Increased bone remodelling around titanium implants coated with chondroitin sulfate in ovariectomized rats

Coating titanium implants with artificial extracellular matrices based on collagen and chondroitin sulfate (CS) has been shown to enhance bone remodelling and de novo bone formation in vivo. The aim of this study was to evaluate the effect of estrogen deficiency and hormone replacement therapy (HRT) on the osseointegration of CS-modified Ti implants. 30 adult female, ovariectomized Wistar rats were fed either with an ethinyl-estradiol-rich diet (E) to simulate a clinical relevant HRT or with a genistein-rich diet (G) to test an alternative therapy based on nutritionally relevant phytoestrogens. Controls (C) received an estrogen-free diet. Uncoated titanium pins (Ti) or pins coated with type-I collagen and CS (Ti/CS) were inserted 8 weeks after ovarectomy into the tibia. Specimens were retrieved 28 days after implantation. Both the amount of newly formed bone and the affinity index (P < 0.05) were moderately higher around Ti/CS implants as compared to uncoated Ti. The highest values were measured in the G-Ti/CS and E-Ti/CS groups, the lowest values for the E-Ti and G-Ti controls. Quantitative synchrotron radiation micro-computed tomography (SRμCT) revealed the highest increase in total bone formation around G-Ti/CS as compared to C-Ti (P < 0.01). The effects with respect to direct bone apposition were less pronounced with SRμCT. Using scanning nanoindentation, both the indentation modulus and the hardness of the newly formed bone were highest in the E-Ti/CS, G-Ti/CS and G-Ti groups as compared to C-Ti (P < 0.05). Coatings with collagen and CS appear to improve both the quantity and quality of bone formed around Ti implants in ovarectomized rats. A simultaneous ethinyl estradiol- and genistein-rich diet seems to enhance these effects.     

Effect of chondroitin sulphate on material properties and bone remodelling around hydroxyapatite/collagen composites

Chondroitin sulphate (CS) has an anti-inflammatory effect and increases the regeneration ability of injured bone. The goal of this study was to characterize the material properties and osteoconductive potency of calcium phosphate bone cements modified with CS. The early interface reaction of cancellous bone to a nanokristalline hydroxyapatite cement containing type I collagen (HA/Coll) without and with CS (HA/Coll/CS) in a rat tibia model was evaluated. Cylindrical implants were inserted press-fit into defect of the tibial head. Six specimens per group were analyzed at 2, 4, 7, 14, and 28 days. HA/Coll/CS composite cylinders showed a 15% increase in compressive strength and by investigations with powder X-ray diffraction more nontransformed cement precursor was found. The microstructures of both types of implants were similar. A significantly higher average number of TRAP positive osteoclasts and ED1 positive mononuclear cells were observed in the interface around HA/Coll/CS implants on day 4 and 7 (p < 0.05). At 28 days the direct bone contact and the percentage of newly formed bone were significantly higher around HA/Coll/CS implants (p < 0.05). The addition of CS appears to enhance bone remodelling and new bone formation around HA/Coll composites in the early stages of bone healing. Possible mechanisms are discussed.     

Osseous tissue reaction around hydroxyapatite block implanted into proximal metaphysis of tibia of rat with collagen-induced arthritis

This study was conducted to investigate the influence of osteoporosis on new bone formation around a hydroxyapatite (HA) block implanted into the proximal metaphysis of the tibia of rats with collagen-induced arthritis (CIA). Ten rats were immunized with an emulsion of bovine type II collagen and Freund's complete adjuvant (arthritis group). Another 10 rats, which were not immunized were used as the control group. Seventeen days after immunization, HA block was implanted into the proximal metaphysis of the tibia. Four weeks after implantation, all rats were killed. The serum level of tetrate-resistant acid phosphatase (TRAP), bone mineral density (BMD) in the proximal metaphysis of the tibia and the affinity index in the arthritis group were 28.0+/-3.5 IU/ml, 130.3+/-28.7 mg/cm2 and 77.6+/-10.8%, respectively, and those in the control group were 24.6+/-5.5 IU/ml, 175.9+/-30.5 mg/cm2 and 56.3+/-14.8%. The serum level of TRAP was higher (P < 0.05) and BMD was lower (P < 0.005) in the arthritis group. The amount of new bone formation around the HA block was larger (affinity index, P < 0.05) in the arthritis group than in the control group. These findings suggest that bone formation around HA block might be enhanced even in conditions associated with highly activated bone resorption and bone formation, such as arthritis.     

