Compensatory Renal Hypertrophy Research Articles

Functional and metabolomic analysis of urinary extracellular vesicles from juvenile mice with renal compensatory hypertrophy

Unilateral nephrectomy, a procedure reducing kidney mass, triggers a compensatory response in the remaining kidney, increasing its size and function to maintain a normal glomerular filtration rate (GFR). Recent research has highlighted the role of extracellular vesicles (EVs) in renal physiology and disease, although their involvement in unilateral nephrectomy has been underexplored. In this study, unilateral nephrectomy was performed on young mice, and urinary extracellular vesicles (uEVs) characterization and cargo were analyzed. Kidney volume increased significantly post-nephrectomy, demonstrating compensatory hypertrophy. Serum creatinine, cystatin C, and urinary electrolytes concentrations were similar in both nephrectomized and control groups. Western blot analysis revealed upregulation of sodium-glucose cotransporter 2 (SGLT2) and sodium chloride cotransporter (NCC), and downregulation of sodium‑potassium-chloride co-transporter (NKCC2) and epithelial sodium channel (ENaC) in the nephrectomized group. Metabolomic analysis of uEVs showed an enrichment of certain metabolites, including citrate and stachydrine. Interestingly, uEVs from the nephrectomized group demonstrated a protective effect, downregulating signal transducer and activator of transcription 3 (STAT3) and reducing reactive oxygen species (ROS) in renal proximal cells, compared to uEVs from the control group. This study suggests that uEVs contain bioactive components capable of inducing protective, anti-inflammatory, anti-fibrinolytic, and antioxidative effects in renal cells. These findings contribute to our understanding of uEVs' role in renal compensatory mechanisms after unilateral nephrectomy and may hold promise for future therapeutic interventions in renal diseases.

Renal transplants increase in size and function in keeping with compensatory renal hypertrophy

AbstractAimTo evaluate changes in allograft kidney length in renal transplant recipients and the relationship with estimated glomerular filtration rate (eGFR).MethodsThis single‐centre retrospective study of renal transplant recipients was conducted at Flinders Medical Centre (FMC) from January 2007 to June 2020. Donor and recipient details, renal allograft length from transplant ultrasounds at 0, 1, 3, 6 and 12 months were collected. The association between compensatory renal hypertrophy (CRH) and eGFR and its magnitude was analysed using multivariate multilevel mixed‐effects linear regression models.ResultsA total of 183 renal transplant recipients were studied. 100 of 175 recipients (62.9%) demonstrated an increase in renal length defined as any increase in maximal longitudinal diameter on serial ultrasounds. Twenty‐three recipients (13.1%) had no change in transplant length and 42 recipients (24%) had a decrease in length. The mean increase in kidney length over the first 12 months was 0.57 cm. Ninety of 156 (57.7%) recipients with a renal ultrasound within a month post‐transplant demonstrated a mean increase kidney length of 0.3 cm. Multivariate analysis demonstrated that eGFR increased by 2.5 mL/min/1.73 m2 (95% CI 0.72– 4.4; p = .006) with every 1 cm increase in kidney length. Absolute changes in kidney length did not demonstrate any statistically significant correlation with eGFR in both complete case and multiple imputation analysis.ConclusionAn increase in transplant kidney length is common in renal transplant recipients and is associated with enhanced eGFR. However, further studies need to be performed to study the association of absolute change in kidney length and eGFR.

Терапия ксеногенным протеомным комплексом из эмбриональных клеток головного мозга тормозит прогрессирование экспериментально вызванной хронической почечной недостаточности.

