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Biomedical subjects

M R Hammerman

Publications and source records attributed to M R Hammerman.

At least 37 records · Page 2Linked to original sources
PubMed1998

Growth factors and apoptosis in acute renal injury.

The precisely orchestrated pattern of growth factor expression within the kidney following acute renal injury indicates that growth factors regulate the process of repair. The use of growth factors as therapeutic agents to accelerate renal regeneration in this setting stems from this observation. In animal models of acute renal injury, administration of epidermal growth factor (EGF), insulin-like growth factor I (IGF-I) or hepatocyte growth factor (HGF) accelerates restoration of kidney function and normalization of histology post-acute renal injury and reduces mortality. IGF-I has been safely administered to humans and protects against post-surgical renal dysfunction. Renal cellular apoptosis occurs in a predictable pattern during recovery from acute ischemic injury. Renal apoptosis is regulated by agents both intrinsic and extrinsic to the kidney cell. The protooncogene, B-cell lymphoma/leukemia gene product-2 (bcl-2), is an important intrinsic factor. The growth factor, EGF, is an important extrinsic regulator. A thorough understanding of the control of renal apoptosis during recovery from ischemic injury coupled with an increased understanding of the roles that growth factors play in this process, is likely to result in the development of new therapies to enhance kidney regeneration.

Acute Kidney Injury↗
PubMed1998

The human plasminogen activator inhibitor type I gene promoter targets to kidney.

The plasminogen activator inhibitor type 1 (PAI-1) gene encodes the physiological inhibitor of tissue-type and urokinase-type plasminogen activators and is induced by cytokines such as transforming growth factor-beta (TGF-beta). Studies have identified DNA sequence elements within the first 1.3 kb of the 5'-upstream DNA that mediate cytokine responsiveness in transfected cells in vitro. However, the DNA sequences that mediate PAI-1 expression in vivo have not yet been delineated. To define these regulatory sequences, we generated transgenic mice that expressed a hybrid gene comprising sequences between -1,272 and +75 of the human PAI-1 gene ligated to a LacZ reporter gene. Transgene expression detected in two independent lines was observed only in kidney from embryonic day 13 to adult and was seen primarily in proximal tubule cells of the outer medulla. Transgene expression and activity were unchanged in response to TGF-beta and remained restricted to kidney. Thus we have identified a promoter region within the PAI-1 gene that targets transgene expression to kidney but, unlike the native promoter, is unresponsive to TGF-beta in the experimental protocol used.

Animals↗
PubMed1998

Extracellular matrix-related genes in kidney after ischemic injury: potential role for TGF-beta in repair.

The renal expression of transforming growth factor-beta1 (TGF-beta1) is enhanced following induction of ischemic injury in rat. In cultured renal cells, TGF-beta stimulates the synthesis of extracellular matrix. To link TGF-beta1 expression with the regulation of extracellular matrix postischemia, we characterized the expression of several genes known to regulate extracellular matrix synthesis at various times during recovery from acute ischemic renal injury in rat. Levels of mRNA for plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloprotease-1 (TIMP-1), alpha1(IV) collagen, and fibronectin-EIIIA (FN-EIIIA) mRNAs were significantly enhanced in kidneys within 12 h to 3 days after injury and remained elevated at 7-28 days postischemia relative to levels in kidneys of sham-operated controls. PAI-1 mRNA and peptide were localized in regenerating proximal tubules at 3 and 7 days postischemic injury. alpha1(IV) Collagen and FN-EIIIA mRNAs were expressed primarily in regenerating proximal tubule cells. Immunoreactivity for FN-EIIIA was enhanced in the tubular basement membrane (TBM) of regenerating proximal tubules, and alpha1(IV) collagen immunoreactivity was detected in thickened tubulointerstitial spaces. In contrast, TIMP-1 immunoreactivity was enhanced in distal nephron structures postischemia. Immunoneutralization of TGF-beta in vivo attenuated the increases in FN-EIIIA, alpha1(IV) collagen, PAI-1, and TIMP-1 mRNAs by 52%, 73%, 43%, and 27%, respectively. These data are consistent with TGF-beta expression postischemic injury participating in renal regeneration of extracellular matrix homeostasis in the proximal TBM.

Animals↗
PubMed1998

TGF-beta in renal development and renal growth.

