Abstract: SA-PO112
Long-Term Outcomes in Mouse Models of Ischemia-Reperfusion-Induced AKI
Session Information
- AKI: Mechanisms - AKI-CKD Transition
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Scarfe, Lauren Nicolle, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Menshikh, Anna, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- de Caestecker, Mark P., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
AKI is a risk factor for CKD, but no therapies have improved outcomes. Therapies that are effective in models that mimic features in patients, and evaluate long-term outcomes, are more likely to be predictive of success in the clinic. Here, we evaluated susceptibility to CKD after unilateral ischemia reperfusion injury (uIRI) with a delayed contralateral nephrectomy (DN-IRI) in mice. We define the conditions to induce renal dysfunction and fibrosis without increased mortality, and evaluate effect of mouse strains, sexes, and pre-existing diabetes.
Methods
Studies were performed in different strains and sexes of mice, and in mice with streptozotocin (STZ)-induced diabetes mellitus (DM). DN-IRI with different renal pedicle clamp times was performed along with contralateral nephrectomy (Nx) 8 days after injury to identify conditions associated with reduced GFR 4 weeks after injury. After optimizing IRI clamp time, we evaluated renal function with serial BUN, creatinine and transdermal GFR. Renal fibrosis: QRT-PCR for fibrosis markers, picro-sirius red (PSR) quantification. Peritubular capillary density (PTCD) by quantifying CD31 immunostaining. Results expressed as means (SD).
Results
Male and female BALB/c mice had >90% survival after uIRI clamp times of 30 and 40 minutes, respectively. C57BL/6 mice from Charles River and Jackson labs had >90% survival with 28 and 21 mins uIRI, respectively, and male DBA2j mice with DM had >90% survival after 22 mins uIRI. These were all associated with reduced GFR and increased renal PSR staining 4 weeks after IRI. Long term studies in male BALB/c mice showed reduced GFR 6 weeks after ND IRI 229.1 (50.1) vs. 296.7 (44.1) microL/min in Nx only mice (p<0.05), but GFR recovered by 12 weeks. This was associated with increased PSR staining at 12 weeks, but PTCD, which was reduced at 4 weeks after IRI 0.67 (0.12) vs. 1 (0.21) FC (p<0.01), was the same as Nx control by 12 weeks.
Conclusion
These data define renal pedicle clamp times for the DN-IRI model in different mouse strains, sexes, and in the presence of DM. Long-term studies showed renal functional recovery at 12 weeks, and showed that peritubular capillary rarefaction is more closely associated with changes in GFR than fibrosis. This provides insight into the role of capillary rarefaction as the driver of AKI to CKD progression.
Funding
- NIDDK Support