Podocyte Loss in Aging OVE26 Diabetic Mice

Inhibition of p38 mitogen-activated protein kinase and cyclooxygenase-2 reduces albuminuria in models of chronic kidney disease marked by podocyte injury. Previously, we identified a feedback loop in podocytes whereby an in vitro surrogate for glomerular capillary pressure (i.e., mechanical stretch) along with prostaglandin E 2 stimulation of its EP4 receptor induced cyclooxygenase-2 in a p38-dependent manner. Here we asked whether stimulation of EP4 receptors would exacerbate glomerulopathies associated with enhanced glomerular capillary pressure. We generated mice with either podocyte-specific overexpression or depletion of the EP4 receptor (EP4 podϩ and EP4 podϪ/Ϫ , respectively). Glomerular prostaglandin E 2 -stimulated cAMP levels were eightfold greater for EP4 podϩ mice compared with nontransgenic (non-TG) mice. In contrast, EP4 mRNA levels were Ͼ50% lower, and prostaglandin E 2 -induced cAMP synthesis was absent in podocytes isolated from EP4 podϪ/Ϫ mice. Non-TG and EP4 podϩ mice underwent 5/6 nephrectomy and exhibited similar increases in systolic BP (ϩ25 mmHg) by 4 weeks compared with sham-operated controls. Two weeks after nephrectomy, the albumin-creatinine ratio of EP4 podϩ mice (3438 g/mg) was significantly higher than that of non-TG mice (773 g/mg; P Ͻ 0.0001). Consistent with more severe renal injury, the survival rate for nephrectomized EP4 podϩ mice was significantly lower than that for non-TG mice (14 versus 67%). In contrast, 6 weeks after nephrectomy, the albumin-creatinine ratio of EP4 podϪ/Ϫ mice (753 g/mg) was significantly lower than that of non-TG mice (2516 g/mg; P Ͻ 0.05). These findings suggest that prostaglandin E 2 , acting via EP4 receptors contributes to podocyte injury and compromises the glomerular filtration barrier.

Section: Discussionmentioning

confidence: 68%

A Maladaptive Role for EP4 Receptors in Podocytes

Stitt-Cavanagh¹,

Faour²,

Takami³

et al. 2010

“…[23][24][25][26][27] Several studies have indicated that loss of podocytes plays an important role in age-related glomerulosclerosis. 26,[28][29][30] It was unclear until now whether lost podocytes were at least partially regenerated and if age-related glomerulosclerosis was, thus, caused by an insufficient replacement of podocytes. 31 The aged PEC-rtTA mice showed typical changes within the glomerulus associated with kidney aging 27 (i.e., mesangial matrix expansion, thickening of the GBM with formation of spikes/humps, proteinuria, and podocyte hypertrophy).…”

Section: Discussionmentioning

confidence: 99%

The Regenerative Potential of Parietal Epithelial Cells in Adult Mice

Berger¹,

Schulte²,

Kuppe³

et al. 2014

Previously, we showed that some podocytes in juvenile mice are recruited from cells lining Bowman's capsule, suggesting that parietal epithelial cells (PECs) are a progenitor cell population for podocytes. To investigate whether PECs also replenish podocytes in adult mice, PECs were genetically labeled in an irreversible fashion in 5-week-old mice. No significant increase in labeled podocytes was observed, even after 18 months. To accelerate a potential regenerative mechanism, progressive glomerular hypertrophy was induced by progressive partial nephrectomies. Again, no significant podocyte replenishment was observed. Rather, labeled PECs exclusively invaded segments of the tuft affected by glomerulosclerosis, consistent with our previous findings. We next reassessed PEC recruitment in juvenile mice using a different reporter mouse and confirmed significant recruitment of labeled PECs onto the glomerular tuft. Moreover, some labeled cells on Bowman's capsule expressed podocyte markers, and cells on Bowman's capsule were also directly labeled in juvenile podocyte-specific Pod-rtTA transgenic mice. In 6-week-old mice, however, cells on Bowman's capsule no longer expressed podocyte-specific markers. Similarly, in human kidneys, some cells on Bowman's capsule expressed the podocyte marker synaptopodin from 2 weeks to 2 years of age but not at 7 years of age. In summary, podocyte regeneration from PECs could not be detected in aging mice or models of glomerular hypertrophy. We propose that a small fraction of committed podocytes reside on Bowman's capsule close to the vascular stalk and are recruited onto the glomerular tuft during infancy to adolescence in mice and humans.

“…A reduction in podocyte density is an accurate predictor of glomerular disease progression. 27 The reduction in podocyte number led to the podocyte density in Yap-KO mice being significantly lower than that of control littermates (436 6.4 versus 3061.5310…”

Section: Yap Deletion Causes Podocyte Depletionmentioning

confidence: 99%

Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure

Schwartzman

Reginensi

Wong

et al. 2016

FSGS is the most common primary glomerular disease underlying ESRD in the United States and is increasing in incidence globally. FSGS results from podocyte injury, yet the mechanistic details of disease pathogenesis remain unclear. This has resulted in an unmet clinical need for cell-specific therapy in the treatment of FSGS and other proteinuric kidney diseases. We previously identified Yes-associated protein (YAP) as a prosurvival signaling molecule, the in vitro silencing of which increases podocyte susceptibility to apoptotic stimulus. YAP is a potent oncogene that is a prominent target for chemotherapeutic drug development. In this study, we tested the hypothesis that podocyte-specific deletion of Yap leads to proteinuric kidney disease through increased podocyte apoptosis. Yap was selectively silenced in podocytes using Cre-mediated recombination controlled by the podocin promoter. Yap silencing in podocytes resulted in podocyte apoptosis, podocyte depletion, proteinuria, and an increase in serum creatinine. Histologically, features characteristic of FSGS, including mesangial sclerosis, podocyte foot process effacement, tubular atrophy, interstitial fibrosis, and casts, were observed. In human primary FSGS, we noted reduced glomerular expression of YAP. Taken together, these results suggest a role for YAP as a physiologic antagonist of podocyte apoptosis, the signaling of which is essential for maintaining the integrity of the glomerular filtration barrier. These data suggest potential nephrotoxicity with strategies directed toward inhibition of YAP function. Further studies should evaluate the role of YAP in proteinuric glomerular disease pathogenesis and its potential utility as a therapeutic target.