Organogenesis of the metanephric kidney is regulated by a number of polypeptide growth factors. Members of the TGF-beta family of growth factors have been shown to be produced in kidney during its development. Available evidence suggests that some of these members play key roles in metanephrogenesis by regulating the process of ureteric bud arborization. The regeneration of the S3 segment of the proximal tubule that occurs following ischemic injury recapitulates in many ways the renal developmental paradigm. The expression of TGF-beta in regenerating kidney is tightly regulated postischemia. We suggest that TGF-beta plays a key role in the repair process following injury and mediates some of the cellular events common to both regeneration and nephrogenesis.

Animals↗
PubMed1998

Potential role of growth factors in the prophylaxis and treatment of acute renal failure.

Strategies for the treatment of acute renal failure in humans are directed toward supportive care to permit regeneration of damaged tissue to occur. There exists a need for new therapeutic approaches that can speed recovery and reduce mortality. Induction of acute renal injury in rats results in changes in expression of a panoply of growth factor genes. The administration of several of these growth factors to animals with ischemic or toxic acute renal failure accelerates recovery of renal function and normal histology. One of these agents, IGF-I, has been used to treat humans at risk to develop acute renal failure. A greater understanding of the patterns of gene expression post-injury will lead to the generation of more effective therapeutic strategies for acute renal failure.

Acute Kidney Injury↗
PubMed1997

Effects of growth hormone and insulin-like growth factor I on renal growth and function.

Polypeptide growth factors regulate kidney development, growth, and function and participate in the repair processes after renal injury. The use of one or more growth factors as therapeutic agents in the settings of acute and chronic renal failure has been proposed. Insulin-like growth factor I (IGF-I) accelerates the restoration of kidney function and the normalization of structure and reduces mortality rates in animal models of acute renal injury. The mechanisms by which IGF-I acts in acute renal failure include stimulation of anabolism, maintenance of glomerular filtration, acceleration of tubular regeneration, and increased expression of ischemia-induced renal genes. It has been safely used in persons at risk of having acute renal failure and in patients with end-stage chronic renal failure, in whom it increases the glomerular filtration rate. Further studies to determine the role of IGF-I as a therapeutic agent for acute renal failure and its utility as a medical therapy for chronic renal insufficiency are required.

Acute Kidney Injury↗
PubMed1997

Acute renal failure in the 21st century: recommendations for management and outcomes assessment.

Acute renal failure (ARF) remains a common and potentially devastating disorder affecting as many of 5% of all hospitalized patients, with a higher prevalence in patients in critical care units. ARF is more frequently observed in the setting of multiorgan dysfunction syndrome (MODS) and in elderly patients with complex disease, where mortality is high. Numerous technical advances have not yet impacted favorably on this high mortality rate. This report summarizes recommendations from participants at the National Institutes of Health Conference: "Acute Renal Failure in the 21st Century," May 6 to 8, 1996, in Bethesda, MD. The focus is on categorizing recent clinically relevant developments in the field and on identification of new research initiatives to transfer a new body of knowledge derived from fundamental studies and laboratory investigation to the management of ARF in the new millennium. The development of a multicenter database through cooperative multicenter studies is advocated. Future studies should define the appropriate outcome measures to assess and emphasize the impact of hemodynamic monitoring, adjunctive agents, and adequacy and modality of renal replacement therapy on outcomes in ARF.

Acute Kidney Injury↗
PubMed1997

Ischemia-induced receptor for activated C kinase (RACK1) expression in rat kidneys.

Differential display-polymerase chain reaction (DD-PCR) was used to identify genes that are expressed in kidney following induction of acute ischemic renal injury. The receptor for activated C kinase (RACK1) mRNA expression in kidneys obtained from rats 12 h following ischemia is enhanced twofold compared with sham-operated rats. The maximal enhancement of expression (3.3-fold) is at 7 days following reperfusion. Expression remains elevated at 14 days. RACK1 transcripts and protein are localized to the damaged and regenerating segments of proximal tubules. At 1 day following injury, RACK1 protein is present in the epithelial cells of the damaged S3 segment and in cells sloughed into the tubular lumen. By 5 days following injury, RACK1 protein expression is enhanced in the regenerating cells relining the injured tubules of the S3 segment and in papillary proliferations within regenerating tubules. Increased expression of RACK1 could enhance the activity of PKC and, in so doing, regulate the process of regeneration of the proximal tubule following ischemic renal injury.

