Compensatory renal hypertrophy after nephrectomy in newborn rats]

The process of the kidney compensatory hypertrophy in young rats has been studied after nephrectomy on the 2nd day of life. The intact kidney was investigated by morphometrical and electron microscopical methods from the 1st day till the 3rd month after operation. The kidney compensatory hypertrophy in the early postnatal ontogenesis is accompanied by the acceleration of growth and differentiation of renal structures. The hypertrophy involves three successive steps: (1) functional tension of ultrastructures; (2) expressed hyperplasia and hypertrophy of cells; (3) structural-functional specialization. Among the cellular factors of the kidney compensatory growth at this age, the main role is played by the process of cell hyperplasia.     

Sequential protooncogene expression in regenerating kidney following acute renal injury

Following loss of functional renal mass due to acute injury, there is significantly increased proliferation of tubular epithelium to replace injured and necrotic cells. In contrast, following uninephrectomy, the contralateral kidney increases in size primarily by hypertrophy, with little cellular proliferation. We and others have demonstrated only modest increases in renal protooncogene expression following uninephrectomy. In this study, we demonstrate markedly elevated expression of the protooncogenes c-fos, c-myc, c-Ki-ras, and c-Ha-ras following acute renal injury induced by a single large parenteral dose of folic acid. The expression of these genes occurs in a sequential pattern similar to that seen in proliferating cells in culture and in regenerating liver. In addition, we demonstrate elevated levels of histone H4 and beta-actin mRNAs consistent with increased cell proliferation. These data suggest that the molecular mechanisms regulating cell proliferation in the kidney are similar to those in regenerating liver and in cultured cells. In addition, it appears that these events are regulated normally after acute renal injury and following uninephrectomy, since in both instances the levels of protooncogene expression correlate with the degree of cell proliferation. This is in direct contrast to a pathologic renal condition, polycystic kidney disease, in which the level of protooncogene expression is out of proportion to the degree of cell proliferation. Further studies of the molecular correlates of acute renal injury may yield insight into the pathogenesis of this and other clinically important renal disorders.     

Immuno-proteasome subunit LMP7 is up-regulated in the ischemic kidney in an experimental model of renovascular hypertension

Immuno-proteasome is thought to be responsible for the processing of intracellular antigens and is induced when cells are treated with the inflammatory cytokines promoting cellular immunity. We tested the possibility that immuno-proteasome can be up-regulated in renal cells exposed to a long-lasting ischemia and inflammation in an experimental model of two-kidney, one-clip renovascular hypertension in the rat. Western blotting showed that immuno-proteasome subunit, LMP7, was up-regulated in the clipped ischemic kidney that was atrophic, but not in the contralateral unclipped kidney that underwent compensatory hypertrophy. Immunohistochemical analysis revealed that LMP7 was highly expressed in cortical epithelial and endothelial cells of the ischemic kidney. Surprisingly, the second immuno-subunit, LMP2, was almost undetectable, indicating that renal ischemia may induce exclusively the LMP7 subunit. We also found that renal ischemia neither reduced the SDS-stimulated proteasomal activity nor affected a high level of the PA28 activator. Thus, the results provide evidence that LMP7 immuno-subunit is induced in renal cells exposed to a long-lasting renal ischemia and inflammation, and that there is a direct link between LMP induction and renal atrophy. This opens an opportunity to study a role for LMP-containing proteasomes in the kidneys and other organs undergoing reduction in mass in diseases accompanied by a long-lasting ischemia and inflammatory responses.     

Structure of the wall of the renal artery during limitation of motor activity

The structure of the renal artery wall has been studied in histological preparations at various time of a restricted motor activity using some morphometric methods. The revealed morphological changes of wave-like character present a respond of certain compensatory processes in the vascular wall to changes of the blood stream in the kidney which is connected with the change of the organ's function.     

Nek8 mutation causes overexpression of galectin-1, sorcin, and vimentin and accumulation of the major urinary protein in renal cysts of jck mice

