mice, but only rarely and under special circumstances. Since progression of DN is related to podocyte loss, reversal of DN requires restoration of podocytes. Here we identified and quantified potential glomerular progenitor cells that could be a source for restored podocytes. DN was identified in 31 human renal biopsy cases and separated into morphologically early or advanced lesions. Markers of podocytes (WT-1, p57), parietal epithelial cells (claudin-1) and cell proliferation (Ki-67) were identified by immunohistochemistry. Podocyte density was progressively reduced with DN. Cells marking as podocytes (p57) were present infrequently on Bowman's capsule in controls, but significantly increased in histologically early DN. Ki-67 expressing cells were identified on the glomerular tuft and Bowman's capsule in DN, but rarely in controls. Cells marking as PECs were present on the glomerular tuft, particularly in morphologically advanced DN. These findings show evidence of phenotypic plasticity in podocyte and PEC populations and are consistent with studies in the BTBR ob/ob murine model in which reversibility of DN occurs with podocytes potentially regenerating from PEC precursors. Thus, our findings support, but do not prove, that podocytes may regenerate from PEC progenitors in human DN. If so, progression of DN may represent a modifiable net balance between podocyte loss and regeneration.

FoxO3 activation in hypoxic tubules prevents chronic kidney disease

“…Podocyte foot process effacement was rarely detected, although we observed more mesangial deposits in FoxO3 tub kidneys ( Figure 5A). Immunostaining for P57, a marker that identifies podocytes (36,37), showed no significant changes in the number of podocytes per glomerulus 4 weeks after IRI (9.1± 0.8 in normal mice and 7.5 ± 1.9 in FoxO3 tub and 7.2 ± 0.7 in FoxO3 ctl mice). In concordance with the electron microscopic (EM) findings, 52% of glomeruli in FoxO3 tub kidneys showed increased vimentin deposition, with focal areas showing loss of capillary loops, whereas FoxO3 ctl kidneys had milder glomerular changes, with 15% of glomeruli affected ( Figure 5B).…”

Segmental Sclerosis and Extracapillary Hypercellularity Predict Diabetic ESRD

“…Markers of parietal epithelial cells (claudin-1) have also been found within the glomerular tuft in advanced DKD without collapsing glomerulopathy. 29 Further, markers of podocytes (WT-1, p57) have been found on Bowman's capsule, suggesting that parietal epithelial cells may have the capacity to act as progenitor cells for injured podocytes. Our finding that EXHC is only present in the setting of SS, a marker of podocyte injury, would also be supportive of this notion.…”

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

“…The extent of albuminuria, as assessed by the albumin-to-creatinine ratio of spot-collected urine samples over 12 weeks duration and by 24-hour urine albumin excretion at 12 weeks post-DM, was markedly attenuated in diabetic Lrg1 2/2 mice compared with diabetic Lrg1 +/+ mice (Figure 2, F and G). DM-induced podocyte foot process effacement and loss (as ascertained by podocyte marker p57 48,49 ) were also reduced in diabetic Lrg1 2/2 mice (Figure 3, A-D). Together, these data indicate that the genetic deletion of LRG1 results in marked attenuation of diabetic glomerulopathy.…”