Loss of TIMP3 Enhances Interstitial Nephritis and Fibrosis

Abstract

The balance of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) determines the integrity of the extracellular matrix. TIMP3 is the most highly expressed tissue inhibitor of metalloproteinase (TIMP) in the kidney, but its function in renal disease is incompletely understood. In this study, TIMP3 Ϫ/Ϫ mice demonstrated an age-dependent chronic tubulointerstitial fibrosis. After unilateral ureteral obstruction (UUO), young TIMP3 Ϫ/Ϫ mice exhibited increased renal injury (tubular atrophy, cortical and medullary thinning, and vascular damage) compared with wild-type mice. In addition, TIMP3 Ϫ/Ϫ mice had greater interstitial fibrosis; increased synthesis and deposition of type I collagen; increased activation of fibroblasts; enhanced apoptosis; and greater activation of MMP2, but not MMP9, after UUO. TIMP3 deficiency also led to accelerated processing of TNF␣, demonstrated by significantly higher TACE activity and greater soluble TNF␣ levels by 3 d after UUO. The additional deletion of TNF␣ markedly reduced inflammation, apoptosis, and induction of a number of MMPs. Moreover, inhibition of MMPs in TIMP3 Ϫ/Ϫ /TNF␣ Ϫ/Ϫ mice further abrogated postobstructive injury and prevented tubulointerestitial fibrosis. In humans, TIMP3 expression increased in the renal arteries and proximal tubules of subjects with diabetic nephropathy or chronic allograft nephropathy. Taken together, these results provide evidence that TIMP3 is an important mediator of kidney injury, and regulating its activity may have therapeutic benefit for patients with kidney disease.

ADAM17 mediates Nox4 expression and NADPH oxidase activity in the kidney cortex of OVE26 mice

“…Initial reports indicate ADAM17 and cleavage of its substrates may be involved in kidney disease and can also contribute to the progression of diabetes (1,3,9,10,15,20,21,26,29,33,35,40,42,45,47). We hypothesized that ADAM17 plays a key role in ECM accumulation in DN.…”

“…ADAM17, a member of this ADAM family of MMPs, was originally described as the sheddase of tumor necrosis factor-␣, referred to as TNF␣-converting enzyme (4, 34). In addition, ADAM17 is also responsible for cleaving membrane-bound growth factors and receptors such as transforming growth factor-␣ (TGF␣), heparin-bound epidermal growth factor (HB-EGF), TNF receptor I and II, adhesion molecules, proinflammatory molecules, amyloid precursor protein, and ErbB4 (4,12,17,28,34,39,41).There is evidence that ADAM17 plays a role in the pathogenesis of DN (1,3,10,11,20,21,26,29,33,35,40,42,47,48). Studies in mesangial cells showed that glucose activates ADAM17 and EGF receptor (EGFR) and regulates profibrotic TGF␤ and the accumulation of matrix proteins (48,(51)(52)(53).…”

“…There is evidence that ADAM17 plays a role in the pathogenesis of DN (1,3,10,11,20,21,26,29,33,35,40,42,47,48). Studies in mesangial cells showed that glucose activates ADAM17 and EGF receptor (EGFR) and regulates profibrotic TGF␤ and the accumulation of matrix proteins (48,(51)(52)(53).…”

Matrix metalloproteinases in kidney homeostasis and diseases

“…Some models show that decreased MMP activity, particularly of MMP-2 and MMP-9, ameliorate kidney lesions (107,114,144,150), whereas in other models maintenance of MMPs, namely, MMP-1 and in some cases even MMP-9, is associated with improvement (see Table 2) (4,34). Similarly contradictory, TIMP-3 was elevated in diabetes, but TIMP-3 null mice actually had worsened fibrosis and increased activation of MMP-2 (55,57). Collectively, these data highlight the complexities of MMP pathobiology and the continued need for mechanistic studies.…”

Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

“…Probably more important in matrix turnover is the role of fibrillar collagen receptors and endocytic receptors, such as discoidin domain receptors (DDRs), leukocyte-associated IG-like receptor 1 (LAIR1), mannose receptor, and Endo180, in phagocytosis of matrix and disposal via the lysosomal pathway in macrophages (see below) and possibly in myofibroblasts (13,22,88). TIMP1 has been shown to be an important cell survival factor in myofibroblasts and this may explain some of the biology associated with its expression, whereas TIMP3 plays inhibitory roles in the activation of myofibroblasts (51,88).…”