Abstract Body: Impaired renal autoregulation in obesity, diabetes and hypertension (HTN) causes elevated glomerular capillary pressure and glomerular hyperfiltration, initiating progressive glomerulosclerosis (GS), nephron loss and chronic kidney disease (CKD). Increased renal perfusion pressure drives renal T cell infiltration. T helper (Th) 17 cells promote vascular stiffening in HTN and renal interstitial fibrosis post AKI, but their roles in GS and CKD are poorly understood. We hypothesized that glomerular hyperfiltration promotes CKD through Th17-mediated GS and tested the hypothesis in 129S6 mice using the reduced kidney mass model (RKM) induced by uninephrectomy and partial renal artery ligation in the remaining kidney (functional renal mass reduced by ~ 5/6). BP (radiotelemetry) and GFR (FITC-sinistrin) of RKM mice were identical to sham controls at baseline (BL, n=4-6). Immediately after the RKM procedure, GFR dropped to 22% of BL, consistent with the extent of renal mass ablation. Mean BP increased by 29 mmHg first week after 5/6 ablation (144 ± 8 vs BL 112 ± 2 mmHg, p<0.05, 2-way ANOVA) and remained elevated through week 12, exposing the remnant nephrons to increased renal perfusion pressure. Serum creatinine, BUN and urinary albumin were significantly elevated after 5/6 ablation. In RKM mice, GFR gradually increased to 38% of BL at day 3, 57% at week 1 and 68% at week 2, suggesting that systemic HTN and impaired renal autoregulation may have caused substantial single-nephron hyperfiltration in the remnant kidney. GFR plateaued at ~ 70% of BL in week 3-4 then declined to 48% at week 8 when glomerular, interstitial, and microvascular fibrosis developed as evidence by Periodic Acid Schiff and Picro Sirius Red staining. Importantly, the early adaptive increase of GFR in the first 2 weeks post 5/6 ablation was accompanied by a striking increase of renal interleukin (IL)-17A+ T cells, which preceded the late infiltration of CD11b+ myeloid cells, F4/80+ monocyte/macrophages, and T regulatory cells. Anti-IL17A antibodies (eBioMM17F3, 100 μg i.p. twice weekly) attenuated the early hyperfiltration, abolished aortic/renal inflammation, and prevented GFR decline and GS at week 8 in male but not female RKM mice, likely due to the anti-hypertensive and anti-inflammatory effects of IL-17A neutralization. We conclude that glomerular hyperfiltration causes progressive nephron loss and kidney fibrosis in CKD, at least in part, through IL-17A mediated renal inflammation.