The jck murine model, which results from a double point mutation in the nek8 gene, has been used to study the mechanism of autosomal recessive polycystic kidney disease (ARPKD). The renal proteome of jck mice was characterized by two-dimensional gel electrophoresis combined with mass spectrometry (MALDI-TOF/TOF). Four newly identified proteins were found to accumulate in the kidneys of jck mice with polycystic kidney disease (PKD) compared with their wild-type littermates. The proteins galectin-1, sorcin, and vimentin were found to be induced 9-, 9-, and 25-fold, respectively, in the PKD proteome relative to the wild type. The identity of these proteins was established by peptide mass fingerprinting and de novo MS/MS sequencing of selected peptides. Up-regulation of these three proteins may be due to the nek8 mutation, and their function may be related to the signaling and structural processes in the primary cilium. Additionally a series of protein isoforms observed only in the ARPKD kidney was identified as the major urinary protein (MUP). Peptide sequencing demonstrated that the isoforms MUP1, MUP2, and MUP6 are contained in this series. The MUP series showed a number of male-specific isoforms and a phosphorylation of the entire series with an increasing degree of phosphorylation of the acidic isoforms. In addition, the MUP series was localized to the cyst fluid of PKD mice, and a cellular mislocalization of galectin-1, sorcin, and vimentin in PKD tubular epithelial cells was shown. The abnormal and extremely high accumulation of the MUPs in the ARPKD kidney may be linked to a defect in protein transport and secretion. The discovery of these proteins will provide new information on the molecular and cellular processes associated with the mechanism of ARPKD.     

Comparative characteristics of compensatory renal hypertrophy following unilateral nephrectomy in mature and old rats]

One of the kidneys was removed in rats from 35 to 900 g in weight; they were then sacrificed 2, 14, 30 and 60 days after the operation. The degree of compensatory hypertrophy of the remaining kidney varied greatly in rats of different age, without decreasing in old age, however. Sixty days after the operation the weight of the hypertrophic kidney in old rats was equal to 55--93% of the weight of both kidneys in control. Hypertrophy of the kidney at any age was accompanied by an increased proliferation of the tubular cells, particularly in their proximal portion. An increase in the size of renal bodies during kidney hypertrophy was characteristic of rats of any age. However, with the advance of age this process developed more rapidly and was stronger. At any periods of investigation the hypertrophic kidney in rats of any age contained a greater number (1 1/2--2 times more) of "open" renal bodies in comparison with the kidney of intact rats.     

Cytologic and ultrastructural organization of the kidney tubules of certain amphibia

As the investigation performed demonstrated, there is no principle differences in cytological organization in kidneys of five species of Amphibia whose mode of life to a certain extent is connected with water environment. Nevertheless, in different species epithelium of proximal parts of nephrons demonstrates various intensity of apocrinic secretion. Granules situating in the supranuclear zone of the epithelial cells of these parts are, in fact, autophagic lysosomes, their function is evidently connected with both lysis of the absorbed proteins and with autolysis of the apical cellular part in the process of secretion. The epithelial cytoplasm in the distal part of the nephron is characterized by a high succinate dehydrogenase activity; it is connected with its main function--osmoregulation. There are dark and light cells, resembling those in higher vertebrates, in the connecting part and in the collecting tubes. Ultrastructural organization of the brown frog nephron cells has much in common with that of epithelium of the secondary kidney urinary canaliculi.     

Inhibition of compensatory renal growth by indomethacin

Renal prostaglandins may be important in the modulation of compensatory renal growth. Reductions in renal mass are associated with increased synthesis of these substances by the remaining kidney, and inhibition of prostaglandin synthesis diminishes renal function in partially nephrectomized animals and in patients with reduced functioning renal mass. We examined the effects of uninephrectomy and treatment with indomethacin on renal prostaglandin E2 and 6-keto prostaglandin F1 alpha concentrations in adult male Sprague Dawley rats. The renal content of these prostaglandins was significantly increased in the remaining kidney two days following uninephrectomy (p less than 0.01). Treatment with 5 mg/kg/day of indomethacin over this period abolished the compensatory increase in renal prostaglandin synthesis and significantly attenuated compensatory increases in renal mass, protein and RNA concentrations (p less than 0.05). No alterations in kidney weight, protein or RNA concentrations were found in intact animals treated with the same dose of indomethacin. These findings suggest renal prostaglandins may participate in the biological events leading to compensatory renal growth.     

Endothelial dysfunction promotes the transition from compensatory renal hypertrophy to kidney injury after unilateral nephrectomy in mice

Loss of functional nephrons associated with chronic kidney disease induces glomerular hyperfiltration and compensatory renal hypertrophy. We hypothesized that the endothelial nitric oxide synthase (eNOS) [soluble guanylate cyclase (sGC)] protein kinase G (PKG) pathway plays an important role in compensatory renal hypertrophy after unilateral nephrectomy. Analysis of mice subjected to unilateral nephrectomy showed increases in kidney weight-to-body weight and total protein-to-DNA ratios in wild-type but not eNOS knockout (eNOSKO) mice. Serum creatinine and blood urea nitrogen increased after nephrectomy in eNOSKO but not in wild-type mice. Furthermore, Bay 41-2272, an sGC stimulator, induced compensatory renal hypertrophy in eNOSKO mice and rescued renal function. The NO donor S-nitrosoglutathione (GSNO) and Bay 41-2272 stimulated PKG activity and induced phosphorylation of Akt protein in human proximal tubular cells. GSNO also induced phosphorylation of eukaryotic initiation factor 4E-binding protein and ribosomal protein S6. Our results highlight the importance of the eNOS-NO-PKG pathway in compensatory renal hypertrophy and suggest that reduced eNOS-NO bioavailability due to endothelial dysfunction is the underlying mechanism of failure of compensatory hypertrophy and acceleration of progressive renal dysfunction.     