Introduction. In previously published experimental studies, we have shown that in rats with pre-modeled acute post-ischemic renal failure, therapy with a proteomic complex isolated from brain cells of pig embryos has a pronounced therapeutic effect, reducing the severity of functional and histological disorders and preventing the transition of the pathological process into chronic kidney insuffiency. The aim of this study is to evaluate the effectiveness of this therapy for the course of artificially induced chronic renal failure (CRF) in rats. Material and methods. Experiments were carried out on 45 white mongrel male rats weighing 200-240 g. CRF was modeled by unilateral nephrectomy and resection of both poles of the remaining kidney, which reduced the mass of the functioning parenchyma by 80%. In the 1-st series of experiments no therapy was performed. In the 2-nd - 4-th series the animals were intraperitoneally injected with a fractionated xenogenic proteomic complex (secretom) from pig brain stem and progenitor cells (SSPC) at a daily dose of 0.1 ml in different modes: two 10-days courses with a 10-days break between them (2nd series); prolongation of the 1st course up to 20 days and a repeated 10-days course after 10 days (3rd series); continuous SSPC therapy for 30 days (4-th series). 5th series – intact animals. The effectiveness of therapy was evaluated based on the severity of the development of compensatory renal hypertrophy, the dynamics of biochemical parameters of kidney function, the activity of enzymes (ALT, AST, LDH, alkaline phosphatase) in blood and urine and the level of uremic neurotoxins 3-indoxyl sulfate and ptolyl sulfate in the blood. Results. SSPC therapy in all variants contributed to a more pronounced compensatory hypertrophy of the remaining kidney, as well as a decrease in the severity of the main functional indicators after 30 and 60 days: the severity of polyuria decreased, the concentration of urea in the blood decreased to a greater extent, and the glomerular filtration rate and tubular reabsorption of sodium and calcium approached normal values, which was not observed in the control series. The severity of the therapeutic effect was more pronounced with continuous 30-day therapy. There was also a less pronounced increase in the activity of enzymes in the blood and their excretion in the urine, which indicated the cytoprotective effect of SSPC therapy. If in the control series of experiments, the deterioration of the studied indicators were noted with an increase in the observation period from 30 to 60 days, whereas in all experimental series they remained at a subnormal level. SSPC therapy also contributed to a lower accumulation of uremic toxins (3-indoxyl sulfate and p-tolyl sulfate) in the blood. Conclusion. Prolonged therapy of SSPC prevents the progression of CRF by stimulating compensatory hypertrophy of the kidney and cytoprotective effect and promotes more effective elimination of uremic toxins, preventing their accumulation in the blood.

Signaling mechanisms in renal compensatory hypertrophy revealed by multi-omics

Loss of a kidney results in compensatory growth of the remaining kidney, a phenomenon of considerable clinical importance. However, the mechanisms involved are largely unknown. Here, we use a multi-omic approach in a unilateral nephrectomy model in male mice to identify signaling processes associated with renal compensatory hypertrophy, demonstrating that the lipid-activated transcription factor peroxisome proliferator-activated receptor alpha (PPARα) is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.

#5799 COMPENSATORY HYPERTROPHY OF THE KIDNEY CONTRIBUTES TO LOSS OF KLOTHO KIDNEY THROUGH PAKT SIGNALING

Abstract Background and Aims Chronic kidney disease (CKD) represents a significant public health burden worldwide, mainly driven by the increase of the incidence of associated risk factors like diabetes. Decreased renal Klotho expression is an early feature of CKD, driving an increase on circulating FGF23 and phosphate. These alterations in mineral metabolism have a direct negative impact on the progression of renal dysfunction and can cause bone alterations, vascular calcification and heart failure. In parallel, during the early stages of CKD, kidneys activate molecular mechanisms of hypertrophy in an attempt to counteract the loss of renal function. The PI3K/Akt/mTOR pathway, activated by growing factors like insulin-like growing factor-1 (IGF-1) participates in compensatory renal growth. The aim of the present study is to investigate the possible role of PI3K/Akt activation on renal Klotho levels during renal compensatory hypertrophy. Method We generated a mice model of kidney compensatory hypertrophy (UNX mice) in which kidney klotho levels and circulating mineral metabolism parameters were analyzed. Furthermore, some of the mice were treated with inhibitors of the PI3K/Akt/mTOR pathway. In vitro, proximal tubular epithelial human cells (PTEC) were stimulated with IGF-1 in order to activate the PI3K/Akt pathway, and the effects on Klotho expression were determined. Results UNX mice present with an activation of the PI3K/Akt/mTOR pathway in kidney, which correlates with the loss on renal Klotho expression. Moreover, UNX mice showed an increase on both, plasma phosphate and FGF23, and a decrease in the fractional excretion of phosphate (% FEPi). Renal function, estimated by BUN plasma levels, was unaltered. Pharmacological inhibition of the pathway restored Klotho and decreased FGF23 levels, normalizing renal phosphate excretion and blood levels. In vitro, IGF-1 stimulated PI3K/Akt activation in PTEC and induced a decline on Klotho expression, which was restored with PI3K/AKT inhibitors. Conclusion The overactivation of PI3K/Akt/mTOR pathway in renal hypertrophy modulates Klotho expression and has direct effects on FGF23 and phosphate. Our findings constitute an important breakthrough in the research of new therapeutic targets in order to maintain renal Klotho levels, and it may be useful in the treatment of kidney disease patients.

