Induction of Heme Oxygenase-1 Can Halt and Even Reverse Renal Tubule-Interstitial Fibrosis

Abstract

BackgroundThe tubule-interstitial fibrosis is the hallmark of progressive renal disease and is strongly associated with inflammation of this compartment. Heme-oxygenase-1 (HO-1) is a cytoprotective molecule that has been shown to be beneficial in various models of renal injury. However, the role of HO-1 in reversing an established renal scar has not yet been addressed.AimWe explored the ability of HO-1 to halt and reverse the establishment of fibrosis in an experimental model of chronic renal disease.MethodsSprague-Dawley male rats were subjected to unilateral ureteral obstruction (UUO) and divided into two groups: non-treated and Hemin-treated. To study the prevention of fibrosis, animals were pre-treated with Hemin at days -2 and -1 prior to UUO. To investigate whether HO-1 could reverse established fibrosis, Hemin therapy was given at days 6 and 7 post-surgery. After 7 and/or 14 days, animals were sacrificed and blood, urine and kidney tissue samples were collected for analyses. Renal function was determined by assessing the serum creatinine, inulin clearance, proteinuria/creatininuria ratio and extent of albuminuria. Arterial blood pressure was measured and fibrosis was quantified by Picrosirius staining. Gene and protein expression of pro-inflammatory and pro-fibrotic molecules, as well as HO-1 were performed.ResultsPre-treatment with Hemin upregulated HO-1 expression and significantly reduced proteinuria, albuminuria, inflammation and pro-fibrotic protein and gene expressions in animals subjected to UUO. Interestingly, the delayed treatment with Hemin was also able to reduce renal dysfunction and to decrease the expression of pro-inflammatory molecules, all in association with significantly reduced levels of fibrosis-related molecules and collagen deposition. Finally, TGF-β protein production was significantly lower in Hemin-treated animals.ConclusionTreatment with Hemin was able both to prevent the progression of fibrosis and to reverse an established renal scar. Modulation of inflammation appears to be the major mechanism behind HO-1 cytoprotection.

Length Polymorphism in Heme Oxygenase-1 and Risk of CKD among Patients with Coronary Artery Disease

“…Desbuards et al 25 used hemin, an inducer of HO-1, to attenuate interstitial fibrosis in 5/6 nephrectomized rats via inhibiting TGF-b and caspase-3 expression and increasing bone morphogenetic protein-7 expression. Correa-Costa et al 26 further revealed that pretreatment or delayed treatment with hemin both reduced renal dysfunction and decreased the expression of proinflammatory molecules, fibrosis-related molecules, and collagen deposition in rats subjected to UUO. In addition, HO-2, which contributes the bulk of HO activity in the unstressed kidney, was also suspected to play a protective role in the animal kidney models.…”

“…The protective effect of HO-1 against kidney injury is well known in a variety of animal models. 2,18,[22][23][24][25][26] We therefore performed an association study in patients with CAD to investigate whether the length polymorphism of the HO-1 gene promoter is associated with the risk of CKD.…”

Association of PAX2 with Cell Apoptosis in Unilateral Ureteral Obstruction Rats

“…Mure et al 48 performed a study in 26 fetal lambs that underwent surgical UUO and found that PAX2 protein was highly expressed in the nephrogenic zone, decreasing progressively to being markedly decreased in control lamb kidneys. Murer et al 30 conducted an investigation in 17 biopsies of juvenile nephronophthisis and observed that the failure of PAX2 repression was involved in 4 , 28th day); TGF-β1 (SHO, C 1 , 14th day, C 2 , 28th day; GU, C 3 , 14th day, C 4 , 28th day); α-SMA (SHO, D 1 , 14th day, D 2 , 28th day; GU, D 3 , 14th day, D 4 , 28th day); Col-IV (SHO, E 1 , 14th day, E 2 , 28th day; GU, E 3 , 14th day, E 4 , 28th day); FN (SHO, F 1 , 14th day, F 2 , 28th day; GU, F 3 , 14th day, F 4 , 28th day); caspase-3 (SHO, G 1 , 14th day, G 2 , 28th day; GU, G 3 , 14th day, G 4 , 28th day); and cell apoptosis (SHO, H 1 , 14th day, H 2 , 28th day; GU, H 3 , 14th day, H 4 , 28th day) were observed in two groups. PAX2 and caspase-3 were also mainly located in the RTEC (red arrow for PAX2 and blue arrow for caspase-3), and the apoptotic cell in our observation was mainly derived from RTEC (black arrow).…”

“…2,3 Unilateral ureteral obstruction (UUO) is a well-characterized model of experimental obstructive nephropathy, culminating in renal tubular apoptosis and interstitial fibrosis. 4,5 Cell apoptosis, such as renal tubular epithelial cells (RTEC) apoptosis, is a critical detrimental event that leads to chronic kidney injury in association with renal fibrosis. 6 deposition of ECM, such as collagen-IV (Col-IV) and fibronectin (FN), are the important characteristics of RIF.…”

Envolvimento da Heme oxigenase-1 nos mecanismos celulares de resposta ao estresse em um modelo de lesão renal aguda.

“…Por outro lado, alguns estudos demonstraram que a regulação positiva da HO---1 pode inibir diretamente a inflamação. Um trabalho recente indicou que, quando a HO---1 é induzida, existe uma modulação negativa de inflamação, com a diminuição da expressão de genes e produção das proteínas de TNF---α, IL---6 e IL---1β, com concomitantes níveis aumentados da citocina imunomoduladora IL ---10 [63].…”