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Podocyte Injury Through Interaction Between Tlr8 and Its Endogenous Ligand miR-21 in Obstructed and Its Collateral
Md Abdul Masum1,2, Osamu Ichii1,3, Yaser Hosny Ali Elewa1,4
1Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Abstract:
While chronic kidney disease is prevalent in adults, obstructive nephropathy (ON) has been reported in both young and old patients. In ON, tubulointerstitial lesions (TILs) have been widely investigated, but glomerular lesions (GLs) have been largely neglected. Here, we show a novel mechanism underlying GL development in ON in young and old mice. TILs develop earlier than GLs owing to infiltration of inflammatory cells in the tubulointerstitium, but GLs develop following the activation of Toll-like receptor 8 (Tlr8) even though the absence of inflammatory cells infiltrating the glomerulus. TLR8 and interleukin 1 beta (IL1β) proteins colocalize with reducing podocyte function markers (PFMs), indicating the activation of TLR8 signaling in injured podocytes. Furthermore, glomerular and serum levels of miR-21, an endogenous ligand for Tlr8, were higher in the ON mouse model than in the sham control. The glomerular expression of Tlr8 positively correlates with miR-21 and the downstream cytokines Il1b and Il6 and negatively correlated with PFMs (Nphs1 and Synpo). We also show the colocalization of TLR8 and IL1β proteins with reducing PFMs in both obstructed and collateral kidney of young and old mice. Furthermore, in vitro study results revealed higher expression of Tlr8 and its downstream cytokines in glomeruli from obstructed kidneys following treatment with miR-21 mimic than in the control. In conclusion, the overexpression of Tlr8 may serve as a plausible mechanism underlying GL development in ON through podocyte injury.
Insights
Obstructive nephropathy causes kidney damage. Toll-like receptor 8 (TLR8) activation, driven by miR-21, leads to glomerular injury in obstructive nephropathy, impacting podocyte function.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Obstructive nephropathy (ON) affects patients of all ages, with tubulointerstitial lesions (TILs) being well-studied.
- Glomerular lesions (GLs) in ON have been largely overlooked, despite their contribution to kidney damage.
Purpose of the Study:
- To elucidate the novel mechanisms of glomerular lesion development in obstructive nephropathy.
- To investigate the role of Toll-like receptor 8 (TLR8) and miR-21 in podocyte injury in ON.
Main Methods:
- Utilized young and old mouse models of obstructive nephropathy.
- Analyzed glomerular and serum levels of miR-21, TLR8, IL1β, IL6, and podocyte function markers (PFMs).
- Conducted in vitro studies using glomeruli from obstructed kidneys treated with miR-21 mimic.
Main Results:
- Glomerular lesions develop following TLR8 activation, independent of inflammatory cell infiltration.
- TLR8 and IL1β colocalize with reduced podocyte function markers, indicating podocyte injury.
- Elevated glomerular and serum miR-21 levels correlate with increased TLR8 expression and downstream cytokines, and decreased PFMs.
Conclusions:
- Overexpression of TLR8, potentially induced by miR-21, is a key mechanism in glomerular lesion development in ON.
- TLR8 signaling contributes to podocyte injury and dysfunction in obstructive nephropathy.
- This study highlights a novel pathway for glomerular damage in ON, relevant to both young and old individuals.
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