Renal cortical hemopexin accumulation in response to acute kidney injury

Abstract

Hemopexin (Hpx) is a liver-generated acute phase reactant that binds and neutralizes prooxidant free heme. This study tested whether acute kidney injury (AKI) triggers renal Hpx accumulation, potentially impacting heme Fe-mediated tubular injury. Mice were subjected to glycerol, cisplatin, ischemia-reperfusion (I/R), or endotoxemic [lipopolysaccharide (LPS)] AKI. In each instance, 3- to 30-fold renal cortical and isolated proximal tubule segment (PTS) Hpx increases resulted. Although renal cortex and PTS showed variable Hpx mRNA increases, due, in part, to increased mRNA stability, mRNA levels did not correlate with renal Hpx protein accumulation. Conversely, AKI evoked three- to fourfold increases in hepatic Hpx gene induction, which corresponded with three- to fourfold plasma Hpx increases. Renal immunohistochemistry, and increased urinary Hpx excretion, indicated that circulating Hpx gains tubule luminal/urinary access, followed by proximal tubule endocytic uptake. Paradoxically, in cultured renal cells (HK-2, HEK-293), Fe depletion, and not free heme excess, increased Hpx mRNA. LPS acutely increased HK-2 cell Hpx mRNA. This finding, coupled with observations that LPS evoked ∼30-fold greater renal Hpx mRNA increases than any other AKI model, suggests that inflammation, not heme exposure, activates the renal Hpx gene. Each form of AKI evoked early increases in circulating free heme, which subsequently fell to subnormal levels as plasma Hpx rose. In addition, purified Hpx blunted free Fe-mediated HK-2 cell death. In sum, these data indicated that AKI-associated hepatic stress generates Hpx, which gains renal tubule access. Given its ability to bind free heme and mitigate free Fe toxicity, Hpx loading can potentially confer cytoprotective effects.

Identification of Leydig cell-specific mRNA transcripts in the adult rat testis

“…In addition to metabolic enzymes, the Leydig cells appear to secrete a number of active proteins such as haemopexin, haptoglobin and lactoperoxidase. Haptoglobin and haemopexin are acute-phase proteins typically secreted by the liver as a stress response (Guillouzo et al 1984) though they are also secreted by other organs in response to acute injury (Zager et al 2012). Both will act to reduce oxidative stress through antioxidant action or through haem binding (Tseng et al 2004, Tolosano et al 2010, while haemopexin also has potent anti-inflammatory effects (Fink 2009).…”

Urinary proteome profile of renal papillary necrosis in experimental model rats

“…Alpha-2-HS-glycoprotein, also known as fetuin-A, was identified in the urinary exosome of a cisplatin-induced acute kidney injury rat model (Zhou et al, 2006). Fibrinogen gamma chain, hemopexin, and kininogen 2 are also associated with kidney injury (Krishnamoorthy et al, 2011;Kaushal and Shah, 2012;Zager et al, 2012;Bompart et al, 1993). However, most of the other identified proteins have not been linked to kidney injury to date, and could therefore represent novel biomarkers.…”

Protection against Heme Toxicity: Hemopexin Rules, OK?

“…Although plasma levels of HPX are high, this protein is readily increased by local synthesis by non-hepatic cells, and the known examples are all related to stress and/or inflammatory responses, for example, by heme in primary neurons, 148 by inflammation in CSF, 132 or by acute kidney injury "renal hepatization." 149 However, in another study, heme did not induce HPX in primary neurons. 76 The proteomics profiles described below, in Sections IV-D and IV-E, in which HPX is implicated, may provide links to some of these processes.…”

“…Furthermore, evidence is accruing that in certain pathological states, HPX expression is turned on in non-hepatic cells, including certain cells of the kidney. 149 An 85 kDa form of HPX was immunologically detected in TNF-α-stimulated human mesangial cells 177 (human plasma HPX is normally 52 kDa 83,178 ). If, and if so how, this kidney metabolism contributes to the plasma proteome has not been defined, but in the case of HPX, it is considered protective against Hb toxicity in rats.…”