肾脏纤维化相关因子研究进展

肾脏纤维化是慢性肾脏病发展的必经之路,是一个复杂的病理过程,近年来受到人们越来越多的关注.与之相关的因子众多,大致分为促纤维化和抑制纤维化两种,本文就近年讨论较多的因子进行综述.     

结缔组织生长因子与肾脏纤维化

结缔组织生长因子（CTGF）属于即刻早期反应基因中的CCN家族成员，CTGF基因的表达受到高糖环境，转移生长因子β、血循环机械应力、CTGF自身，糖皮质激素、肿瘤坏死因子α的影响，CTGF可能是转移生长因子β促纤维化活性的下游信号介质，刺激细胞增殖及细胞外基质的形成，在肾脏纤维化中有着重要地位。     

Smad信号通路在肾脏纤维化中的作用

Smad蛋白是TGF—β超家族的下游信号传导蛋白．近年来许多研究结果表明TGF—β超家族在肾脏的促／抗纤维化效应主要是通过激活其细胞内信号传导蛋白Smad家族来实现的。本文拟对Smad信号通路在肾脏纤维化发生、发展中的作用作一综述。     

尿蛋白成分与肾脏纤维化关系研究

蛋白尿不仅是反映肾小球损伤的标志,还是导致小管间质纤维化的一个独立因素,这一观点已成为共识。目前有大量研究致力于探讨尿蛋白成分与小管间质纤维化的关系。本文综述了蛋白尿致小管间质纤维化的机制,各尿蛋白成分与小管间质纤维化的关系。     

肾脏纤维化的发病机制和治疗新进展

现代研究认为无论是什么原因引起的慢性肾功能不全,在组织学上都存在着肾脏纤维化的过程。在肾脏纤维化的过程中有系膜细胞和成纤维细胞的激活、小管上皮细胞向系膜质细胞的转变、单核细胞/巨噬细胞、T淋巴细胞的浸润以及细胞的凋亡。从基因水平上来看,TGF-β和Smad在肾脏纤维化中起了很大的作用。基质降解酶能够降解细胞间基质,防止间质的纤维化过程。在肾脏纤维化的治疗上强调抗纤维化和致纤维化的阴阳平衡,其中肝细胞生长因子和成骨蛋白-7是有效的抗纤维化因子。本文将就肾脏纤维化的发病机制和治疗两个方面作一综述。     

MAPK信号转导通路与肾纤维化

肾纤维化是各种原发和继发性肾脏病进展到终末期肾衰(end-stage renal disease, ESRD)的基本病理过程,明确其发病机制以减缓乃至阻断其进展是研究的难点、热点所在.近年来,越来越多的证据表明,丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信号转导通路与肾纤维化关系密切.本文就二者关系作一综述.     

结缔组织生长因子与肾脏纤维化

结缔组织生长因子 (CTGF)属于即刻早期反应基因中的CCN家族成员。CTGF基因的表达受到高糖环境、转移生长因子β、血循环机械应力、CTGF自身、糖皮质激素、肿瘤坏死因子α的影响。CTGF可能是转移生长因子β促纤维化活性的下游信号介质 ,刺激细胞增殖及细胞外基质的形成 ,在肾脏纤维化中有着重要地位     

microRNA在肾脏纤维化中的研究进展

微小核糖核酸(miRNA)是一种在基因转录后水平调控基因表达的内源性非编码小分子RNA.它参与细胞的增殖与分化、胚胎的发育、信号的传导以及人类的一些相关疾病的调控.近年研究发现,在肾脏组织中存在的一些miRNAs对肾脏纤维化的发生与发展有着重要的作用,深入地了解它们之间的关系可以为临床肾脏纤维化的治疗提供新的方案.     

组织型转谷氨酰胺酶与肾脏纤维化

组织型转谷氨酰胺酶是转谷氨酰胺酶家族成员之一,具有转谷氨酰胺酶活性和GTP酶活性两种作用。晚近研究发现组织型转谷氨酰酶与肾脏纤维化关系密切。     

己酮可可碱在肾脏疾病中的抗纤维化作用

己酮可可碱是一种非特异的磷酸二酯酶抑制剂，早先针对其调节血流动力学特性，主要用于血管性疾病治疗。近来研究发现，己酮可可碱还是一种有效的抗纤维化制剂。本文就己酮可可碱在肾脏疾病中的抗纤维化作用作一综述。     

(Pro)renin receptor blocker improves survival of rats with sepsis

Background

The renin-angiotensin system (RAS) affects inflammatory responses during sepsis. Nonproteolytic activation of prorenin by the (pro)renin receptor has recently been shown to stimulate the tissue RAS. In the present study, the effect of (pro)renin receptor blocker (PRRB) pretreatment on sepsis in a rat cecal ligation and puncture (CLP) model was investigated.

