Abstract: SA-PO502
CD248 Modulates Unfolded Protein Response in Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Krishnan, Shruthi, Otto-von-Guericke University, Magdeburg, Germany
- Biemann, Ronald, Otto-von-Guericke University, Magdeburg, Germany
- Mathieu, Sophie-Cecil, Otto-von-Guericke University, Magdeburg, Germany
- Manoharan, Jayakumar, Otto-von-Guericke University, Magdeburg, Germany
- Kohli, Shrey, Otto-von-Guericke University, Magdeburg, Germany
- Malhotra, Akshay, Otto von Guericke University, Magdeburg, Germany
- Naumann, Michael, Otto von Guericke University, Magdeburg, Germany
- Isermann, Berend Heinrich, Otto-von-Guericke University, Magdeburg, Germany
Background
Diabetic nephropathy (DN) is a major cause of end-stage renal disease and a growing public health burden. Recently DN has been linked with maladaptive unfolded protein response (UPR) and sterile inflammation, but the underlying mechanism triggering the glucose induced maladaptive UPR and sterile inflammation remain poorly defined. We focused on CD248, a type I transmembrane glycoprotein expressed by pericytes, such as glomerular mesangial cells and tubulointerstitial fibroblasts whose expression correlates with renal fibrosis in chronic kidney disease. Hence, the aim of our study is to investigate the role of CD248 in regulating UPR and sterile inflammation in DN.
Methods
C57Bl/6 (WT) mice and CD248-/- mice were used for the study. Diabetes was induced using streptozotocin (STZ) and samples were obtained after 26 weeks. Albuminuria (UACR), PAS staining and WT-1 immunostaining of kidney sections were done to study development of renal disease. To evaluate mechanistic insights, genetic knockdown or overexpression of CD248 was done followed by immunoblotting and co-immunoprecipitation approaches.
Results
We detected a marked increase of renal CD248 expression after 26 weeks in diabetic mice versus nondiabetic controls. CD248 knockout protected mice from diabetes induced albuminuria, podocyte loss and mesangial expansion. In vitro, shRNA mediated CD248 knockdown in renal pericytes prevented high glucose induced maladaptive UPR signaling (lower levels of CHOP, ATF4, cATF6α), inflammasome activation (lower levels of NLRP3, cleaved IL-1β), SMAD2/3 phosphorylation and mTORC1 activation (lower levels of p-Raptor and p-p70S6Kinase). Vice versa, overexpression of CD248 amplifies these glucose induced cellular responses. Mechanistically, the chaperone HSP90 interacts with the transmembrane receptor CD248 and may thus transduce extracellular glucose-dependent stress signals to the ER via IRE-1α.
Conclusion
CD248 modulates hyperglycemia induced UPR, inflammasome activation and renal fibrosis. HSP90 appears to serve as the cytosolic mediator linking the receptor CD248 with ER membrane proteins such as IRE1α. Our findings identify pericyte-specific CD248 as a potential target for therapeutic interventions of DN.
Funding
- Government Support - Non-U.S.