Animals↗
PubMed1997

Insulin-like growth factor I preserves renal function postoperatively.

Deterioration of renal function, which can lead to postoperative renal failure, is a complication of surgery involving the suprarenal aorta and surgery involving the renal arteries. Fifty-four patients who were at risk for developing this complication were enrolled in a double-blind, randomized, placebo-controlled trial of insulin-like growth factor (IGF-I) as a therapeutic agent to prevent the decline in renal function. The primary end point was the incidence of renal dysfunction, defined as a reduction of the glomerular filtration rate (creatinine clearance) at each of three measurements over 72 h. IGF-I (100 microg/kg subcutaneously every 12 h for 6 doses) or placebo was administered on admission to the intensive care unit immediately postoperatively. IGF-I- and placebo-treated groups were well matched for sex, age, type of surgery, renal ischemic time during surgery (ischemic index), baseline creatinine clearance, and baseline serum creatinine. No patient in the study developed acute renal failure postoperatively. IGF-I was well tolerated. A smaller proportion of patients in the IGF-I group had a postoperative decline in renal function (22%) than in the placebo-treated group (33%). There were no significant differences in levels of serum creatinine at time of discharge, length of hospital stay, length of intensive care unit stay, length of intubation, or incidence of dialysis or death. Our findings establish the feasibility and potential utility for the use of IGF-I to reduce the incidence of postoperative renal dysfunction in high-risk patients.

Aged↗
PubMed1997

Metanephric osteopontin regulates nephrogenesis in vitro.

Renal expression of osteopontin is enhanced in the setting of acute ischemic injury. Because of the parallels that exist between recovery from renal ischemia and renal development, we characterized the role that osteopontin plays during metanephrogenesis in the rat. Osteopontin mRNA is present in kidneys obtained from rat embryos as early as embryonic day 13 (E13). Immunohistochemical staining of metanephroi obtained from E16 rat embryos and metanephroi obtained from E13 embryos and cultured for 3 days in vitro demonstrated that osteopontin is expressed both in the developing nephron and in the ureteric bud. Addition of anti-osteopontin antibodies to metanephric organ cultures results in failure of the metanephric blastema to undergo normal tubulogenesis. Addition of the arginine-glycine-aspartic acid-containing peptide, cyclo-RGDfV, or the anti-alpha(v)beta3-integrin antibody, LM609, to cultures has a similar effect. These findings establish that osteopontin is produced within the rat metanephros during development in vivo and suggest that the binding of osteopontin to the alpha(v)beta3-integrin is required for tubulogenesis to occur in vitro. Blastemal cells within metanephroi cultured in the presence of OP199 manifest increased apoptosis compared with controls. It is possible that osteopontin plays an important anti-apoptotic role during the process of metanephric blastema condensation that is a prerequisite for the formation of nephrons in vivo.

Animals↗
PubMed1997

Expression of bcl-2 and bax in regenerating rat renal tubules following ischemic injury.

To define potential roles for bcl-2 and bax in adult kidney as regulators of regeneration, their expressions were characterized postischemic injury. A 2.1-fold increase in levels of renal bcl-2 mRNA occurred within 24 h of injury relative to levels in kidney of sham-operated control rats. The levels of bcl-2 mRNA remained elevated for 3 days but returned to baseline by day 5 postischemia. In situ hybridization of kidneys from sham-operated rats demonstrated faint expression of bcl-2 mRNA localized diffusely throughout the nephron. After renal injury, the expression of bcl-2 mRNA was markedly enhanced in regenerating proximal tubule cells relining the basement membrane. Immunohistochemistry showed a similar localization for bcl-2 protein. Levels of bax mRNA in kidney were elevated beginning at 24 h postischemia and remained elevated for 7 days postinjury. Bax mRNA and bax protein were colocalized to regenerating proximal tubules postischemia and were prominently expressed in papillary proliferations. We conclude that the expressions of bcl-2 and bax in kidney are enhanced in a predictable pattern following acute ischemic injury. Our findings suggest that these regulators of apoptosis play key roles in the process of repair of the damaged proximal tubule postischemia.

Animals↗
PubMed1997

Induction of calcyclin after ischemic injury to rat kidney.

