Glomerular Hyperfiltration and Th17 Responses Promote Glomerulosclerosis Following Nephron Loss
Authors: Liu Jing , Chen Luojing , Lusco Mark , Le Thu , Wu Jing 
Published: May 2024

Objective: 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 whole-kidney hyperfiltration, leading to progressive glomerulosclerosis and CKD. In advanced CKD with less than 50% functional nephron mass, single-nephron hyperfiltration causes further nephron loss, ultimately leading to hypofiltration and end-state kidney disease. Increased renal perfusion pressure directly drives T cell infiltration to the kidney. We and others have shown that T helper (Th) 17 cells promote vascular stiffening in hypertension and renal interstitial fibrosis after ischemia-reperfusion injury, but their roles in glomerulosclerosis and CKD are poorly understood. We hypothesized that glomerular hypertension and hyperfiltration promote renal fibrosis through Th17-mediated immune responses. Methods: We investigated the causal roles of glomerular hyperfiltration and Th17 responses in a mouse CKD model induced by reduced kidney mass (RKM), which involved right kidney nephrectomy and partial renal artery ligation in the left kidney such that the functional renal mass is reduced by ~ 5/6. 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 week 1, 2, 3, 4, 8, and 12 post-surgery. Results: BP and GFR of RKM mice were identical to sham controls at BL (n=4-6). Immediately after the RKM procedure, GFR dropped to 22% of BL, consistent with the extent of renal mass ablation. BP increased by 29 mmHg first week after 5/6 ablation (144 ± 8 vs BL 112 ± 2 mmHg, p<0.05, 2-way ANOVA), exposing the remnant nephrons to increased renal perfusion pressure. Serum creatinine, blood urea nitrogen and urinary albumin were significantly elevated by week 2. BP and CKD markers remained elevated through week 12 in the 5/6 ablation mice. The GFR of ablated mice gradually increased to 38% of BL at day 3, 57% at week 1 and 68% at week 2, suggesting that systemic hypertension and impaired renal autoregulation may have caused substantial single-nephron hyperfiltration in the remnant kidney mass. GFR plateaued at ~ 70% of BL in week 3-4 then declined to 48% at week 8-12 when glomerular, interstitial, and microvascular fibrosis developed as evidence by Periodic Acid Schiff and Picro Sirius Red staining. Supporting a causal role of hemodynamic derangements in CKD progression, calcium channel blocker amlodipine, a potent vasodilator, dose dependently (5-10 mg/kg/day, n=7-9) exacerbated glomerular hyperfiltration, glomerulosclerosis and mortality despite marked BP-lowering effects. Importantly, the adaptive increase of GFR in the first 2 weeks post 5/6 ablation was accompanied by significant increase of renal Th17 cells, which not only preceded the infiltration of CD11b+ myeloid cells, F4/80+ monocyte/macrophages and T regulatory cells, but also the glomerulosclerosis and GFR decline in week 8. Conclusions: Our data suggest that glomerular hyperfiltration causes progressive nephron loss and kidney fibrosis, at least in part, through Th17-mediated renal inflammation. To further establish causality, ongoing studies will assess if Th17 blockade ameliorates glomerulosclerosis and retard CKD progression.

Funding: This work was supported by NIDDK R01 DK094907, R01 DK113632, R01 DK128677 to THL, and K01 DK126972 to JW. JW is also supported by an American Heart Association Second Century Early Faculty Independence Award (23SCEFIA1148464), a University of Rochester Environmental Health Science Center pilot award (Prime sponsor: NIEHS P30ES001247), and a University of Rochester Program for Advanced Immune Bioimaging Pilot Award (Prime Sponsor: NIAID P01AI102851).

This is the full abstract presented at the American Physiology Summit 2024 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.