Identification of Periostin as a Critical Marker of Progression/Reversal of Hypertensive Nephropathy

Progression of chronic kidney disease (CKD) is a major health issue due to persistent accumulation of extracellular matrix in the injured kidney. However, our current understanding of fibrosis is limited, therapeutic options are lacking, and progressive degradation of renal function prevails in CKD patients. Uncovering novel therapeutic targets is therefore necessary

Restoration of Podocyte Structure and Improvement of Chronic Renal Disease in Transgenic Mice Overexpressing Renin

Proteinuria is a major marker of the decline of renal function and an important risk factor of coronary heart disease. Elevated proteinuria is associated to the disruption of slit-diaphragm and loss of podocyte foot processes, structural alterations that are considered irreversible. The objective of the present study was to investigate whether proteinuria can be reversed and to identify the structural modifications and the gene/protein regulation associated to this reversal.We used a novel transgenic strain of mouse (RenTg) that overexpresses renin at a constant high level. At the age of 12-month, RenTg mice showed established lesions typical of chronic renal disease such as peri-vascular and periglomerular inflammation, glomerular ischemia, glomerulosclerosis, mesangial expansion and tubular dilation. Ultrastructural analysis indicated abnormal heterogeneity of basement membrane thickness and disappearance of podocyte foot processes. These structural alterations were accompanied by decreased expressions of proteins specific of podocyte (nephrin, podocin), or tubular epithelial cell (E-cadherin and megalin) integrity. In addition, since TGFbeta is considered the major pro-fibrotic agent in renal disease and since exogenous administration of BMP7 is reported to antagonize the TGFbeta-induced phenotype changes in kidney, we have screened the expressions of several genes belonging in the TGFbeta/BMP superfamily. We found that the endogenous inhibitors of BMPs such as noggin and Usag-1 were several-fold activated inhibiting the action of BMPs and thus reinforcing the deleterious action of TGFbeta.Treatment with an AT1 receptor antagonist, at dose that did not decrease arterial pressure, gradually reduced albuminuria. This decrease was accompanied by re-expression of podocin, nephrin, E-cadherin and megalin, and reappearance of podocyte foot processes. In addition, expressions of noggin and Usag-1 were markedly decreased, permitting thus activation of the beneficial action of BMPs.These findings show that proteinuria and alterations in the expression of proteins involved in the integrity and function of glomerular and renal epithelial phenotype are reversible events when the local action of angiotensin II is blocked, and provide hope that chronic renal disease can be efficiently treated

Angiotensin II activates collagen type I gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and TGF-beta

Hypertension is frequently associated with the development of renal vascular fibrosis. This pathophysiologic process is due to the abnormal formation of extracellular matrix proteins, mainly collagen type I. In previous studies, it has been observed that the pharmacologic blockade of angiotensin II (Ang II) or endothelin (ET) blunted the development of glomerulo- and nephroangiosclerosis in nitric oxide-deficient hypertensive animals by inhibiting collagen I gene activation. The purpose of this study was to investigate whether and how AngII interacts with ET to activate the collagen I gene and whether transforming growth factor-beta (TGF-beta) could be a player in this interaction. Experiments were performed in vivo on transgenic mice harboring the luciferase gene under the control of the collagen I-alpha 2 chain promoter (procol alpha 2[I]). Bolus intravenous administration of AngII or ET produced a rapid, dose-dependent activation of collagen I gene in aorta and renal cortical slices (threefold increase over control at 2 h, P < 0.01). The AngII-induced effect on procol alpha 2(I) was completely inhibited by candesartan (AngII type 1 receptor antagonist) and substantially blunted by bosentan (dual ET receptor antagonist) (P < 0.01), whereas the ET-induced activation of collagen I gene was blocked only by bosentan. In subsequent experiments, TGF-beta (also administered intravenously) produced a rapid increase of procol alpha 2(I) in aorta and renal cortical slices (twofold increase over control at 1 h, P < 0.01) that was completely blocked by decorin (scavenger of the active form of TGF-beta). In addition, decorin attenuated the activation of collagen I gene produced by AngII (P < 0.01). These data indicate that AngII can activate collagen I gene in aorta and renal cortex in vivo by a mechanism(s) requiring participation and/or cooperation of ET and TGF-beta

Role of renal urothelium proliferation in the onset of calcium oxalate stones

International audienceBackgroundMost mice kidney stone models induce nephrocalcinosis rather than urolithiasis.Materials and methodsC57B6 mice under vitamin D and water containing 4% hydroxyl-L-proline, ammonium chloride (0.28M) and calcium (0.25%) were follow up until day 42. A group receiving Fibroblast Growth Factor 7 (FGF7 i.p. once a week), a urothelial cell mitogen was compared to control group. Localization and identification of crystal deposits were performed with polarizing microscopy, infrared imager and Scanning Electron Microscopy. Urothelial and tubular phenotypes were studied by immunohistochemistry, immunofluorescence and RT PCR.ResultsCalcium oxalate monhydrate (COM) deposits in fornices were detected in all kidneys as soon as day 14 with very few crystals in tubules. On day 21, crystal number was increased in FGF7 compared to control group. Though osteopontin (OPN) was unregulated and detected in urothelial cells, de novo expression of CD44 (osteopontin receptor) receptor was induced only in proliferating urothelial cells either induced by FGF7 or by long standing urine crystal exposure altogether with a loss of apical uroplakines III expression. ConclusionOur model seems interesting to study in KO mice, in order to investigate the critical events leading to urolithiasis. Our data show that urothelial cells proliferation promotes renal crystal retention especially within fornices, probably through different processes involving specific and non-specific crystal adhesion, and thus appears per se as a relevant risk factor for stone formation