Serum renotropic factor stimulates prostaglandin synthesis in primary cultures of rabbit kidney cells

Compensatory growth of the kidney occurs in response to a partial reduction in renal mass. This compensatory renal growth may be regulated by a circulating renotropic factor. Prostaglandin synthesis has been shown to be increased in kidneys undergoing compensatory renal growth in vivo. In the present study we observed that the addition of rabbit sera obtained after uninephrectomy enhanced DNA synthesis in primary cultures of rabbit kidney cells compared to sera obtained prenephrectomy. The stimulated kidney cells produced more prostaglandin E2 than control cells. Furthermore, the addition of prostaglandin E2 to rabbit kidney cells in the presence of control sera also stimulated DNA synthesis. These results provide further evidence that prostaglandins may participate in the biological events which regulate renal growth in response to a circulating renotropic factor.     

Inhibition of compensatory renal growth by indomethacin

Renal prostaglandins may be important in the modulation of compensatory renal growth. Reductions in renal mass are associated with increased synthesis of these substances by the remaining kidney, and inhibition of prostaglandin synthesis diminishes renal function in partially nephrectomized animals and in patients with reduced functioning renal mass. We examined the effects of uninephrectomy and treatment with indomethacin on renal prostaglandin E₂ and 6-keto prostaglandin F_1α concentrations in adult male Sprague Dawley rats. The renal content of these prostaglandins was significantly increased in the remaining kidney two days following uninephrectomy (p<0.01). Treatment with 5 mg/kg/day of indomethacin over this period abolished the compensatory increase in renal prostaglandin synthesis and significantly attenuated compensatory increases in renal mass, protein and RNA concentration (p<0.05). No alterations in kidney weight, protein or RNA concentrations were found in intact animals treated with the same dose of indomethacin. These findings suggest renal prostaglandins may participate in the biological events leading to compensatory renal growth.     

Renal glutathione homeostasis in compensatory renal growth

Glutathione homeostasis was investigated in unilaterally nephrectomized and sham-operated rats. Following twelve days of compensatory renal growth, it was found that the concentrations of glutathione and glutathione disulfide in representative samples of the entire remnant right kidney from the nephrectomized rats were similar to those found in corresponding samples of the right kidneys from the sham-operated rats. However, since the mass of the remnant right kidneys in the nephrectomized rats was greater than that of the right kidneys from the sham-operated rats, the absolute content of glutathione and glutathione disulfide was greater in the remnant right kidneys of the nephrectomized rats than in the right kidneys of the sham-operated rats. In general, the findings from the present study indicate that the absolute content of glutathione and glutathione disulfide in renal epithelial cells increases in proportion to the increase in mass that results from compensatory renal cellular hypertrophy.     

Early renal hemodynamic modifications following the ablation of the controlateral kidney]

Instantaneous measurements of renal blood flow (RBF) and glomerular filtration rate (GFR) have been performed in anesthetized dogs to determine if removal of one kidney induces early functional adaptation in the remaining kidney. Increases in RBF (10%) and GFR (20%) were observed within the first minutes after exclusion of controlateral kidney; these are the earliest events described until now. These observations favour the concept that a functional adjustement may contribute to development of compensatory renal hypertrophy.     

Aldosterone Binding by Compensatory Hypertrophied Kidney with Disturbed Neurotrophic Supply in Rats

We studied certain aspects of interaction between (³H)aldosterone and the cytoplasmic as well as nuclear receptors of renal cells in the rats during compensatory renal hypertrophy at the background of reflex renal dystrophy. The dystrophy developing in the kidney after cutting the sciatic nerve blocks the compensatory increase in specific accumulation of (³H)aldosterone in the cytoplasm of the renal tubular cells. (³H)Aldosterone transport from the cytoplasmic receptors to the nuclear receptors during rat reflex dystrophy of compensatory hypertrophied kidney is lower as compared to the control. The reflex dystrophy induced by a sciatic nerve injury proved to have no effect on the degree of hypertrophy of the only kidney.     

