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Immunolocalization of Kim-1, RPA-1, and RPA-2 in Kidney of Gentamicin-, Mercury-, or Chromium-Treated Rats: Relationship to Renal Distributions of iNOS and Nitrotyrosine
1 Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA Correspondence: Address correspondence to: Jun Zhang, MD, MS, Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration (HFD-910), 10903 New Hampshire Ave, Silver Spring, MD 20993; e-mail:jun.zhang{at}fda.hhs.gov.
Immunohistochemical studies for kidney injury molecule-1 (Kim-1), renal papillary antigen-1 (RPA-1), and renal papillary antigen-2 (RPA-2) were conducted to explore their relationship to inducible nitric oxide synthase (iNOS) and nitrotyrosine expression. Male Sprague-Dawley rats were exposed to gentamicin (100 mg/kg/day Gen, sc, for 3 days), mercury (0.25 mg Hg/kg, iv, single dose), or chromium (5 mg Cr/kg, sc, single dose) and kidney tissue was examined 24 hours or 72 hours after the last dose of the nephrotoxicant. Another group of kidneys was evaluated 24 hours after rats were administered 3 daily doses (50, 100, 150, 200, or 300 mg/kg/day) of Gen. Gen- and Cr-treated rats exhibited increased immunoreactivity of Kim-1, RPA-1, and RPA-2 largely in the S1/S2 segments and to a lesser extent in the S3 segments of the proximal tubule of the kidney, whereas Hg-treated rats showed increased immunoreactivity of Kim-1, RPA-1, and RPA-2 in the S3 segments. Up-regulation of Kim-1, RPA-1, and RPA-2 expression correlated with injured tubular epithelial cells and also correlated with immunoreactivity of iNOS and nitrotyrosine. It is possible that iNOS activation with nitrotyrosine production in injured nephron segments may be involved in the induction of Kim-1, RPA-1, and RPA-2 following exposure to nephrotoxicants.
Key Words: chromium • gentamicin • Kim-1 (kidney injury molecule-1) • mercury • nitrotyrosine • RPA-1 (renal papillary antigen-1) • RPA-2 (renal papillary antigen-2) Abbreviations: CD, collecting ducts • Cr, chromium (K2Cr2O7) • DCT, distal convoluted tubule • Gen, gentamicin sulfate • Hg, mercury (HgCl2) • iNOS, inducible nitric oxide synthase • Kim-1, kidney injury molecule-1 • LH, loop of Henle • mAb, monoclonal antibody • NO, nitric oxide • pAb, polyclonal antibody • RPA-1, renal papillary antigen-1 • RPA-2, renal papillary antigen-2 • S1/S2, segments and S3 segment, the S1 & S2 segments of proximal convoluted tubules and the S3 segment of proximal straight tubule
Localization of the site of injury in nephron segments has pathogenic and practical implications in the preclinical study of nephrotoxicity. Topographic histomorphology of segmental injury can help define mechanisms of toxic action and aid the search for site-specific biomarkers. The mechanisms underlying this site-selective injury are multifaceted but may be attributed in part to site-specific differences in pathophysiological properties (Schnellmann, 2001). Other factors such as animal species, age, dose regimen, treatment duration, the route of drug administration, and the choice of anesthetics may also contribute to the differences (Daugaard et al., 1987). Recent studies demonstrated that in immature and young Sprague-Dawley (SD) rats, gentamicin sulfate (Gen), an aminoglycoside antibiotic, induced renal tubular necrosis and apoptosis predominantly in the S1/S2 segments and partially in the S3 segments of the proximal tubule, whereas cisplatin, an antineoplastic agent, selectively induced necrosis and apoptosis in the S3 segment, the loop of Henle (LH), and collecting ducts (CD) of the medulla (Espandiari et al., 2007a, 2007b). In contrast to injury induced by Gen, cisplatin-induced renal injury spared most of the S1/S2 segments. Likewise, a recent study on male Wistar rats revealed that chromium (Cr; K2Cr2O7) exclusively affected the S1/S2 segments, whereas cisplatin selectively damaged the S3 segment of the proximal tubule (Cristofori et al., 2007). In previous studies cited in the literature, most histological observations are in agreement on drug-induced segmental injury; however, it was noted that there was inconsistency in the localization of segmental injury induced by some nephrotoxicants. For example, evidence of this inconsistency can be