Angiotensin II as a mediator of tubulointerstitial injury.

a pivotal role in many of these above-tubulointerstitial fibrosis mentioned processes leading to tubulointerstitial scarring and tubular atrophy [3,4]. Cell culture studies investigating potential effects of ANG II on tubular cells and fibroblasts in the absence of haemodynamic alterations have contributed considerably to a better understanding of the multiple cellular actions of this Morphological alterations of the tubulointerstitial small peptide (see Figure 1). architecture currently are seen as a major determinant ANG II induces hypertrophy of proximal tubular in the progression of chronic renal disease [1]. cells but stimulates proliferation of cells isolated from Structural changes such as the degree of tubulointersti-tial fibrosis and tubular atrophy correlate better with the loop of Henle (for review, see [5]). The hyper-the decline of renal function than glomerular lesions, trophic action of ANG II in proximal tubular cells is even in primary glomerulopathies. Evidence suggests mediated through AT 1 receptors, and depends on an an evolution of the tubulointerstitial changes in chronic oxygen radical-mediated increase in p27Kip1, an inhib-renal disease over time, with early compensatory hyper-itor of G 1 phase cyclin–cyclin-dependent kinase com-trophy of tubular changes and an increase in functional plexes [4,5]. Furthermore, ANG II also reduces protein capacity, recruitment of inflammatory cells into the degradation by inhibition of proteases [3]. ANG II tubulointerstitial spaces and proliferation of interstitial mediates the transcription and biosynthesis of trans-fibroblasts [2]. In addition, tubular cells may transforming growth factor-b (TGF-b), a major pro-differentiate to fibroblasts under certain conditions, fibrogenic cytokine, in proximal tubular cells [6 ]. In partly explaining tubular atrophy and the local increase addition, ANG II also stimulates TGF-b receptor type in interstitial fibroblasts [1]. An increase in extracellu-II, but not type I, transcription and surface expression, lar matrix synthesis by tubular cells and interstitial further amplifying the effects of ANG II-induced TGF-fibroblasts as well as a decrease in local turnover of b expression [7]. ANG II also induces the transcription such components finally leads to the irreversible devel-and synthesis of various chains of basement-associated opment of tubulointerstitial fibrosis. Many of these collagen type IV including the a3(IV) chain with a diverse effects on tubular cells and fibroblasts are quite restricted distribution [4,8]. In contrast, tubuloin-mediated by autocrine/paracrine release of growth terstitial fibroblasts proliferate and secrete more of the factors, cytokines and chemokines [1–3]. Several interstitial collagen types I and III after exposure to pathophysiological disturbances including proteinuria, ANG II ([9] Figure 1). Interestingly, …