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  • DDR upregulation in patients with kidney diseases

    2019-11-19

    DDR1 upregulation in patients with kidney diseases such as lupus nephritis and Goodpasture\'s syndrome [8] as well as in animal models of kidney injury [7], [8], [18] suggests that DDR1 plays an important role in kidney disease. Studies in various mouse models of kidney injury indicate that DDR1 deletion results in improved renal function and reduced inflammation and fibrosis. In this context, angiotensin-induced abnormal extracellular matrix (ECM) deposition, perivascular and glomerular infiltrate and albuminuria were reduced in DDR1-null mice [19]. Similarly, collagen deposition, macrophage infiltration and pro-inflammatory cytokine levels were significantly reduced in DDR1 null mice following unilateral ureteral obstruction [7]. In genetic models of chronic kidney disease, such as the Alport mice, DDR1 deletion improves survival and reduces fibrosis and inflammation [9]. Moreover, inhibition of DDR1 expression by using antisense oligodeoxynucleotides in a model of crescentic glomerulonephritis attenuates glomerular and tubular injuries decreases proteinuria and reduces inflammatory Nalidixic acid infiltration and fibrosis [8]. Overall, loss of DDR1 protects mice from kidney injury and the beneficial effects seems to reside in reduced inflammatory cells infiltration due to impaired migration and/or reduced inflammatory cytokines production in the DDR1-null mice. In addition to its pro-inflammatory action, DDR1 controls collagen synthesis. Mice lacking DDR1 show increased fibrillar collagen deposition in the mammary gland [20] and DDR1-null smooth muscle show increased mRNA levels of fibrillar collagens I and III [21], suggesting that DDR1 is a negative regulator of fibrillar collagen synthesis. In contrast to these findings, DDR1-null smooth muscle cells showed decreased mRNA levels of non-fibrillar collagen, such as the basement membrane collagen IV [21]. Thus, DDR1 can promote and/or inhibit collagen synthesis and this effect is dependent on the type of collagen. DDR1 is normally expressed at low levels by cells comprising the glomerulus, the functional filtration unit of the kidney, but its expression increases following glomerular injury [8]. The glomerulus consists of three major cell types, namely endothelial cells, podocytes and mesangial cells that are kept together by an extracellular network composed primarily of collagen IV. Insult to these cells can lead to glomerulosclerosis, the process by which glomerular tissue is replaced by ECM (mainly collagens I and IV) and the final common pathway for loss of functioning glomeruli [22], [23]. Podocytes and endothelial cells are likely critical for initiation of sclerosis; however, mesangial cells are the major contributor to progression. Mesangial cells express DDR1 in vitro [24] and DDR1 expression increases in glomerular injury [19]. However, whether DDR1 contributes to glomerulosclerosis by directly regulating collagens I and/or IV production is unknown.
    Results
    Discussion The finding that DDR1 is upregulated in both glomeruli and tubules of injured kidneys [7], [8], [18], [19] together with the finding that mice lacking DDR1 are protected from the progression to chronic kidney disease ([9] and this study), clearly implies that DDR1 is an important contributor to kidney disease. However, how DDR1 contributes to kidney diseases is poorly understood. The goal of this study was to determine whether the collagen binding receptor DDR1 contributes to kidney fibrosis by directly regulating collagen production. DDR1 has been shown to have a pro-inflammatory role as it promotes inflammatory cell infiltration [7], [19] and production of pro-inflammatory cytokines like TGF-β, CTGF and IL-1 [8], [9]. Thus, it is conceivable that the protective effect observed in the DDR1-null mice is due to reduced inflammatory cell infiltration to the site of injury. Another explanation is that loss of DDR1 might lead to reduced production of TGF-β and CTGF, two well established pro-fibrotic cytokines, thus indirectly contributing to reduced fibrosis following injury.