Abstract: FR-PO1089
Glomerular Hyperfiltration and Th17 Responses Precede Glomerulosclerosis Following Nephron Loss
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Liu, Jing, University of Rochester Medical Center Department of Medicine, Rochester, New York, United States
- Chen, Luojing, University of Rochester Medical Center Department of Medicine, Rochester, New York, United States
- Le, Thu H., University of Rochester Medical Center Department of Medicine, Rochester, New York, United States
- Wu, Jing (Jason), University of Rochester Medical Center Department of Medicine, Rochester, New York, United States
Background
Chronic kidney disease (CKD) affects 37 million Americans resulting in $87 billion healthcare cost annually. Impaired renal autoregulation in obesity, diabetes and hypertension causes elevated glomerular capillary pressure and glomerular hyperfiltration (GHF), ultimately leading to glomerulosclerosis (GS) and CKD. Increased renal perfusion pressure directly drives T cell infiltration and T helper (Th) 17 cells promote renal fibrosis in hypertension and kidney ischemia-reperfusion injury, but their roles in GS are poorly understood.
Methods
We investigated the roles of GHF and Th17 responses in GS in a mouse CKD model induced by reduced kidney mass (RKM), which involved uninephrectomy and partial renal artery ligation in the remaining kidney such that the functional renal mass is reduced by ~ 3/4. Male 129/S6 mice received sham or RKM surgery at 8 weeks of age, and blood pressure (BP, by radiotelemetry), glomerular filtration rate (GFR, by transcutaneous FITC-sinistrin) and serum/urine CKD markers were assessed at baseline (BL), and day (D) 0, 3, 7, 14, 21, 28, 56, and 84 post-surgery.
Results
BP and GFR of RKM mice were identical to sham controls at BL (n=4-6). Immediately after RKM, GFR dropped to 22% of BL, consistent with the extent of renal mass ablation. BP increased by 29 mmHg by D5 post RKM (144 ± 8 vs 112 ± 2 mmHg, p<0.05, 2-way ANOVA), and serum creatinine, blood urea nitrogen and urinary albumin were significantly elevated by D14. BP and CKD markers were significantly elevated through D84 in RKM mice, but remained at BL levels in sham controls. The GFR of RKM mice gradually increased to 38% of BL at D3, 57% at D7 and 68% at D14, and plateaued at ~70% at D21-28, suggesting that the early rise in BP and impaired autoregulation may have caused GHF following initial nephron loss. The adaptive increase in GFR post-RKM was associated with marked renal Th17 cell infiltration at D14, preceding glomerular hypertrophy and mesangial expansion at D28 and subsequent recruitment of myeloid cells, monocyte/macrophages and T regulatory cells. Importantly, GFR declined to 42% of BL at D56 post-RKM, with concomitant GS and interstitial fibrosis as evidenced by Periodic Acid Schiff and Picro Sirius Red staining.
Conclusion
Together, our data suggest that both GHF and Th17 responses promote CKD progression and further loss of nephrons through glomerular fibrosis.
Funding
- NIDDK Support