observed in reports demonstrating that cisplatin preferentially induced histological changes in proximal tubules in adult rats and not in distal tubules and CD in 10- and 55-day-old rats (Appenroth et al., 1990), or in the S1/S2 and S3 segments in rats (Daugaard et al., 1987, 1988; Daugaard and Abildggard, 1989), or in the proximal tubules in dogs (Daugaard et al., 1987), or in the distal convoluted tubules (DCT) and CD in patients (Gonzales-Vitale et al., 1977). Localization of the histological distribution of inducible nitric oxide synthase (iNOS) and nitrotyrosine in the nephron may have important implications for elucidating why certain nephron segments are affected by certain toxicants, but not by others, and advance the search for biomarkers of toxic injury mediated by oxidative stress. In healthy male SD rats, constitutive iNOS mRNA is expressed differentially in the various segments of the nephron. Prominent expression of iNOS was detected in the S3 segment, the thick ascending limb of LH, DCT, and the cortical and inner medullary CD, whereas much less expression of iNOS was noted in the thin limbs of LH, PCT, and the outer medullary CD (Ahn et al., 1994; Bachmann, 1997; Wu et al., 1999). In healthy male SD rats, much less nitrotyrosine immunoreactivity was seen in the epithelial cells of proximal tubules (Bian et al., 1999). Since peroxynitrite is produced by the reaction of nitrotyrosine with iNOS-derived NO, peroxynitrite formation is considered to be an important step in the development of many NO-mediated pathological processes in vivo (Forbes et al., 2002; Pacher et al., 2007). To correlate urinary biomarkers with the site of injury in the nephron, a panel of monoclonal and polyclonal antibodies (mAbs and pAbs) specific for the recognition of antigens in specific individual tubule segments has been developed. The expression of kidney injury molecule-1 (Kim-1) by immunohistochemistry (IHC) was reported to predominate in the S3 segments in rats in models of injury where that segment is most affected (Ichimura et al., 1998, 2004; Amin et al., 2004; van Timmerren et al., 2006; Vaidya et al., 2006; de Borst et al., 2007; Zhou et al., 2008) and in the S1/S2 proximal tubule segments in biopsy specimens from humans (Han et al., 2002; Zhang et al., 2008; Lin et al., 2007; van Timmerren et al., 2007; for summary, see Table 1) where there is little outer medullary tissue. New antibodies to renal papillary antigen-1 (RPA-1) and renal papillary antigen-2 (RPA-2) have been demonstrated to recognize antigens in the CD and the LH epithelial cells, respectively (Falkenberg et al., 1996; Hilderbrand et al., 1999; Shaw, 2005; Kilty et al., 2007). Thus, these new site-specific antibodies provide an opportunity to study the localization of tubular injury and may serve as robust biomarkers in preclinical and clinical studies of nephrotoxicity (Vaidya and Bonventre, 2006; Kilty et al., 2007).
The goal of the present study was to elucidate mechanisms that may trigger site-specific up-regulation of Kim-1, RPA-1, and RPA-2 and to explore morphological evidence of these proteins as biomarkers of nephrotoxicity. Specifically, we have employed rat models of Gen-, mercury (Hg)-, or Cr-induced nephrotoxicity: (a) to investigate the specific cellular distribution of Kim-1, RPA-1, and RPA-2 in different segments of the nephron using immunohistochemical methods; (b) to relate these findings to the immunohistochemical localization of iNOS and nitrotyrosine in an attempt to elucidate mechanisms possibly responsible for the up-regulation of Kim-1, RPA-1, and RPA-2; and (c) to correlate these immunoreactivities with the extent of the site-selective necrosis and apoptosis.
The experimental protocol was approved by the Institutional Animal Care and Use Committee, Center for Devices and Radiological Health, FDA, and conducted in an AAALAC (Association for Assessment & Accreditation of Laboratory Animal Care) accredited facility. All procedures for animal care and housing were in compliance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). All animals were housed in an environmentally controlled room (18–21°C, 40%–70% relative humidity) with a 12-hour light/dark cycle and were fed Certified Purina Rodent Chow and water ad libitum.