Materials and methods

Male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: PRRB-treated group and control peptide–treated group. Survival was analyzed for 7 d after CLP. The serum concentrations of cytokines and high-mobility group box chromosomal protein 1 (HMGB1) were measured at three time points (0, 3, and 6 h after CLP). Hematoxylin-eosin staining and immunohistochemical staining for nonproteolytically activated prorenin and HMGB1 were performed on the cecum to assess pathologic changes found 6 h after CLP.

Results

Treatment with PRRB improved the survival rate of the post-CLP septic rats (P = 0.023). PRRB also significantly reduced serum tumor necrosis factor-α, interleukin-1β, and HMGB1 levels 6 h after CLP. In CLP rats that were treated with control peptide, the expression of activated prorenin was elevated in peritoneal foam cells. Moreover, expression of HMGB1 was increased in peritoneal inflammatory cells. In contrast, both were markedly suppressed in CLP rats that were treated with PRRB.

Conclusions

PRRB significantly improved the survival rate of rats with clinically relevant sepsis, possibly by attenuating a sepsis-induced systemic inflammatory response. We propose that overactivation of the RAS by activation of prorenin in foam cells may be a significant contributor to sepsis.     

Regression of nephropathy developed in diabetes by (Pro)renin receptor blockade

Activation of prorenin by (pro)renin receptor stimulates the tissue renin-angiotensin system and plays a significant role in the development of nephropathy in diabetic animals. This study examined whether (pro)renin receptor blockade inhibits the progression of nephropathy that has already developed in diabetic rats. Seventeen-week-old heminephrectomized streptozotocin-induced diabetic rats with an increased urinary protein excretion and a significant glomerulosclerosis had been treated for 12 wk with the (pro)renin receptor blocker (PRRB), angiotensin-converting enzyme inhibitor (ACEi), or vehicle peptide by using subcutaneously implanted osmotic minipumps. At the end of observation, in diabetic rats that were treated with vehicle, urinary protein excretion was progressively increased and a significant progression of glomerulosclerosis was observed. In diabetic rats that were treated with PRRB, however, no further increase in urinary protein excretion or glomerulosclerosis was observed, but 12-wk treatment with ACEi only attenuated further increases in urinary protein excretion and glomerulosclerosis. The enhanced expression of activated prorenin was observed in the kidneys of diabetic rats that were treated with vehicle, whereas it was markedly suppressed in the kidneys of diabetic rats that were treated with PRRB but not ACEi. These results suggest that (pro)renin receptor blockade does not only inhibit the progression of nephropathy but also reverses the glomerulosclerosis that has already developed in diabetic rats.     

The (pro)renin receptor: pathophysiological roles in cardiovascular and renal pathology

PURPOSE OF REVIEW: The pathophysiological role of the (pro)renin receptor is yet to be established. The present review summarizes the findings, suggesting that it may play pathological role in cardiac and renal fibrosis, and in hypertensive and diabetic nephropathy. RECENT FINDINGS: In-vitro and animal studies have shown that increased receptor expression could be linked to high blood pressure and to cardiac and glomerular fibrosis by activating mitogen-activated protein kinases and by upregulating gene expression of profibrotic molecules. Studies also suggest that the receptor is involved in diabetic nephropathy by activating receptor-bound prorenin, thereby increasing angiotensin II tissue generation. Moreover, in diabetic mice, a peptide able to block prorenin binding to the receptor was claimed to be more effective for renal protection than angiotensin-converting enzyme inhibitor. SUMMARY: The experimental data confirmed the pivotal role of the receptor in cell surface generation of angiotensin and suggested its potential role in tissue fibrosis via receptor activation and intracellular signaling. The data also questioned the ability of soon available renin inhibitors to inhibit the activity of receptor-bound renin and prorenin, and the benefit of a new class of drug--(pro)renin receptor blockers--to prevent tissue damage.     

The (pro)renin receptor and the kidney

Prorenin binding to the (pro)renin receptor not only causes a nonproteolytic activation of prorenin leading to the activation of the renin-angiotensin system (RAS), but also stimulates the receptor's own intracellular signaling pathways independent of the RAS. Within the kidneys, the (pro)renin receptor is present in the glomerular mesangium and podocytes, which play an important role in the maintenance of the glomerular filtration barrier. Therefore, prorenin-receptor blockers, which competitively bind to the receptor as a decoy peptide, have superior benefits with regard to proteinuria and glomerulosclerosis in experimental animal models with elevated plasma prorenin levels such as diabetes and hypertension compared with conventional RAS inhibitors, possibly by inhibiting both the nonproteolytic activation of prorenin and RAS-independent intracellular signals.     