Divergent roles of angiotensin II upon the immediate and sustained increases of renal blood flow following unilateral nephrectomy.

Although the molecular and functional responses related to renal compensatory hypertrophy after unilateral nephrectomy (UNX) has been well described, many aspects of these events remain unclear. One question is how the remaining kidney senses the absence of the contralateral organ, and another is what the role of the renin-angiotensin system is in these responses. Both acute anesthetized and chronic unanesthetized experiments were performed using the angiotensin II type 1 receptor blocker losartan and the renin inhibitor aliskiren to determine the contribution of the renin-angiotensin system to immediate changes and losartan for chronic changes of renal blood flow (RBF) and the associated hypertrophic events in male Sprague-Dawley rats. Chronic experiments used implanted RBF probes and arterial catheters for continuous data collection, and the glomerular filtration rate was determined by noninvasive transcutaneous FITC-sinistrin measurements. The results of the acute experiments found that RBF increased nearly 25% (4.6 ± 0.5 to 5.6 ± 0.6 mL/min/g kidney wt) during the first 15 min following UNX and that this response was abolished by losartan (6.7 ± 0.7 to 7.0 ± 0.7 mL/min/g kidney wt) or aliskiren (5.8 ± 0.4 to 6.0 ± 0.4 mL/min/g kidney wt) treatment. Thereafter, RBF increased progressively over 7 days, and kidney weight increased by 19% of pre-UNX values. When normalized to kidney weight determined at day 7 after UNX, RBF was not significantly different from pre-UNX levels. Semiquantification of CD31-positive capillaries revealed increases of the glomeruli and peritubular capillaries that paralleled the kidney hypertrophy. None of these chronic changes was inhibited by losartan treatment, indicating that neither the compensatory structural nor the RBF changes were angiotensin II type 1 receptor dependent.NEW & NOTEWORTHY This study found that the immediate increases of renal blood flow (RBF) following unilateral nephrectomy (UNX) are a consequence of reduced angiotensin II type 1 (AT1) receptor stimulation. The continuous monitoring of RBF and intermittent measurement of glomerular filtration rate (GFR) in conscious rats during the 1-wk period of rapid hypertrophy following UNX provided unique insights into the regulation of RBF and GFR when faced with increased metabolic loads. It was found that neither kidney hypertrophy nor the associated increase of capillaries was an AT1-dependent phenomenon.