Bone marrow derived cells and reactive oxygen species in hypertrophy of contralateral kidney of transient unilateral renal ischemia-induced mouse

Renal mass reduction, such as unilateral nephrectomy induces a compensatory hypertrophy of remaining renal mass in response to overload induced by reduction of functional renal parenchyma. In our recent study, we observed that the recovery of ischemic injured kidney following transient unilateral renal ischemia took longer time than that following transient bilateral renal ischemia, indicating that non-damaged kidney may affect the damaged kidney and vice versa. Here, we investigated whether transient and partial renal parenchymal injury by transient unilateral renal ischemia (UI) results in the hypertrophy of its contralateral kidney (CLK) and reactive oxygen species is associated with the hypertrophy. Thirty minutes of UI resulted in gradual increase in CLK weight over time. UI increased superoxide formation, but not lipid peroxidation in the CLK. After UI, a significant increase in the number of NADPH oxidase 2 (Nox2)-expressing cells and the level of Nox2 expression in the CLK was observed. In parallel with the increases in Nox2-expressing cells in CLKs, infiltration of bone marrow-derived cells (BMDC) increased in CLK. Treatments with Mn(III) Tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP, a superoxide dismutase (SOD) mimetic) and apocynin (a putative NADPH oxidase inhibitor) inhibited UI-induced hypertrophy of CLK along with reduction in Nox2-positive cell, BMDC, amount of Nox2 expression and superoxide formation. In conclusion, transient and partial renal mass reduction by UI resulted in the hypertrophy of CLK through increased ROS formation by infiltrated cells into the interstitium of CLK.     

Bone marrow derived cells and reactive oxygen species in hypertrophy of contralateral kidney of transient unilateral renal ischemia-induced mouse

Abstract

Renal mass reduction, such as unilateral nephrectomy induces a compensatory hypertrophy of remaining renal mass in response to overload induced by reduction of functional renal parenchyma. In our recent study, we observed that the recovery of ischemic injured kidney following transient unilateral renal ischemia took longer time than that following transient bilateral renal ischemia, indicating that non-damaged kidney may affect the damaged kidney and vice versa. Here, we investigated whether transient and partial renal parenchymal injury by transient unilateral renal ischemia (UI) results in the hypertrophy of its contralateral kidney (CLK) and reactive oxygen species is associated with the hypertrophy. Thirty minutes of UI resulted in gradual increase in CLK weight over time. UI increased superoxide formation, but not lipid peroxidation in the CLK. After UI, a significant increase in the number of NADPH oxidase 2 (Nox2)-expressing cells and the level of Nox2 expression in the CLK was observed. In parallel with the increases in Nox2-expressing cells in CLKs, infiltration of bone marrow-derived cells (BMDC) increased in CLK. Treatments with Mn(III) Tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP, a superoxide dismutase (SOD) mimetic) and apocynin (a putative NADPH oxidase inhibitor) inhibited UI-induced hypertrophy of CLK along with reduction in Nox2-positive cell, BMDC, amount of Nox2 expression and superoxide formation. In conclusion, transient and partial renal mass reduction by UI resulted in the hypertrophy of CLK through increased ROS formation by infiltrated cells into the interstitium of CLK.     

Long-Term Responses to Loss of Renal Mass: Control Mechanisms: The Role of Renal “Work” in Compensatory Kidney Growth

In a series of studies designed to test the role of renal “work” in compensatory kidney growth we examined the relationship between absolute sodium reabsorption—which constitutes the bulk of renal energy expenditure, and growth of the remaining kidney at various intervals after contralateral nephrectomy.The increase in weight of the remaining kidney preceded the rise in sodium reabsorption and these two processes took place at different rates between 24 hours and 21 days after uninephrectomy.Absolute sodium reabsorption did not change during the first hours after contralateral nephrectomy, at a time when biochemical alterations are known to occur.The rate of [¹⁴C] choline incorporation into renal phospholipid, an early biochemical indicator of compensatory kidney growth, increased significantly one hour after contralateral nephrectomy but remained unchanged after sham-nephrectomy, regardless of the magnitude or direction of the concomitant change in absolute sodium reabsorption (“kidney work”).These results indicate that renal work expended in the reabsorption of glomerular filtrate is neither the initiating, nor the primary controlling factor, of the compensatory kidney growth that follows unilateral nephrectomy.     

Age-related ultrastructural characteristics of various cells in acute hypoxia

Ultrastructural peculiarities, concerning reaction of cells in various populations brain-sensorimotor cortex, mammillary nuclei, vascular plexus; myocardium; liver; jejunum) in mature (6-8 months) and old (24-30 months) male white Wistar rats have been studied at an experimental acute hypobaric hypoxic hypoxia. Both general changes, that are manifested in various degree in different cell groups and organo-specific ones are noted. The manifestation degree of the reactive changes is evidently connected with certain metabolic and functional peculiarities, as well as with the character of cell restoration. In the old animals hypoxic hypoxia produces more profound destructive processes in all cell populations studied. This is accompanied with a restriction in ability to adaptation.