Quantitative bone remodelling resulting from the use of porous dental implants

Histomorphometric analyses were used to quantitatively determine the patterns of bony ingrowth which resulted from the placement of porous-surfaced dental implants into the mandibles of Rhesus monkeys for up to 74 months utilizing a two-stage approach. Quantitative histopathologic evaluations were made using ground section microscopy. Implant stability resulting from bone remodelling and ingrowth occurred to varying degrees with all implants. Bone ingrowth occurred from medullary trabeculae and contact with the adjacent cortical plates. Quantitative histomorphometric analyses revealed that in only one case was the bone ingrowth into the available internal pores less than 45%. Minimal fibrous connective tissue ingrowth was observed in the implant crypts and was not thought to be due to micro-motion. The observed bone remodelling indicated a favorable prognosis for long-term implant performance.     

Intracortical remodelling increases in highly loaded bone after exercise cessation

Resorption within cortices of long bones removes excess mass and damaged tissue and increases during periods of reduced mechanical loading. Returning to high-intensity exercise may place bones at risk of failure due to increased porosity caused by bone resorption. We used point-projection X-ray microscopy images of bone slices from highly loaded (metacarpal, tibia) and minimally loaded (rib) bones from 12 racehorses, 6 that died during a period of high-intensity exercise and 6 that had a period of intense exercise followed by at least 35 days of rest prior to death, and measured intracortical canal cross-sectional area (Ca.Ar) and number (N.Ca) to infer remodelling activity across sites and exercise groups. Large canals that are the consequence of bone resorption (Ca.Ar >0.04 mm²) were 1.4× to 18.7× greater in number and area in the third metacarpal bone from rested than exercised animals (p = 0.005–0.008), but were similar in number and area in ribs from rested and exercised animals (p = 0.575–0.688). An intermediate relationship was present in the tibia, and when large canals and smaller canals that result from partial bony infilling (Ca.Ar >0.002 mm²) were considered together. The mechanostat may override targeted remodelling during periods of high mechanical load by enhancing bone formation, reducing resorption and suppressing turnover. Both systems may work synergistically in rest periods to remove excess and damaged tissue.     

Uptake and biodistribution of technetium methylene-[P]diphosphonate during endosteal healing around titanium, stainless steel and hydroxyapatite implants in rat tibial bone

Early evaluation of intraosseous implant success and failure is critical, but, until now, there have been no reliable systems of measurement. The present study assessed whether the use of ^99mtechnetium methylene-[³²P]diphosphonate (^99mTcMD³²P), a marker for both bone formation and mineralization, can indicate if an implant is bone-bonding or non-bonding. Moreover, this study examined how bone-bonding (titanium and hydroxyapatite) and non-bonding (stainless steel) implants affected the normal healing of bone after marrow ablation, as measured by uptake of ^99mTc and ³²P. Titanium, hydroxyapatite and stainless steel implants were placed in the right tibiae of Sabra strain rats following ablation of the marrow, and ^99mTcMD³²P was injected 18h before harvest. At 3, 6, 14, 21 and 42 d (and in some experiments, on days 28 and 35) post-injury, the treated and contralateral tibiae were removed and cleaned of soft tissue. The uptake of ^99mTc and ³²P was measured in the whole bone, as well as in its organic and inorganic phases. Effects of the implants were assessed by comparing the treated to the untreated tibia in each rat. The distribution of ^99mTc and ³²P varied with each implant. After the insertion of titanium, increased ^99mTc uptake was seen in whole bone and in the inorganic and organic phases at days 6–14. ³²P uptake in whole bone and in the inorganic phase increased only at day 6, and ³²P uptake was decreased in the organic phase at that time. In tibiae implanted with hydroxyapatite, ^99mTc and ³²P uptake was seen in the whole bone at days 6 and 14. While ^99mTc uptake was increased in both the organic and inorganic phases, ³²P uptake into the organic phase was decreased at both day 6 and day 14. In tibiae implanted with stainless steel, effects were observed only on day 6. The increased ^99mTc uptake in whole bone reflected increases in both the organic and mineral phases. Increased ³²P uptake was observed in whole bone as well, due to an increase in the ³²P uptake in the mineral phase only; incorporation of ³²P in the organic phase was comparable to that found in the contralateral limb. The results of this study indicate that implants alter bone healing, as indicated by the uptake of ^99mTc and ³²P in the different bone compartments. Moreover, decreased ³²P uptake by the organic phase in the presence of bone-bonding implants suggests that cleavage of ^99mTcMD³²P into its technetium and methylene diphosphonate moieties was inhibited, perhaps as a function of the onset of calcification in the newly synthesized osteoid. The effect of the implants on bone healing was observed on days 6–14, when active bone formation and mineralization were occurring, supporting the hypothesis that these materials modulate events associated with initial calcification. Uptake of ^99mTc varies as a function of time, and uptake of ³²P varies with time and distribution in the mineral or organic phase of bone, suggesting that these parameters may be useful as indicators of bone-bonding.     