Study 1 (Time Response Study)
Study 2 (Dose Response Study) In studies 1 and 2, kidneys were collected at necropsy and fixed in 10% zinc-formalin for about 48 hours, embedded in paraffin, cut at a thickness of 5 µm, and then stained with hemotoxylineosin for histopathological study. Unstained, formalin-fixed, paraffin-embedded tissue sections were used for immunohistochemical studies.
Grading System for Renal Lesions
Immunohistochemical Studies For detection of Kim-1, RPA-1, and RPA-2, indirect immunoperoxidase staining procedures were used. Serial sections of formalin-fixed, paraffin-embedded renal tissue were mounted on glass slides coated with poly-L-Lysine (American HistoLabs, Inc, Gaithersburg, MD). Preparation of these sections included microwave irradiation in a pressure cooker with antigen retrieval Citra solution. After microwave treatment, slides were cooled in the antigen retrieval Citra solution for 20 minutes and then rinsed with dH2O. For blocking endogenous peroxidase activity, sections were incubated with 0.3% hydrogen peroxide in methanol for 30 minutes and then with 5% normal horse serum for 30 minutes. Sections were incubated overnight at 4°C with the following primary mAb at 1:50 dilutions: mouse anti-rat Kim-1 ectodomain (MARKE) mAb (Harvard Medical School), RPA-1 purified mAb (Code: BI087CD, Biotrin International Ltd), and RPA-2 purified mAb (Code: BI088LH, Biotrin International Ltd). Subsequently, sections were incubated with a biotinylated secondary antibody (Vector, Burlingame, CA) for 1 hour and then incubated with avidin-biotinylated horseradish peroxidase complex (Vector) for 30 minutes. The peroxidase reaction was carried out with 0.05% 3’3’-diaminobenzidine in 0.1 M Tris-HCl buffer and 0.01% hydrogen peroxide for 10 minutes. The immunostained sections were counterstained with hematoxylin for 1 minute. For negative control staining, the primary mAb was omitted from the incubation step. The isotype mouse IgGs matched for the primary mAbs for Kim-1, RPA-1, and RPA-2 are not available from the manufacturers. Immunoperoxidase stains for iNOS (1:100 dilution; BD Biosciences, San Diego, CA) and nitrotyrosine (1:100 dilution; Cell Sciences, Norwood, MA) were performed on 5-µm sections of formalin-fixed, paraffin-embedded tissues utilizing the avidinbiotin complex immunoperoxidase technique (Vectastain Elite kit, Vector Laboratories, Burlingame, CA) with antigen retrieval by microwave for 30 minutes in a 10 mM Citra solution. For negative controls, the primary antibodies recognizing iNOS and nitrotyrosine were omitted or replaced by the isotype-matched mouse IgG2a (BD Biosciences) for iNOS and mouse IgG2b (Cell Sciences) for nitrotyrosine, respectively (Zhang et al., 2006).
Statistics
Histopathology In Gen-, Hg-, or Cr-treated rats (study 1, time response study), renal lesion scores were greater at 72 hours after the last dose (scores of 3.3, 3.8, 4.8, for Gen, Hg, and Cr, respectively) than at 24 hours (scores of 1.5, 3.0, 2.8, for Gen, Hg, and Cr, respectively) (Table 2). In the dose-response Gen study (study 2), renal lesion scores at 24 hours after the last dose increased with dose (scores of 1.2, 1.5, 2.3, 3.5, and 4.8 at doses of 50, 100, 150, 200, and 300 mg/kg, respectively) (Table 3).
In studies 1 and 2, the patterns of tubular injury were similar. Epithelial cell necrosis was more prominent in the S1/S2 segments compared to the S3 segments in Gen- or Cr-treated rats. No significant changes were seen in any segments of LH and CD in the outer and inner medulla. Epithelial cell necrosis was usually accompanied with other less severe morphological alterations: cytoplasmic vacuolization, regeneration, and hyperplasia. Vacuolization of tubular epithelial cells of the S3 segments was prevalent in Hg-treated rats, whereas epithelial regeneration and hyperplasia of the S1/S2 and S3 segments were more evident in Gen- or Cr-treated rats.
