Role of atrophic changes in proximal tubular cells in the peritubular deposition of type IV collagen in a rat renal ablation model

Abstract

Background. Tubular atrophy, dilation and interstitial fibrosis are common in tubulointerstitial lesions, but the precise roles and inter-relationships of these components in the development of interstitial lesions have not been determined. This study focused on the origin and roles of atrophic tubules in the peritubular deposition of type IV collagen in a rat renal ablation model. Methods. Male Wistar rats underwent 5/6 nephrectomy or sham operation, and then were sacrificed at 4, 8 or 12 weeks, their remaining kidneys removed for histological and immuno-histochemical studies as well as in situ hybridization for type IV collagen mRNA.Results. Immuno-histochemistry demonstrated the positive staining of atrophic tubules to vimentin, platelet-derived growth factor-B chain (PDGF) and heat shock protein 47 (HSP47). Cells positive to one or more of PDGF receptor b, a-smooth muscle actin (a-SMA), and HSP47 accumulated around atrophic tubules. Type IV collagen was also increased in the proximity of the atrophic tubules. These intimate relationships were more clearly demonstrated in 'mosaic tubules', which are composed of both intact and atrophic proximal tubular epithelial cells, and which had a mixed pattern of staining with vimentin, PDGF and HSP47. The interstitial cells positive to a-SMA or HSP47, or both, were in close contact with atrophic but not with intact epithelial cells. Type IV collagen was exclusively deposited between atrophic tubules and HSP47-positive interstitial cells. In situ hybridization of type IV collagen mRNA demonstrated predominant expression in atrophic tubular epithelial cells, but not in surrounding interstitial cells.Conclusions. These findings suggest that atrophic proximal tubular cells are active in the development of collagen deposition in the peritubular space, i.e. in this model type IV collagen in the interstitial fibrotic area may be produced mainly by atrophic proximal tubules.

Apocynin attenuates tubular apoptosis and tubulointerstitial fibrosis in transgenic mice independent of hypertension

“…The present results may have clinical implications. As tubular apoptosis is detectable in various renal diseases [7][8][9][10][11][12][13][14] and tubular atrophy appears to be a better indicator of disease progression than glomerular pathology, 4,19,50,51 we postulate that RPTC apoptosis may be an initial step leading to tubular atrophy and that ROS is one of the key mediators of this process.…”

“…[1][2][3][4][5][6] Tubular atrophy has been observed in various experimental models of nephropathy as well as in human renal diseases, [7][8][9][10][11][12] including diabetic nephropathy. 13,14 However, the pathogenesis of tubular atrophy remains poorly understood.…”

Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy?

“…In some studies of renal disease models with fibrosis expression, α-SMA has been found in tubular cells, and that finding was considered as evidence for EMT (27)(28)(29). However, in most other studies α-SMA was exclusively found in interstitial cells around injured tubules, whereas the tubules themselves remained α-SMA-negative (15,17,19,(30)(31)(32)(33). The same observation was made in biopsies of patients with nephritic syndrome (34).…”

Maladaptive Proximal Tubule Repair: Cell Cycle Arrest

“…These dedifferentiated cells may produce bioactive molecules with autocrine and paracrine functions, which may have detrimental effects and potentiate fibrosis [4,15,16]. De Borst et al [17] reported that c-Jun NH 2 -terminal kinase (JNK) remained active in proximal tubule cells weeks after the ischemic insult and was associated with tubulointerstitial inflammation and fibrosis.…”