The putative (pro)renin receptor blocker HRP fails to prevent (pro)renin signaling

The prorenin/renin receptor is a recently discovered component of the renin-angiotensin system. The effects of aliskiren, a direct inhibitor of human renin, were compared with the handle region decoy peptide (HRP), which blocks the prorenin/renin receptor, in double-transgenic rats overexpressing the human renin and angiotensinogen genes. After 7 wk, all aliskiren-treated rats were alive, whereas mortality was 40% in vehicle-treated and 58% in HRP-treated rats. Aliskiren but not the HRP reduced BP and normalized albuminuria, cystatin C, and neutrophil gelatinase-associated lipocalin, a marker of renal tubular damage, to the levels of nontransgenic controls. In vitro, human renin and prorenin induced extracellular signal-regulated kinase 1/2 phosphorylation, independent of angiotensin II (AngII), in vascular smooth muscle cells. Preincubation with the HRP or aliskiren did not prevent renin- and prorenin-induced extracellular signal-regulated kinase 1/2 phosphorylation, whereas the MAP kinase kinase (MEK1/2) inhibitor PD98059 prevented both. In conclusion, renin inhibition but not treatment with the HRP protects against AngII-induced renal damage in double-transgenic rats. In addition, the in vitro data do not support the use of the HRP to block AngII-independent prorenin- or renin-mediated effects.     

Mannose receptor 2 attenuates renal fibrosis

Mannose receptor 2 (Mrc2) expresses an extracellular fibronectin type II domain that binds to and internalizes collagen, suggesting that it may play a role in modulating renal fibrosis. Here, we found that Mrc2 levels were very low in normal kidneys but subsets of interstitial myofibroblasts and macrophages upregulated Mrc2 after unilateral ureteral obstruction (UUO). Renal fibrosis and renal parenchymal damage were significantly worse in Mrc2-deficient mice. Similarly, Mrc2-deficient Col4α3(-/-) mice with hereditary nephritis had significantly higher levels of total kidney collagen, serum BUN, and urinary protein than Mrc2-sufficient Col4α3(-/-) mice. The more severe phenotype seemed to be the result of reduced collagen turnover, because procollagen III (α1) mRNA levels and fractional collagen synthesis in the wild-type and Mrc2-deficient kidneys were similar after UUO. Although Mrc2 associates with the urokinase receptor, differences in renal urokinase activity did not account for the increased fibrosis in the Mrc2-deficient mice. Treating wild-type mice with a cathepsin inhibitor, which blocks proteases implicated in Mrc2-mediated collagen degradation, worsened UUO-induced renal fibrosis. Cathepsin mRNA profiles were similar in Mrc2-positive fibroblasts and macrophages, and Mrc2 genotype did not alter relative cathepsin mRNA levels. Taken together, these data establish an important fibrosis-attenuating role for Mrc2-expressing renal interstitial cells and suggest the involvement of a lysosomal collagen turnover pathway.     

Antihypertensive therapy upregulates renin and (pro)renin receptor in the clipped kidney of Goldblatt hypertensive rats

Recently, a (pro)renin receptor has been identified which mediates profibrotic effects independent of angiotensin II. Because antihypertensive therapy induces renal injury in the clipped kidney of two kidney-1-clip hypertensive rats, we examined the regulation of renin and the (pro)renin receptor in this model. Hypertensive Goldblatt rats were treated with increasing doses of the vasopeptidase inhibitor AVE 7688 after which the plasma renin and prorenin as well as the renal renin and (pro)renin receptor expression were measured. The vasopeptidase inhibitor dose-dependently lowered blood pressure, which was associated with a massive increase in plasma prorenin and renin as well as increased renal renin expression. The (pro)renin receptor was upregulated in the clipped kidney of the Goldblatt rat indicating a parallel upregulation of renin and its receptor in vivo. Immunohistochemistry showed a redistribution of renin upstream from the glomerulus in preglomerular vessels and renin staining in tubular cells. Expression of the (pro)renin receptor was increased in the vessels and tubules. This upregulation was associated with thickening of renin-positive vessels and tubulointerstitial damage. We propose that renin and the (pro)renin receptor may play a profibrotic role in the clipped kidney of Goldblatt rats treated for hypertension.