Immunolocalization of Kim-1
In the dose-response study, 24 hours after the last administration of Gen injected sc for 3 days, Kim-1 immunoreactivity increased with the dose. At 24 hours after Gen 50 or 100 mg/kg, sc for 3 days, Kim-1 immunoreactivity was localized to individual S1/S2 segments. At doses of 150 and 200 mg/kg Gen, Kim-1 immunoreactivity extended to clusters of the S1/S2 segments. At the highest dose of 300 mg/kg of Gen, Kim-1 expression was localized in most of the S1/S2 segments and in a few S3 segments in the medullary rays (Figure 1D). A lower magnification photomicrograph of a Kim-1-stained kidney section clearly showed the topographic distribution of Kim-1 expression; immunoreactivity was higher in the S1/S2 segments of the cortex but lower in the S3 segments of the outer medulla and medullary rays 72 hours posttreatment in rats injected with Gen 100 mg/kg, sc (Figure 2). A summary of time- and dose-dependent Kim-1 expression is presented in Tables 2 and 3, respectively.
Immunolocalization of RPA-1 Control rats exhibited positive immunostaining for RPA-1, which was mainly concentrated in the CD epithelial cells in the outer and inner medulla and papilla (Figure 3A) and expressed in the cytoplasm of CD cells (cover illustration). RPA-1 immunoreactivity was also diffusely localized in the cytoplasm of the cortical CD epithelial cells (Figure 3B) in control rats.
The immunostaining pattern and intensity of RPA-1 in the cortical, medullary, and papillary CD were similar between control (Figure 3A) and Gen-treated rats (Figures 3C, 3E). However, additional RPA-1 expression was noted in necrotic and apoptotic epithelial cells of the S1/S2 segments in rats 24 hours after the final of 3 daily injections of 50 mg Gen/kg (Figure 3D). In rats treated with 300 mg Gen/kg for 3 days, RPA-1 expression in the S1/S2 segments became intense (Figure 3F). A lower magnification photomicrograph showed that constitutive, basal RPA-1 expression in the cortical CD cells coexisted with nascent RPA-1 in the S1/S2 segments of the cortex and in the S3 segments of the outer medulla in rats 72 hours after the final of 3 daily injections of 100 mg Gen/kg, sc (Figure 2). In Hg-treated rats, RPA-1 expression was observed in the S3 segments 24 hours posttreatment (Figure 3G). In contrast, in Cr-treated rats, RPA-1 immunoreactivity was expressed in the S1/S2 segments 24 hours posttreatment (Figure 3H).
Immunolocalization of RPA-2
In Hg-treated rats, RPA-2 expression was not increased above basal levels in the cortical LH epithelial cells (Figure 4G) and no RPA-2 was detected in the S1/S2 segments. In Cr-treated rats, basal RPA-2 expression was localized to the cortical LH epithelial cells; however, in contrast to Hg treatment, RPA-2 expression was also observed in the S1/S2 segments (Figure 4H).
Immunolocalization of Apoptosis, iNOS, and Nitrotyrosine
The present study has provided some new and interesting information regarding the immunolocalization of Kim-1, RPA-1, and RPA-2 in response to nephrotoxicants. The data will provide a critical basis to generate hypotheses for future studies.
Increased Immunoreactivity of Kim-1, RPA-1, and RPA-2 in Necrotic and Apoptotic Proximal Tubular Cells Interestingly, RPA-1 and RPA-2 immunoreactivity above constitutive levels was also detected in Gen-, Hg-, and Cr-treated rats. Differences in RPA-1 and RPA-2 immunolocalization were also observed between rats treated with Gen or Cr (the S1/S2 segments, or the S3 segments) and rats treated with Hg (the S3 segments). An explanation for why Gen, Hg, and Cr induced different immunolocalization of Kim-1, RPA-1, and RPA-2 is unknown.