种植早期大鼠种植体周围骨组织CXCR4蛋白的表达及意义

背景：CXCR4与SDF-1构成SDF-1/CXCR4轴,在组织损伤及骨损伤修复过程中发挥重要作用。 目的：观察分析种植早期大鼠种植体周围骨组织CXCR4蛋白表达及其意义。 方法：Wistar大鼠20只,随机分为4组。将阳极氧化种植体植入除空白对照组外所有大鼠左侧胫骨。种植体植入6,12,24 h组分别于对应时间点处死大鼠,旋出种植体,截取种植体周围直径约2 cm骨组织,空白对照组截取胫骨近骺端直径约2 cm骨组织,制备蛋白样品。 结果与结论：从大鼠体内取出的各组阳极氧化种植体表面均可见大量的纤维成分附着。种植体植入6,12,24 h组CXCR4/β-actin灰度比值均明显高于空白对照组(P < 0.01)。种植体植24 h内种植体周围骨组织CXCR4表达量明显上调,提示CXCR4阳性细胞参与种植早期骨组织的修复。     

Interface between bone tissue and implants of solid hydroxyapatite or hydroxyapatite-coated titanium implants

Loaded prestressed implants of dense hydroxyapatite and non-loaded hydroxyapatite-coated titanium implants were placed in edentulous regions of the lower jaw of dogs. After 6 month the jaw specimens were fixed and embedded in methyl-methacrylate. Thin non-decalcified ground sections were made for histology. Although the hydroxyapatite showed histological differences between the coated implants and the prestressed solid ones, both had an extensive apposition of normal lamellar bone on the whole surface of the bone-buried part of the implant. The bone contact was very intimate and without any visible intermediate tissue layer. The tissue response observed forms a good biological base for the clinical application of hydroxyapatite-coated titanium implants.     

Osteocalcin enhances bone remodeling around hydroxyapatite/collagen composites

The effect of osteocalcin (OC), an extracellular bone matrix protein, on bone healing around hydroxyapatite/collagen composites was investigated. Cylindrical nanocrystalline hydroxyapatite implants of 2.5-mm diameter containing 2.5% biomimetically mineralized collagen type I were inserted press-fit into the tibial head of adult Wistar rats. To one implant group, 10 mug/g OC was added. Six specimens per group were analyzed at 2, 7, 14, 28, and 56 days. After 14 days, newly formed woven bone had reached the implant surface of the OC implants whereas a broad fibrous interface could still be observed around controls. Woven bone was formed directly around both implant groups after 28 days and had been replaced partially by lamellar bone around the OC implants only. No significant differences in total bone contact were seen between both groups after 56 days. The higher number of phagocytosing cells and osteoclasts characterized immunohistochemically with ED1, cathepsin D, and tartate-resistant alkaline phosphatase around the OC implants at the early stages of bone healing suggests an earlier onset of bone remodeling. The earlier and increased expression of bone-specific matrix proteins and multifunctional adhesion proteins (osteopontin, bone sialoprotein, CD44) at the interface around the OC implants indicates that OC may accelerate bone formation and regeneration. This study supports the observations from in vitro studies that OC activates both osteoclasts and osteoblasts during early bone formation.     

