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Kidney Week

Abstract: TH-PO896

Angptl4 Is a Critical Mesenchymal Inducer That Contributes to Renal Fibrosis

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

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

Kidney fibrosis is characterized by excess deposition of extracellular matrix leading to renal function deterioration and kidney injury. Several angiopoietin-like proteins (ANGPTLs) regulate lipid metabolism in the kidneys. However, the role of angiopoietin-like 4 (ANGPTL4) protein has not been explored yet. We hypothesized that loss of ANGPTL4 would be protective against renal fibrosis.

Methods

Two mouse models were used to recapitulate renal fibrosis. In one model, a single dose of streptozotocin (STZ) was used to induce diabetes and diabetic nephropathy in global Angptl4 knockout mice (ANGPTL4 KO) and wild-type littermates; mice were monitored for 4 months post-STZ. In the second model, the surgical procedure of unilateral ureteral obstruction (UUO) was used to induce renal fibrosis in 10-week old global ANGPTL4 KO mice and wild-type littermates. Interstitial fibrosis was analyzed by histological analysis of Trichrome, Sirius red and Periodic-Acid–Schiff staining in the kidneys. Immunofluorescent staining of kidney tissue for mesenchymal markers was also performed. Blood glucose, kidney weight, and severity of proteinuria as measured by albumin-to-creatinine ratios were measured in animals subjected to both models. One way Anova with Tukey's post-test was performed for the analysis of statistical significance.

Results

At the time of sacrifice, diabetic global ANGPTL4 KO mice did not shown any significant difference in blood glucose compared to controls. However, kidney weight (-14.5%), collagen deposition (-55.4%), and albumin-to-creatinine ratios (-59.2%) were significantly lower in global ANGPTL4 KO mice when compared to wild-type controls (n=6/gentoype; p<0.05). Similarly, in the UUO model, we observed that the UUO-operated kidneys of global ANGPTL4 KO mice showed less collagen deposition (-48.9%) and interstitial fibrosis (-45.2%) when compared to those of the controls (n=7/genotype, p<0.05). Immunofluorescence analysis of kidney tissue from both genotypes revealed suppression of fibronectin and collagen-1 deposition in global ANGPTL4 KO mice compared to controls, in both models, suggesting suppression of mesenchymal activation.

Conclusion

We conclude that ANGPTL4-associated mesenchymal activation is critical for disruption of kidney homeostasis and contributes to renal fibrosis.