Immunoreactivity of RPA-1 and RPA-2 in CD and LH
Relation of the Site Predilection of Kim-1, RPA-1, and RPA-2 to Renal Distribution of iNOS and Nitrotyrosine
Up-Regulation of Peroxynitrite as a Potential Mechanism of Renal Injury In this context, the present study is consistent with the reported cytotoxic effects of NO generated from iNOS on acute tubular necrosis and apoptosis in Gen-, Hg-, and Cr-induced nephrotoxicity (Kim et al., 1997; Yanagisawa et al., 1998; Baliga et al., 1999; Bagchi et al., 2001; Basnakian et al., 2002; Maldonado et al., 2003; Pedraza-Chaverri et al., 2005; Parlakpinar et al., 2005). Furthermore, it was reported that NO results in oxidative damage and contributes to the "point of no return" of host cell injury, necrosis, and apoptosis (Thuraisingham et al., 2000; Goligorsky et al., 2002; Yokozawa et al., 2002; Forbes et al., 2002; Nakajima et al., 2006; Pacher et al., 2007). A recent review suggests that NO does not have as many potential toxic effects as previously reported. Most of the cytotoxicity attributed to NO is rather due to the peroxynitrite and peroxynitrite anion, which is more reactive and toxic than NO (Pacher et al., 2007). Peroxynitrite is capable of causing protein tyrosine nitration (Radi, 2004) and is also capable of mediating damage in renal mitochondria and apoptosis (Yokozawa et al., 2002). Radi (2004) suggested that peroxynitrite can cause protein tyrosine nitration in vitro and in vivo. NO does not directly produce nitrotyrosine, but it reacts rapidly with superoxide anion and forms peroxynitrite, a potent nitrating and oxidizing agent (Kim et al., 1997). Peroxynitrite can induce oxidative damage to proteins, DNA, and lipids (Bian et al., 1999; Schnellmann, 2001). Nitrotyrosine can be detected immunohistochemically using an antibody against nitrotyrosine (Bosse and Bachmann, 1997). Immunohistochemical localization of nitrotyrosine in the proximal tubular epithelial cells was detected in Gen-treated rats (Maldonado et al., 2003). Enhanced expression of nitrotyrosine correlated with necrotic tubular cells in Cr-treated rats (Pedraza-Chaverri et al., 2005). Recent reports suggest that nitrotyrosine represents the nitration of protein-bound tyrosine residues by peroxynitrite (Forbes et al., 2002) and that nitrotyrosine can be used as a marker for endogenous production of peroxynitrite (Maldonado et al., 2003).
Kim-1: A Possible Link to the Reaction of Peroxynitrite with Cysteine
Spatial Relationship between the Apical Location of Kim-1 and the Subapical Location of Nitrotyrosine
Kim-1, RPA-1, and RPA-2: Potential Tissue Markers for Tubular Cell Injury Control experiments with isotype-matched control antibodies on a serial section are important (Gillett et al., 2002). At present, these immunoglobulins are not commercially available. To compensate for the lack of these sera, immunostaining for Kim-1, RPA-1, and RPA-2 has been performed in a study using a non-nephrotoxic agent. SD rats (10-, 25-, 40-, 80-day-old) treated with valproic acid (a hepatotoxic agent) were used as animal experimental controls and compared with Gen-treated rats. No tubular epithelial injury of the kidney was found, nor was any positive reaction of Kim-1, RPA-1, and RPA-2 in renal tissues obtained from valproic acid–treated rats, compared to the positive immunostaining for these markers detected in the kidney of Gen-treated rats (manuscript, in preparation). In the present study, omission of primary antibodies of Kim-1, RPA-1, and RPA-2 resulted in a negative reaction in renal tissue sections obtained from Gen-, Hg-, and Cr-treated rats. Furthermore, no immunostaining for Kim-1, RPA-1, and RPA-2 was found in any of the proximal epithelial cells and glomerular cells in the kidney from vehicle-treated rats (Figures 1A, 3B, 4C).
The present study demonstrated that Kim-1, RPA-1, and RPA-2 are induced in the kidney, but with different immunolocalization, in Gen-, Cr-, and Hg-treated rats. The spatial relationship between expression of Kim-1, RPA-1, RPA-2, and expression of iNOS and nitrotyrosine suggests that peroxynitrite-mediated oxidative pathways may be involved in the renal injury induced by these nephrotoxicants.
The authors thank Ms. Jacintha Tolson for assistance with animal injections and necropsies. This project was supported with funds provided by the U.S. Food and Drug Administration; an appointment to the Research Fellowship Program administered by the Oak Ridge Associated Universities through a contract with the U.S. Food and Drug Administration (YZ); by NIH Grants DK-039773, DK-072831, and DK-074099 (JVB); and a Scientist Development Grant 0535492T from the American Heart Association (VSV).
This article was written in a personal capacity and does not represent the opinion of the Food and Drug Administration.
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1, 2008 Toxicologic Pathology, Vol. 36, No. 3,
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Abstract
Introduction
75% of the tubules showing tubular epithelial cell necrosis and apoptosis accompanied with other concomitant alterations, respectively. 