Mechanical basis for bone retention around dental implants

This study, analytically, through finite element analysis, predicts the minimization of crestal bone stress resulting from implant collar surface treatment. A tapered dental implant design with (LL) and without (control, C) laser microgrooving surface treatment are evaluated. The LL implant has the same tapered body design and thread surface treatment as the C implant, but has a 2-mm wide collar that has been laser micromachined with 8 and 12 microm grooves in the lower 1.5 mm to enhance tissue attachment. In vivo animal and human studies previously demonstrated decreased crestal bone loss with the LL implant. Axial and side loading with two different collar/bone interfaces (nonbonded and bonded, to simulate the C and LL surfaces, respectively) are considered. For 80 N side load, the maximum crestal bone distortional stress around C is 91.9 MPa, while the maximum crestal bone stress around LL, 22.6 MPa, is significantly lower. Finite element analysis suggests that stress overload may be responsible for the loss of crestal bone. Attaching bone to the collar with LL is predicted to diminish this effect, benefiting crestal bone retention.     

Conversion of bulk seashells to biocompatible hydroxyapatite for bone implants

Strombus gigas (conch) shells and Tridacna gigas (Giant clam) shells have dense, tailored structures that impart excellent mechanical properties to these shells. In this investigation, conch and clam seashells were converted to hydroxyapatite (HAP) by a hydrothermal method at different temperatures and for different conversion durations. Dense HAP structures were created from these shells throughout the majority of the samples at the relative low temperature of 200 °C. The average fracture stress was found to be 137–218 MPa for partially converted conch shell samples and 70–150 MPa for original and converted clamshell samples, which is close to the mechanical strength of compact human bone. This indicates that the converted shell samples can be used as implants in load-bearing cases. In vivo tests of converted shell samples were performed in rat femoral defects for 6 weeks. The microtomography images at 6 weeks show that the implants did not move, and untreated control defects remain empty with no evidence of a spontaneous fusion. Histological study reveals that there is newly formed bone growing up to and around the implants. There is no evidence of a fibrosis tissue ring around the implants, also indicating that there is no loosening of the implants. In contrast, the untreated controls remain empty with some evidence of a fibrosis ring around the defect hole. These results indicate good biocompatibility and bioactivity of the converted shell implants.     

Comparison of metal concentrations in rat tibia tissues with various metallic implants

To compare metal concentrations in tibia tissues with various metallic implants, SUS316L stainless steel, Co-Cr-Mo casting alloy, and Ti-6Al-4V and V-free Ti-15Zr-4Nb-4Ta alloys were implanted into the rat tibia for up to 48 weeks. After the implant was removed from the tibia by decalcification, the tibia tissues near the implant were lyophilized. Then the concentrations of metals in the tibia tissues by microwave acid digestion were determined by inductively coupled plasma-mass spectrometry. Fe concentrations were determined by graphite-furnace atomic absorption spectrometry. The Fe concentration in the tibia tissues with the SUS316L implant was relatively high, and it rapidly increased up to 12 weeks and then decreased thereafter. On the other hand, the Co concentration in the tibia tissues with the Co-Cr-Mo implant was lower, and it increased up to 24 weeks and slightly decreased at 48 weeks. The Ni concentration in the tibia tissues with the SUS316L implant increased up to 6 weeks and then gradually decreased thereafter. The Cr concentration tended to be higher than the Co concentration. This Cr concentration linearly increased up to 12 weeks and then decreased toward 48 weeks in the tibia tissues with the SUS316L or Co-Cr-Mo implant. Minute quantities of Ti, Al and V in the tibia tissues with the Ti-6Al-4V implant were found. The Ti concentration in the tibia tissues with the Ti-15Zr-4Nb-4Ta implant was lower than that in the tibia tissues with the Ti-6Al-4V implant. The Zr, Nb and Ta concentrations were also very low. The Ti-15Zr-4Nb-4Ta alloy with its low metal release in vivo is considered advantageous for long-term implants.     

The structure of the bond between bone and porous silicon-substituted hydroxyapatite bioceramic implants

The significance of micrometer-sized strut porosity in promoting bone ingrowth into porous hydroxyapatite (HA) scaffolds has only recently been noted. In this study, silicon-substituted HA (0.8 wt % Si-HA) with approximately 8.5% of the total porosity present as microporosity within the struts of the implant was prepared for high-resolution transmission electron microscopy (HR-TEM) via both ultramicrotomy and focused ion beam milling. Between the struts of the porous Si-HA, pores with varying shapes and sizes (1-10 microm in diameter) were characterized. Within the struts, the Si-HA contained features such as grain boundaries and triple-junction grain boundaries. Bone ingrowth and dissolution from a Si-HA implant were studied using HR-TEM after 6 weeks in vivo. Minor local dissolution occurred within several pores within the struts. Organized, mineralized collagen fibrils had grown into the strut porosity at the interface between the porous Si-HA implant and the surface of the surrounding bone. In comparison, deeper within the implant, disorganized and poorly mineralized fibers were observed within the strut porosity. These findings provide valuable insight into the development of bone around porous Si-HA implants.     

