Abstract: SA-OR087
Gli1+ Pericytes Are Required for AKI Recovery and Regulate Renal Function
Session Information
- Understanding AKI to CKD Progression
November 04, 2017 | Location: Room 392, Morial Convention Center
Abstract Time: 05:42 PM - 05:54 PM
Category: Acute Kidney Injury
- 002 AKI: Repair and Regeneration
Authors
- Machado, Flavia G., Washington University in St Louis, School of Medicine, St Louis, Missouri, United States
- O hAinmhire, Eoghainín, Washington University , Lake St. Louis, Missouri, United States
- Humphreys, Benjamin D., Washington University School of Medicine, Clayton, Missouri, United States
Background
Gli1+ pericytes support the peritubular vasculature, and their ablation causes transient tubular injury and permanent, subclinical, capillary rarefaction. Whether Gli1+ pericytes are required for renal repair after AKI is unknown.
Methods
We evaluated distribution and density of Gli1+ pericytes after bilateral IRI (bIRI) using Gli1-nLacZ reporter mice. We tested whether the Gli1+ population is fixed or dynamic using Gli1-nLacZ;Gli1CreERT2;R26-tdTomato triple transgenic mice. We asked whether Gli1+ pericytes are required for AKI repair by ablating them and measuring GFR by FITC-sinistrin, then performing biIRI. We also tested the effect of pharmacologic blockade of hedgehog signaling on biIRI recovery with the smoothened inhibitor LDE225.
Results
Gli1+ cells expand in the cortex and outer medulla during AKI recovery. There is substantial de novo Gli1+ expression, as well as loss of Gli1 expression in previously Gli1+ cells, as assessed with Gli1-nLacZ; Gli1CreERT2; R26-tdTomato mice. tdTom single positive and tdTom/nLacZ double positive cell populations increased 3-fold by two weeks after IRI. By contrast, nLacZ single positive cells increased 7-fold. Genetic ablation of Gli1+ cells spontaneously reduced GFR of 242±108ml/min/100gBW (delta baseline vs. after DTX). Mice with ablated Gli1+ pericytes had substantially increased mortality after biIRI (50% 7d after injury, p<0.05 vs. PBS injected mice with 100% survival). Surviving mice 7 days after bIRI had poorer renal recovery compared to controls (434±69 ml/min/100gBW) with 35% of their baseline renal function (vs. 62% on PBS group, p<0.05). Inhibition of hedgehog signaling had a similar effect: 3 days after bIRI mice that received LDE225 exhibited 60 – 80% mortality whether drug was given before or after IRI. Mice receiving vehicle had no mortality.
Conclusion
The Gli1+ pericyte population is not fixed but expands after AKI through both recruitment and proliferation. These cells are required for repair from AKI since their ablation increases mortality and reduces GFR during repair. We suggest that the mechanism is via the hedgehog-Gli signaling pathway itself, since inhibition of smoothened had the same effect after biIRI as Gli1+ cell ablation.