Abstract: SA-PO494
The Contact Pathway of Coagulation and Complement Activation Participates in the Progression of CKD in Obese Diabetic Rats
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
- Kelly, Katherine J., Indiana University, Indianapolis, Indiana, United States
- Dominguez, Jesus H., Indiana University, Indianapolis, Indiana, United States
Background
Diabetic nephropathy is the leading cause of end stage renal disease. Obese diabetic ZS rats become nephrotic at age 12 weeks and develop advanced chronic renal failure (CKD), the hallmark of human diabetic nephropathy, by 24 weeks. We have proposed that episodes of ischemic acute kidney injury (AKI) are key in the progression of CKD. We have also found that, in AKI, disordered clotting and inflammation prevent reflow and promote ongoing ischemia, leading to loss of functional tissue and fibrosis. We hypothesize that activation of the contact pathway of intrinsic coagulation with complement activation is involved in the development of CKD.
Methods
Male lean (L) and obese, diabetic ZS rats were subjected to sham surgery (DS) or bilateral renal ischemia (DI) at 10 weeks of age (total n=24). The rats were terminated at 28 weeks of age. Renal function and structure were assessed and comprehensive genomic sequencing was performed.
Results
The nephropathy in the diabetic rats postischemia was characterized by renal failure, the sin que non of human disease. The relevant renal transcripts (table) included activation of the contact pathway with increases in F9, 10, 12 and 13 as well as fibrinogen chains A, B, G, platelet MRNA pg1B, F2R, PF4 and C3.
Conclusion
This rat renal transcript profile strongly points to a persistent disorder of renal coagulation and immunity consistent with activation of renal contact pathway. This pathway is a critical juncture of coagulation and inflammation and has multiple therapeutic target opportunities for diabetic nephropathy.
Coagulation Contact Pathway
| transcript | Fold change (DI v L) | P value |
| F12 | 2.2 | <0.04 |
| F10 | 2.2 | <0.02 |
| F9 | 7.7 | 0.15 |
| F2 | -- | NS |
| F7 | -- | NS |
| fibrinogen (F) A | 1.2 | <0.04 |
| FB | 1.5 | <0.04 |
| FC | 3.5 | <0.04 |
| F13 | 1.2 | 0.005 |
| gp1B | 1.8 | 0.007 |
| F2R | 1.2 | 0.002 |
| PF4 | 1.3 | <0.007 |
| C3 | 1.6 | 0.002 |
| kininogen | 1.7 | 0.003 |
Funding
- Veterans Affairs Support