Long-term measurement of bone strain in vivo: the rat tibia

Despite the importance of strain in regulating bone metabolism, knowledge of strains induced in bone in vivo during normal activities is limited to short-term studies. Biodegeneration of the bond between gauge and bone is the principle cause of this limitation. To overcome the problem of bond degeneration, a unique calcium phosphate ceramic (CPC) coating has been developed that permits long-term attachment of microminiature strain gauges to bone. Using this technique, we report the first long-term measurements of bone strain in the rat tibia. Gauges, mounted on the tibia, achieved peak or near peak bonding at 7 weeks. Measurements were made between 7-10 weeks. Using ambulation on a treadmill, the pattern and magnitude of strain measured in the tibia remained relatively constant between 7-10 weeks post implantation. That strain levels were similar at 7 and 10 weeks suggests that gauge bonding is stable. These data demonstrate that CPC-coated strain gauges can be used to accurately measure bone strain for extended periods, and provide an in vivo assessment of tibial strain levels during normal ambulation in the rat.     

Novel in vivo method for evaluation of healing around implants in bone

A material implanted in bone is always inserted into coagulating blood. Protein and cell interactions during this initial implantation time will govern later healing. Many studies have focused on the tissue surrounding implants. We have developed a method for evaluation of healing around implants in bone by studying cells adhering to the implant surface. Hydrophilic titanium discs were inserted into rat tibiae. Samples were retrieved after 1, 2, 4, and 8 days of implantation and were analyzed by fluorescence microscopy techniques and scanning electron microscopy. Both proliferating and apoptotic cells were found on the surface. Generally, cells closest to the implant surface were nonviable whereas cells in the fibrin network a distance from the surface were viable. Bone morphogenetic protein-2 (BMP-2) is an osteogenic substance. An increase in BMP-2-positive cells was seen during the implantation period, and a population of large BMP-2-positive cells appeared on the surface after 4 days of implantation. The method developed here is a suitable tool for rapid evaluation of the initial healing around implant material.     

Saline irrigation does not affect bone formation or fixation strength of hydroxyapatite/tricalcium phosphate-coated implants in a rat model

Intramembranous bone regeneration is critical to implant fixation. In cementless joint replacement (as opposed to cemented joint replacement), saline irrigation is not typically performed during surgery so that the osteogenic stimulus provided by the marrow is preserved. Several groups are now using the rat marrow ablation model to study intramembranous bone regeneration and implant fixation. In this model, the marrow contents are mechanically disrupted, and debris is often cleared by saline irrigation, a step that appears inconsistent with the clinical situation. Furthermore, in contrast to conventional wisdom, it has been reported that saline irrigation enhanced bone-implant contact and peri-implant bone formation in the rat model (Ishizaka et al. Bone 1996;19:589-594), although mechanical fixation of the implant was not investigated. Accordingly, the present study was performed to determine if saline irrigation leads to enhanced mechanical fixation of implants in the rat model. Forty-eight 400 to 450 g male rats were divided equally into two groups. The treatment group, in contrast to the control group, received saline irrigation in the ablated medullary canal prior to placement of hydroxyapatite/tricalcium phosphate-coated implants. Eight animals in each group were killed at 2, 4, or 8 weeks after implantation, at which time the specimens were analyzed by micro computed tomography to measure bone formation around the implant, followed by a mechanical pull-out test to measure the strength of fixation of the implant. As expected, there was increased fixation strength over time, but there were no significant differences in peri-implant bone volume, bone-implant contact, or implant fixation strength between the two groups. Thus, we found no effect of saline irrigation on bone formation or implant fixation strength in this study in which the implant had an osteoconductive coating.     