Genes differentially expressed after acute renal ischemic injury were identified using differential display-polymerase chain reaction (DD-PCR). Messenger RNA for calcyclin, a member of the S100 family of calcium-binding proteins, is increased in kidneys by 6 h following ischemic injury to rats compared with sham surgery. The level of calcyclin mRNA is increased 10-fold by 1 day postinjury and declines thereafter. In situ hybridization demonstrates little calcyclin mRNA in kidneys of sham-operated rats. However, calcyclin protein is present in glomeruli and distal tubules (DT). Compared with kidneys from sham-operated controls, both calcyclin mRNA and protein expression are increased at 1-3 days following ischemic injury in the thick ascending limb of Henle, the DT, and in damaged regenerating segments of proximal tubules. By 7 days postischemia there is a reduction in mRNA and protein expression. Calcyclin could play a role in the regulation of renal cell proliferation and regeneration in the recovery process after acute ischemic injury.

Animals↗
PubMed1996

Altered EGF expression and thyroxine metabolism in kidneys following acute ischemic injury in rat.

To define the relationship between renal epidermal growth factor (EGF) expression and thyroid hormones in acute renal failure, we performed an analysis of the renal thyroid hormone-EGF axis following acute ischemic renal injury in rats. Levels of mature EGF extractable from kidney were elevated 24 h postinjury, and levels of membrane-associated EGF precursor were reduced. Administration of triodothyronine (T3) to rats, either prior to or immediately following the induction of injury, did not further increase levels of extractable EGF. Levels of EGF mRNA in kidneys were reduced 24 h following acute ischemic damage and not affected by administration of T3. Enhanced production of mature EGF from EGF precursor occurred in membranes isolated from kidneys of rats 24 h postinjury compared with production in membranes from kidneys of normal rats. In addition, levels of thyroxine 5'-deiodinase activity in renal membranes were increased 24 h following injury. Levels of circulating total thyroxine (T4), free T4, and free T3 were reduced postischemic injury. Total T3 was unchanged. The administration of T3 to normal rats increased renal 5'-deiodinase activity and EGF precursor cleavage. Administration of propylthiouracil to rats inhibited renal 5'-deiodinase activity and prevented the increase in extractable EGF postischemic injury. We conclude that the increase in levels of mature EGF extractable from kidneys of rats postischemic injury results from enhanced activity of the serine protease that cleaves the EGF precursor. This activity may be stimulated by T3 produced in kidney. These alterations in renal T4 metabolism and EGF expression could serve to facilitate recovery of renal function following ischemia.

Acute Disease↗
PubMed1996

Increased transforming growth factor-beta 1 expression in regenerating rat renal tubules following ischemic injury.

To gain insight into the role that transforming growth factor-beta 1 (TGF-beta 1) plays in the regeneration of kidneys following acute renal failure, we characterized the expression of TGF-beta 1 mRNA and the expression of active and latent TGF-beta peptide at various times during recovery from acute ischemic injury in rat. Levels of whole kidney TGF-beta 1 mRNA were elevated significantly at 12 h postinjury (1.5-fold vs. sham-operated controls), and by 24 h postinjury were elevated by 3.6-fold. Levels remained elevated for 14 days following ischemia, but were no longer elevated at 28 days postinjury. In situ hybridization demonstrated that the elevated expression of TGF-beta 1 was localized predominantly to cells in the regenerating tubules in the outer medulla. When examined at 14 days postischemia, levels of TGF-beta 1 mRNA were elevated in the outer medulla only in tubules that appeared incompletely regenerated. Immunohistochemical staining localized active TGF-beta to the lumen of proximal tubules in control animals and in desquamated and regenerating tubular epithelial cells following ischemia. TGF-beta 1 latency-associated peptide was present intracellularly in proximal tubules of sham-operated rats and reduced following ischemia. We hypothesize that endogenous renal TGF-beta serves to promote tissue regeneration following acute injury via an autocrine or paracrine mechanism.

Animals↗
PubMed1996

Abnormal postpartum renal development and cystogenesis in the bcl-2 (-/-) mouse.

