Podocytes from Hypertensive and Obese Mice Acquire an Inflammatory, Senescent and Aged Phenotype

Patients with hypertension or obesity can develop glomerular dysfunction characterized by injury and depletion of podocytes. To better understand the molecular processes involved, young mice were treated with either deoxycorticosterone acetate (DOCA) or fed a high-fat diet (HFD) to induce hypertension or obesity, respectively. The transcriptional changes associated with these phenotypes were measured by unbiased bulk mRNA-sequencing of isolated podocytes from experimental models and their respective controls. Key findings were validated by immunostaining. In addition to a decrease in canonical proteins and reduced podocyte number, podocytes from both hypertensive and obese mice exhibited a sterile inflammatory phenotype characterized by increases in NLRP3 inflammasome, protein cell death-1, and Toll-Like Receptor pathways. Finally, although the mice were young, podocytes in both models exhibited increased expression of senescence and aging genes, including genes consistent with a senescence-associated secretory phenotype. However, there were differences between the hypertension- and obesity-associated senescence phenotypes. Both show stress-induced podocyte senescence characterized by increased p21 and p53. Moreover, in hypertensive mice, this is superimposed upon age-associated podocyte senescence characterized by increased p16 and p19. These results suggest that senescence, aging, and inflammation are critical aspects of the podocyte phenotype in experimental hypertension and obesity in mice. Overall design: C57BL/6J mice were separated into two groups, (i) treatment with Deoxycorticosterone Acetate Salt (DOCA) or (ii) fed a high fat diet to induce obesity (HFD) and each group had its separate set of controls. Kidneys were removed from the mice at 5.5 months in the case of the DOCA treatment and 7 months in the case of HFD feeding. Podocytes we isolated by MAC sorting and injury and senescence were assessed with mRNA sequencing.