Healing of complement activating Ti implants compared with non-activating Ti in rat tibia

Recent studies have revealed that ozone ultraviolet (UVO) illumination of titanium (Ti) implants improves bone-implant anchorage by altering the physico-chemical and immune activating properties of the titanium dioxide (TiO(2)) layer. In the present rat tibia model, the authors compared the early events of inflammation and bone formation around UVO-treated Ti and complement activating immunoglobin g (IgG)-coated Ti. Machined Ti and machined Ti coated with a physical vapour-deposited Ti layer were used as references. Screw-shaped test and reference implants were implanted into rat tibia and harvested after 1, 7 and 28 days. Messenger RNA expression of implant adhered cells and peri-implant tissue ~250 μm from the surface were subsequently analysed with regard to IL-1β, TNF-α, osteocalcin, cathepsin K, BMP-2 and PDGF. Separate implants were retrieved after 7 and 28 days for removal torque measurements, and histological staining and histomorphometric analysis of bone area and bone-to-implant contact. While enhanced expression of inflammatory markers, TNF-α and IL-1β, was observed on IgG-coated surfaces throughout the observation time, UVO-treated surfaces indicated a significantly lower early inflammatory response. In the early phases (1 and 7 days), the UVO-treated surfaces displayed a significantly higher expression of osteoblast markers BMP-2 and osteocalcin. In summary, complement activating Ti implants elicited a stronger inflammatory response than UVO-treated Ti, with low complement activation during the first week of healing. In spite of this, the UVO-treated Ti induced only marginally more bone growth outside the implants.     

Sustained release of adiponectin improves osteogenesis around hydroxyapatite implants by suppressing osteoclast activity in ovariectomized rabbits

Lack of estrogen could lead to decreased bone mass and increased risk for osteoporosis, which has a negative influence on biomaterial implantation. Adiponectin (APN), an adipose-derived hormone, has been shown to increase bone density by inhibiting osteoclast formation and promoting the formation of osteoblasts. This study was designed to investigate the direct effects of APN released from the Matrigel controlled-release system on the activity of rabbit mature osteoclasts and osteoclast precursor RAW264.7 cells in vitro, and to determine its effects by improving osteogenesis around the hydroxyapatite (HA) implant in ovariectomized (OVX) rabbits. APN+Matrigel+HA, APN+HA, Matrigel+HA and HA were implanted into mandibular defects of OVX rabbits. At 4 weeks after implantation, the mandibles were examined by histology, microcomputed tomography and biomechanical testing. The results demonstrated that Matrigel extended the length of APN released to achieve long-term persistence. The sustained release of APN suppressed the osteoclastic activity both in vitro and in vivo, and improved the peri-implant osteogenesis in OVX rabbits, while the short-term APN treatment did not. Sustained release of APN may be an effective strategy to improve the restoration of bone defects by the use of HA materials under osteoporotic conditions in which osteoclasts are highly activated.     

Acute kidney injury in the rat causes cardiac remodelling and increases angiotensin-converting enzyme 2 expression

Patients with kidney failure are at high risk of a cardiac death and frequently develop left ventricular hypertrophy (LVH). The mechanisms involved in the cardiac structural changes that occur in kidney failure are yet to be fully delineated. Angiotensin-converting enzyme (ACE) 2 is a newly described enzyme that is expressed in the heart and plays an important role in cardiac function. This study assessed whether ACE2 plays a role in the cardiac remodelling that occurs in experimental acute kidney injury (AKI). Sprague-Dawley rats had sham (control) or subtotal nephrectomy surgery (STNx). Control rats received vehicle (n = 10), and STNx rats received the ACE inhibitor (ACEi) ramipril, 1 mg kg(-1) day(-1) (n = 15) or vehicle (n = 13) orally for 10 days after surgery. Rats with AKI had polyuria (P < 0.001), proteinuria (P < 0.001) and hypertension (P < 0.001). Cardiac structural changes were present and characterized by LVH (P < 0.001), fibrosis (P < 0.001) and increased cardiac brain natriuretic peptide (BNP) mRNA (P < 0.01). These changes occurred in association with a significant increase in cardiac ACE2 gene expression (P < 0.01) and ACE2 activity (P < 0.05). Ramipril decreased blood pressure (P < 0.001), LVH (P < 0.001), fibrosis (P < 0.01) and BNP mRNA (P < 0.01). These changes occurred in association with inhibition of cardiac ACE (P < 0.05) and a reduction in cardiac ACE2 activity (P < 0.01). These data suggest that AKI, even at 10 days, promotes cardiac injury that is characterized by hypertrophy, fibrosis and increased cardiac ACE2. Angiotensin-converting enzyme 2, by promoting the production of the antifibrotic peptide angiotensin(1-7), may have a cardioprotective role in AKI, particularly since amelioration of adverse cardiac effects with ACE inhibition was associated with normalization of cardiac ACE2 activity.