Mice deficient for B cell leukemia/lymphoma gene 2 [bcl-2(-/-) mice] manifest congenital renal hypoplasia and develop multicystic kidney disease and renal failure postnatally. To characterize postpartum renal development, to identify the cellular origin of the cysts, and to provide insight into the role that bcl-2 deficiency plays in the cystogenic process, we examined the morphology of kidneys from bcl-2 (-/-) mice and wild-type littermates [bcl-2 (+/+)] from birth (P0) to postpartum day 28 (P28), determined whether abnormalities of cellular proliferation and apoptosis accompany cyst development, and characterized expression of the bcl-2-related protein, bax. Between P0 and P7, kidneys from bcl-2 (-/-) and bcl-2 (+/+) mice undergo a comparable increase in weight and have similar histological appearances. However, during the next 2 wk of life, weight gain in kidneys from bcl-2 (-/-) mice is reduced compared with that in kidneys from bcl-2 (+/+) animals, and cysts develop in tubules with staining characteristics of proximal tubule, distal tubule/medullary thick ascending limb of Henle's loop, and collecting duct. Unaffected glomeruli and proximal tubules in kidneys of bcl-2 (-/-) mice undergo compensatory growth. Cystogenesis is accompanied by enhanced incorporation of 5-bromo-2'-deoxyuridine in cells within cortex and medulla and apoptosis of cells within cysts and in the renal interstitium. Bax protein is expressed in the distal tubule in kidneys of bcl-2 (+/+) and bcl-2 (-/-) mice and in some, but not all cysts. We conclude that abnormal regulation of DNA synthesis and apoptosis accompany cystogenesis in bcl-2 (-/-) mice during postpartum kidney development. Continued expression of bax could enhance apoptotic cell death.

Animals↗
PubMed1996

Abnormal renal development in the Os/+ mouse is intrinsic to the kidney.

The oligosyndactylism (Os/+) mouse, is a genetic model for oligomeganephronic congenital renal hypoplasia. To define the abnormality in renal development and to determine whether the abnormality is kidney autonomous, we examined kidneys from newborn and 21- and 63-day-old Os/+ and wild-type (+/+) mice, obtained metanephric kidneys from embryonic day 12 (E12) Os/+ and +/+ embryos, and compared growth and development of the metanephroi in vitro. Kidneys from newborn Os/+ mice were smaller than those from newborn +/+ mice and contained fewer glomeruli per midsagittal section. Following birth, kidneys from Os/+ mice manifest compensatory growth of glomeruli and proximal tubules. Metanephroi from E12 Os/+ and +/+ embryos were comparable in size. However, during 4 days in culture, growth and development of metanephroi from Os/+ embryos were visibly reduced compared with metanephroi from +/+ embryos. Expression of B cell leukemia/lymphoma gene 2 (bcl-2), the absence of which is known to result in congenital renal hypoplasia, was detected in the Os/+ mouse kidneys. We conclude that the renal abnormality in Os/+ mice is intrinsic to the kidney and does not result from the absence of bcl-2 expression.

Animals↗
PubMed1996

Insulin-like growth factor I-enhanced renal expression of osteopontin after acute ischemic injury in rats.

Pretreatment of rats with insulin-like growth factor I (IGF-I) ameliorates the course of acute ischemic renal injury. Differential display PCR was used to identify genes that are expressed in kidney after induction of acute ischemic renal injury in rats pretreated with vehicle or IGF-I. One amplification product that showed enhanced expression in kidneys of rats rendered ischemic compared to kidneys of sham-operated rats was identified as osteopontin. Sequence analysis of full-length complementary DNAs revealed a single species. Renal tissue was obtained for study 12 h and 1, 2, 3, 5, 7, 14, and 28 days postinjury. Levels of whole kidney osteopontin messenger RNA (mRNA) in rats rendered ischemic 1 day previously were elevated approximately 18-fold compared to levels measured in sham-operated controls, as determined by Northern analysis. No differences were noted 12 h postinjury. Levels of osteopontin mRNA remained elevated for 14 days after ischemia, but were no longer elevated at 28 days. IGF-I pretreatment resulted in enhanced levels of osteopontin mRNA 12 h, 1 day, and 5 days postinjury. In situ hybridization demonstrated that the elevated expression of osteopontin 1 day postinjury was localized predominantly to cells in the distal tubule and medullary thick ascending limb of Henle's loop. Immunostaining showed an identical localization for elevated protein expression. Five days postinjury, osteopontin peptide and mRNA were clearly detected in regenerating proximal tubules in addition to distal tubule and medullary thick ascending limb. We propose that endogenous osteopontin serves to promote tissue regeneration and tissue remodeling within 1 day after acute ischemic injury of kidney. IGF-I enhanced expression of osteopontin at an earlier time postischemia may ameliorate the course of injury.

Animals↗