Complement deposition on renal histopathology of patients with diabetic nephropathy

SummaryCoagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM’s lectin like domain dampens complement activation, while its EGF-like domains independently enhance activation of the anticoagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating complement. Diabetic nephropathy was analysed in mice lacking TM’s lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 μg/mg vs. 166 μg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeDmice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeDmice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeDmice (e.g. albuminuria 85 μg/mg vs. 290 μg/mg, p <0.001). In vitroTM’s lectin-like domain cell-autonomously prevented glucose-induced complement activation on endothelial cells and –notably –on podocytes. Podocyte injury, which was enhanced in diabetic TMLeD/LeDmice, was reduced following complement inhibition with enoxaparin. The current study identifies a novel mechanism regulating complement activation in diabetic nephropathy. TM’s lectin-like domain constrains glucose-induced complement activation on endothelial cells and podocytes and ameliorates albuminuria and glomerular damage in mice.

Download Full-text

IgG Subclass Expression in Diabetic Nephropathy

10.21203/rs.3.rs-70687/v1 ◽

2020 ◽

Author(s):

Xuanli Tang ◽

Xue Jiang ◽

Feng Wan ◽

Xiaohong Li ◽

Ruchun Yang ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Basement Membrane ◽

Collagen Iv ◽

Igg Subclasses ◽

Igg Subclass ◽

Tubular Injury ◽

Tubular Basement Membrane ◽

Cd34 Expression ◽

Complement Deposition ◽

Linear Expression

Abstract Background: This study aimed to analyze the distribution of IgG subclasses in diabetic nephropathy (DN) and its association with clinico-pathological features. Methods: Forty DN cases were analyzed to identify IgG subclasses, as well as collagen IV α5, CD34, and KIM-1.Results: Both IgG and its subclasses showed a linear expression and overlapped with collagen IV α5 on glomerular basement membrane (GBM) and some of tubular basement membrane (TBM), without complement deposition. Eleven cases of IgG subclass deposition along both GBM and TBM were associated with more proteinuria. Five cases of TBM-only IgG subclass deposition were accompanied with less KIM-1 positivity and more arteriosclerosis. The major IgG subclasses expressed on GBM were IgG1 and IgG2, while TBM expression was mainly IgG1 and IgG3. Glomerular IgG1-positive status was associated with less CD34 expression, while IgG2-positive status was associated with thicker GBM. Expression of multiple IgG subclasses along TBM showed less KIM-1 positivity and interstitial inflammation than those with isotype or no IgG subclass expression.Conclusions: IgG subclasses were selectively deposited along GBM and TBM in DN, which was determined by their profiles and severity of glomerular/tubular injury. IgG and its subclass deposition is not causal, but the consequence of renal injury and these positive statuses are associated with different DN injuries.

Download Full-text