MMP-10 is Increased in Early Stage Diabetic Kidney Disease and can be Reduced by Renin-Angiotensin System Blockade

José María Mora-Gutiérrez,María A Fernández-Seara,José Antonio Páramo,María Fernanda Slon Roblero,José Antonio Rodríguez,Francisco Javier Escalada,María José Soler,Nuria Garcia-Fernandez,Josune Orbe,Marta Riera

doi:10.1038/s41598-019-56856-3

Abstract

Matrix metalloproteinases have been implicated in diabetic microvascular complications. However, little is known about the pathophysiological links between MMP-10 and the renin-angiotensin system (RAS) in diabetic kidney disease (DKD). We tested the hypothesis that MMP-10 may be up-regulated in early stage DKD, and could be down-regulated by angiotensin II receptor blockade (telmisartan). Serum MMP-10 and TIMP-1 levels were measured in 268 type 2 diabetic subjects and 111 controls. Furthermore, histological and molecular analyses were performed to evaluate the renal expression of Mmp10 and Timp1 in a murine model of early type 2 DKD (db/db) after telmisartan treatment. MMP-10 (473 ± 274 pg/ml vs. 332 ± 151; p = 0.02) and TIMP-1 (573 ± 296 ng/ml vs. 375 ± 317; p < 0.001) levels were significantly increased in diabetic patients as compared to controls. An early increase in MMP-10 and TIMP-1 was observed and a further progressive elevation was found as DKD progressed to end-stage renal disease. Diabetic mice had 4-fold greater glomerular Mmp10 expression and significant albuminuria compared to wild-type, which was prevented by telmisartan. MMP-10 and TIMP-1 are increased from the early stages of type 2 diabetes. Prevention of MMP-10 upregulation observed in diabetic mice could be another protective mechanism of RAS blockade in DKD.

Highlights

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease
Our study demonstrates that circulating Matrix metalloproteinases (MMPs)-10 is increased in T2DM, together with its inhibitor tissue inhibitors of matrix metalloproteinases (TIMPs)-1, starting at the earliest stages of diabetic kidney disease (DKD), and their concentration increases with the severity of kidney disease
We demonstrated overexpression of renal Mmp[10] in an experimental murine model of T2DM, which was prevented by renin-angiotensin system (RAS) inhibition

Summary

Introduction

Matrix metalloproteinases (MMPs) have been found to play a role in various pathogenic mechanisms involved in microvascular complications of diabetes mellitus (DM). Previous studies on the endogenous inhibitor of MMP-10, TIMP-1, show inconclusive data, demonstrating elevated circulating levels on DM5, while others observed similar levels as compared to healthy subjects[7]. No data linking RAS activation and renal Mmp[10] expression has been previously reported. The clinical study aimed to assess circulating levels of MMP-10 and TIMP-1 in T2DM, in different stages of DKD. An experimental study was performed to analyse renal Mmp[10] and Timp[1] expression in a mouse model of early DKD, and their potential modulation by RAS blockade

Methods

Results

Conclusion