Vasoactive Factors and Tubulointerstitial Injury

Abstract

Morphological changes of the tubulointerstitial architecture are a major determinant in the progression of chronic renal disease. The evolution of the tubulointerstitial lesion includes early tubular hypertrophy, recruitment of inflammatory cells into the tubulointerstitial space, and proliferation of interstitial fibroblasts resulting in the irreversible changes of tubular atrophy and tubulointerstitial fibrosis. Many of these diverse effects are mediated by autocrine or paracrine release of growth factors, cytokines, and chemokines. Proteinuria, reduction in functional renal mass per se, alterations in tubular fluid reabsorption, and well as hemodynamic changes in the injured kidney may all stimulate local release of such growth factors. A more recent conception is that vasoactive substances, traditionally viewed to be only involved in the regulation of vascular tone, could actually mediate many of these functions of the more 'classical’ growth factors and cytokines. In this regard, one of the most intensively studied vasoactive substances is angiotensin II which has been linked to the progression of renal disease by a host of mechanisms, including the induction of tubular hypertrophy and proliferation of interstitial fibroblasts. There is also increasing evidence that other vasoconstrictive factors such as endothelins and eicosanoids are involved in pathophysiological changes leading eventually to tubulointerstitial fibrosis. On the other hand, natriuretic peptides may exert antifibrogenic properties. Although interference with the renin angiotensin system is currently the only treatment being effective in attenuating the loss of function in patients with chronic renal insufficiency, it is likely that future studies will also investigate the role of other vasoactive substances in the progression of human chronic renal disease.

Fluvastatin inhibits activation of JAK and STAT proteins in diabetic rat glomeruli and mesangial cells under high glucose conditions

“…Diabetic nephropathy is characterized by excessive deposition of ECM in the kidney, leading to glomerular mesangial expansion and tubulointerstitial fibrosis. Recent studies have demonstrated that early renal hypertrophy is detrimental to the kidney in the long term and is a precursor of development of renal fibrosis [19,20] . Although the exact mechanisms of renal hypertrophy are still unclear, several growth factors, cytokines, chemokines, and vasoactive agents have been implicated in the development of renal hypertrophy, which include TGF-β, insulin like growth factor-1 (IGF-1), and platelet derived growth factor (PDGF) [21][22][23] .…”

SGK1-Dependent Upregulation of Connective Tissue Growth Factor by Angiotensin II

“…The pleotropic actions of angiotensin II include the stimulation of matrix protein formation and deposition leading to fibrosis in a variety of tissues including heart [1,2] , vascular tissue [3][4][5][6] , kidney [7][8][9][10][11][12][13] , liver [14,15] , lung [16] and retina [17] . The effect of angiotensin II is mediated by upregulation of connective tissue growth factor (CTGF) [15,[18][19][20][21][22][23][24][25][26][27] .…”

Connective Tissue Growth Factor-Mediated Angiotensin II-Induced Hypertrophy of Proximal Tubular Cells

“…Although all the structural components of the nephron are involved in such responses, enlargement of proximal tubular epithelial cells principally accounts, in quantitative terms, for the predominant component of compensatory renal hypertrophy [1]. Recent studies have demonstrated that tubular hypertrophy is detrimental to the kidney in the long term and serves as a precursor of development of tubulointerstitial fibrosis [2, 3]. It is therefore important to clarify the exact mechanisms of tubular epithelial cell hypertrophy, which may provide a new strategy to prevent renal fibrosis early.…”