Kidney Week

Abstract: SA-PO107

Loss of Podocyte Glucocorticoid Receptor Worsens Fibrosis in a Mouse Model of Diabetes

Session Information

• Diabetic Kidney Disease: Basic - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Srivastava, Swayam Prakash, Yale University School of Medicine, New Haven, Connecticut, United States

Swayam Prakash Srivastava,

• Goodwin, Julie, Yale University School of Medicine, New Haven, Connecticut, United States

Julie Goodwin,

Background

Glomerular fibrosis, which is a key component of diabetic nephropathy, is characterized by deposition of extracellular matrix, alteration of the glomerular structure and dysfunction of the glomerular filtration barrier. The role of the podocyte glucocorticoid receptor (pGR) in the pathogenesis of diabetic nephropathy has not been explored yet. Based on previous studies which showed that pGR was critical in the response to renal injury, we hypothesized that loss of pGR would result in worsened fibrosis.

Methods

Streptozotocin (STZ) 200 mg/kg was used to induce diabetes in 10-week old pGR KO mice ((GR^fl/fl; podocin Cre+) and control litter mates (GR^fl/fl; podocin Cre-). After STZ injection, mice were maintained for 4 months prior to sacrifice. Body weight, kidney weight, blood glucose and urine microalbumin/creatinine ratio were assessed in normal and diabetic mice of both genotypes. Glomerular fibrosis and segmental glomerulosclerosis were analyzed by staining kidney sections in diabetic mice of both genotypes. Western blot and immunofluorescent staining were also used to examine key pro-fibrotic targets. One way ANOVA with Tukey’s post-test was used to determine statistical significance.

Results

Non-diabetic control and pGR KO mice did not have any differences in body weight, kidney weight, blood glucose, urinary microalbumin excretion, or kidney histology. Diabetic control and pGR KO mice showed similar body weight, and blood glucose levels, but kidney weight was significantly higher in diabetic pGR KO mice (15.8 vs. 14.7 mg/g body weight, n= 5/group, p=0.04). Glomerular collagen deposition, glomerular surface area and mesangial expansion were all significantly increased in pGR KO mice. We did not observe any significant differences in the level of interstitial fibrosis. Western blotting and immunofluorescent staining of kidney sections revealed induction of mesenchymal activation which was associated with glomerular deposition of fibronectin and collagen I in diabetic pGR KO mice.

Conclusion

From these results we conclude that:
1. loss of pGR worsens the severity of fibrosis in our mouse model of diabetes
2. pGR is tonically suppressing mesenchymal activation pathways
3. modulation of pGR may represent a novel therapeutic pathway for diabetic nephropathy

Funding

• NIDDK Support