TNF-α Pathway and Podocyte Dysfunction in Male and Female BTBR ob/ob Mice
- Diabetic Kidney Disease: Basic - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
- de Ponte, Mariana Charleaux, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Sao Paulo, São Paulo, Brazil
- Thieme, Karina, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Sao Paulo, São Paulo, Brazil
Diabetic kidney disease (DKD) is the major cause of chronic kidney disease (CKD) in patients with diabetes. Studies suggest that tumor necrosis factor alpha (TNF-α) pathway signaling is important for DKD progression. TNF-α contributes to glomerular inflammation and injury, however, the mechanisms underlying this dysfunction, especially in podocytes, need to be further elucidated. Thus, the aim of this study is to elucidate how TNF-α may contribute to podocyte dedifferentiation in DKD and whether sexual dimorphism can modulate this process.
For this, male and female BTBR WT and ob/ob mice, a gold standard model of experimental type 2 diabetes and obesity were studied. The mice were observed up to a period of 16 weeks of age, and at the end of the experimental protocol, urine and kidneys were collected for analysis of albuminuria and gene expression. In vitro, immortalized mouse podocytes were treated with TNF-α for gene expression analysis.
Preliminary data show that BTBR ob/ob mice presented elevated blood glucose levels, body weight and albumin excretion in comparison to WT mice. Among these parameters, blood glucose levels were affected by sex, as females were less hyperglycemic than males. In the kidneys, gene expression of TNF-α and TNF-α receptor type 1 (TNFR1) were not statistically different among groups, but gene expression of TNF-α receptor type 2 (TNFR2) were upregulated in BTBR ob/ob mice independently of the sex. Snai1 transcript levels were not changed, but there were an effect of sex and obesity on Snai2 transcript levels. Females have higher gene expression of nephrin and podocin, but obesity reduces the expression of these genes, regardless of sex. In vitro experiments show that TNF-α treatment induced increased TNF-α gene expression and decreased Snai2 transcript levels in podocytes.
In conclusion, these data suggest that BTBR ob/ob mice presented kidney inflammation, podocyte dysfunction and alteration of the cellular dedifferentiation pathway. Sexual dimorphism was observed in the gene expression of podocyte markers and Snai2 transcript levels. In vitro, we confirmed the association of an inflammatory millieu with the dedifferentiation and inflammatory response of podocytes.
- Government Support – Non-U.S.