Pivotal role of adipocyte‐Na/K‐ATPase Signaling in the pathogenesis of Experimental Uremic Cardiomyopathy by fat transplantation
Authors: Pillai Sneha S. , Lakhani Hari Vishal , Zehra Mishghan , Pereira Duane G. , Sodhi Komal 
Published: May 2022

Objective

Mounting evidence highlights the role of adipose tissue in the development of systemic inflammation that contributes to various metabolic abnormalities. We have recently demonstrated that administration of NaKtide, antagonist of Na/K‐ATPase (NKA) signaling, coupled to adipocyte specific promoter can improve adipocyte phenotype and further attenuated experimental uremic cardiomyopathy. Studies have shown that transplanting brown adipose tissue from C57BL6 mice reduced obesity and improved whole energy metabolism. Therefore, the objective of the present study is to explore the specific role of adipocyte function in systemic inflammation and associated pathologies of uremic cardiomyopathy using adipose tissue transplantation studies.

Hypothesis

In the present study, we hypothesize that, the transplantation of NaKtide transfected subcutaneous fat into mice with partial nephrectomy (PNx) may help to provide a deeper understanding of adipocyte‐NKA signaling, that modulate the progression of uremic cardiomyopathy.

Methods

Following 4 weeks of PNx or Sham surgery and lenti‐adiponectin‐Naktide in C57BL6 mice, 200 mg of subcutaneous fat pads were dissected and subcutaneously transplanted into the dorsal interscapular region of the recipient mice at the time of the PNx surgery. The tissues were harvested for morphological and molecular analyses after 8 weeks of transplantation. Statistical analysis of the data were performed by one‐way analysis of variance.

Results

The immunofluorescence staining showed high expression of NaKtide in fat tissues of mice transplanted with NaKtide transfected fat. The pSrc protein expression in the fat tissue was significantly upregulated in PNx, which was significantly down‐regulated by PNx+NaKtide fat transplantation (p<0.01). The adipose tissue dysfunction during PNx was assessed by the level of protein carbonylation and mRNA expression of IL‐1β and Sirt2, which were significantly reversed by NaKtide transfected fat (p<0.01). The transplantation of NaKtide transfected adipose tissue significantly improved the systemic inflammation (p<0.01). The altered plasma miRNA expressions in PNx were also normalized by NaKtide transfected fat transplantation. PNx mice developed cardiomyopathy characterized by increased heart weight and decreased cardiac function, assessed by echocardiography measurements (p<0.01). These alterations were reversed by the transplantation of adipose tissues from PNx+NaKtide donor mice (p<0.01). The mice transplanted with the fat tissue of PNx+NaKtide showed significantly decreased cardiac fibrosis, when compared to PNx heart, which was further confirmed by the mRNA expression of major fibrotic genes in cardiac tissues.

Conclusion

The study demonstrates that, the inhibition of adipocyte‐NKA signaling in uremic cardiomyopathy could modulate the adipocyte redox state that resulted in the manipulation of systemic inflammatory milieu and associated pathophysiological mechanisms, which can be used as a clinical target for therapeutic intervention of uremic cardiomyopathy.