Glomerular Hyperfiltration and Inflammation Promote Glomerular Injury in a CKD Model Induced by Reduced Kidney Mass

Abstract

Renal autoregulation maintains renal blood flow and glomerular filtration rate (GFR) in a wide range of renal perfusion pressure (RPP). This mechanism is impaired in diabetes and chronic kidney disease (CKD), such that even modest increases in arterial pressure (AP) are transmitted to glomerular capillaries resulting in glomerular injury. Elevated RPP drives renal immune cell infiltration ( Hypertens. 76: 849-858, 2020). We showed that hypertensive mechanical stretch and T cell cytokine interleukin (IL)-17A synergistically promote vascular fibrosis ( Wu, Circ. Res. 114: 616-625, 2014). However, the mechanisms by which hemodynamic and inflammatory stimuli cause CKD remain poorly understood. We sought to investigate the contributions of glomerular hyperfiltration (GHF) and inflammation on glomerular damage in a mouse CKD model induced by reduced kidney mass (RKM). This model is characterized by impaired autoregulation, early onset hypertension and subsequent lymphocytic inflammation, albuminuria and glomerulosclerosis. We hypothesize that the initial rise in AP post RKM surgery promotes kidney injury through both GHF and renal inflammation. Eight-week old male 129/S6 mice were implanted with radiotelemeters. After a 10-day recovery, mice underwent sham surgery or RKM which involved uninephrectomy and partial renal artery ligation in the remaining kidney, such that the functional renal mass is reduced by ~ 2/3. AP, urine albumin, and transcutaneous GFR were measured at baseline, day (D) 3, D7, D14, D21, D28, and D56 after RKM.Immediately after RKM, GFR dropped to 30% of sham levels (Mean ± SEM in μL/min/100 g: RKM 279 ± 59 vs Sham 913 ± 61, n = 4 – 6, p < 0.05, two-way ANOVA RM), consistent with the extent of renal mass ablation. The mean AP of RKM mice was identical to sham controls at baseline (115 ± 2 vs 116 ± 2 mmHg) but increased by 29 mmHg by D5 (144 ± 8 vs 112 ± 2 mmHg, p < 0.05), and remained significantly elevated through D56, albeit a declining trend. Compared to GFR of sham mice (100%), the GFR of RKM mice gradually increased to 36% at D3, 43% at D7 and 69% at D14. By D21 post surgery, the GFR of RKM mice rose to 71% of sham (800 ± 106 vs 1121 ± 47 μL/min/100 g, p > 0.05) and plateaued through day 28 (69% of sham), suggesting that the early rise in AP and impaired autoregulation may have caused GHF in the RKM mice. The adaptive increase in GFR post RKM surgery was associated with a trend towards increased renal leukocytes, monocyte/macrophages, CD3 T cells and CD4/CD8 subsets at D14 and significantly elevated albuminuria at D28 (832 ± 227 vs 341 ± 15 μg/day, p < 0.05), implying hyperfiltration-induced renal inflammation and glomerular damage. Importantly, the GFR declined to 57% of sham levels by day 56 (597 ± 86 vs 1047 ± 80 μL/min/100 g, p < 0.05), suggesting progressive glomerular injury. We conclude that impaired autoregulation exposes the kidney to both inflammation and GHF, causing glomerular injury, albuminuria, and CKD progression. This work is supported by a NIDDK K01 DK126792 and a University of Rochester Environmental Health Science Center Pilot award (as part of a NIEHS P30ES001247) to JW. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.