Absence of TIMP-1 reduces renal complement C3 response and fibrosis in type-1 diabetic mice

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Abstract Background Diabetic kidney disease (DKD) is a leading cause of end-stage renal failure characterized by progressive renal fibrosis and inflammation. We previously identified tissue inhibitor of metalloprotease-1 (TIMP-1) and complement C3 as major contributors to kidney fibrosis in mouse models with varying disease progression and in human FSGS. However, the role of TIMP-1 in DKD progression and potential renal TIMP-1/C3 interactions remain unclear. Methods We investigated TIMP-1-driven molecular pathogenesis of DKD by inducing type-1 diabetes with streptozotocin in TIMP-1 knockout (Timp −/− ) and wild-type mice, and compared them to non-diabetic controls. Eight weeks later, serum, urine, and kidney samples were evaluated. Additionally, we analyzed human DKD biopsies and control kidney tissues for translational relevance. Statistical significance ( p < 0.05) was evaluated using ANOVA, Kruskal-Wallis, or Mann-Whitney tests. Results The lack of functional TIMP-1 markedly ameliorated the diabetes-induced glomerulosclerosis and tubular damage, normalized serum urea and creatinine levels, as well as the extent of proteinuria despite comparable hyperglycemia and weight loss with wild-type diabetic mice. Interestingly, the kidneys of diabetic Timp −/− mice exhibited not only lower Ctgf , Col1a1 , Col3a1 , Lcn2 mRNA expression but also dramatically suppressed complement C3 and NF-κB/p65 activity similar to non-diabetic control levels. Additionally, the lack of TIMP-1 inhibited diabetes-induced activation of EGR1, EGR2 and STAT3 transcription factors. Human DKD biopsies mirrored murine findings. Conclusions The absence of TIMP-1 ameliorates DKD pathogenesis by reducing fibrosis, inflammation, and complement activation. The loss of functional TIMP-1 highlights a potential TIMP-1/C3 pathway as a promising therapeutic target.

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