ZO-2 favors Hippo signaling, and its re-expression in the steatotic liver by AMPK restores junctional sealing

ABSTRACT ZO-2 is a peripheral tight junction (TJ) protein whose silencing in renal epithelia induces cell hypertrophy. Here, we found that in ZO-2 KD MDCK cells, in compensatory renal hypertrophy triggered in rats by a unilateral nephrectomy and in liver steatosis of obese Zucker (OZ) rats, ZO-2 silencing is accompanied by the diminished activity of LATS, a kinase of the Hippo pathway, and the nuclear concentration of YAP, the final effector of this signaling route. ZO-2 appears to function as a scaffold for the Hippo pathway as it associates to LATS1. ZO-2 silencing in hypertrophic tissue is due to a diminished abundance of ZO-2 mRNA, and the Sp1 transcription factor is critical for ZO-2 transcription in renal cells. Treatment of OZ rats with metformin, an activator of AMPK that blocks JNK activity, augments ZO-2 and claudin-1 expression in the liver, reduces the paracellular permeability of hepatocytes, and serum bile acid content. Our results suggest that ZO-2 silencing is a common feature of hypertrophy, and that ZO-2 is a positive regulator of the Hippo pathway that regulates cell size. Moreover, our observations highlight the importance of AMPK, JNK, and ZO-2 as therapeutic targets for blood-bile barrier dysfunction.

Maintaining Normal Blood Pressure in a Renovascular Stenosis Model of Hypertension in Adult Lewis Rats: Putative Physiological Modulation of the Renin‐Angiotensin System

Prolonged unilateral renal artery stenosis using a Goldblatt Two-Kidney-One Clip (2K1C) technique is a validated scientific approach to inducing experimental hypertension in laboratory animals. This patho-physiological modulation is associated with the activation of the renin-angiotensin system with increased renin and angiotensin II release to initiate hypertension. This mode of experimental hypertension has been demonstrated for many rat strains including Sprague Dawley, Brown Norway and Wistar Kyoto but has not been fully characterized in syngeneic Lewis rats. The objective of this study was to develop and characterize a unilateral renal artery stenosis model of hypertension in adult male Lewis rats using a 2K1C method for hypertension studies in our laboratory. Thirty animals were randomly assigned to two groups to undergo sham or the 2K1C surgical procedure under isoflurane-induced anesthesia; approval was granted by our institutional animal ethics committee (A2404, n =15 per group). Hemodynamic parameters including heart rate; systolic and diastolic blood pressure were monitored weekly for 6 weeks, using a volume-pressure tail cuff and a CODA pressure computer. Plasma concentrations of critical biomarkers of the renin-angiotensin system were quantified using standard ELISA assays and renal histopathological changes were assessed microscopically. Unilateral renal arterial stenosis caused marked renal atrophy, glomerulosclerosis and interstitial fibrosis, but a compensatory renal hypertrophy was observed in contralateral kidneys. Interestingly, unilateral renal arterial stenosis failed to induce hypertension over the six week period. The resistance to develop hypertension in the 2K1C group was associated with a significant decrease in total plasma renin (P = 0.023), an increase in the ratio of plasma angiotensin (1-7) to total renin (P = 0.034) and a decrease in the ratio of angiotensin II to total renin (P = 0.013). There were no changes in plasma electrolytes, glucose, creatinine or urea. These data demonstrate that adult male Lewis rats may have physiologically modulated the activation of the renin-angiotensin system to maintain a homeostatic balance and resist hypertension following unilateral renal artery stenosis.

Pathology of severe urolithiasis in a flock of egg-laying hens

Fourteen, 31-week-old Lohmann white layers from a flock of 30,000 chickens had a history of apathy, and a drop in egg production. Clinical signs were observed in approximately 40% of the flock, and lasted for three months. Fourteen hens were euthanized for post-mortem examinations. Macroscopic findings included marked atrophy and loss of renal lobes along with compensatory renal hypertrophy of the contralateral lobe. Ureters were markedly dilated and filled with mucus and/or with molded white to yellow-grey uroliths that obliterated the lumen. At histopathology, the uroliths inside ureters and tubules were composed of concentrically arranged mineralized concretions, as well as urates associated with heterophilic infiltrations and epithelial hyperplasia. Renal parenchyma adjacent to obstructed ureters was compressed with tubules replaced by fibrous tissue. Multifocal interstitial lymphocytic nephritis, proteinuria and membranoproliferative glomerulonephritis were also found. Heterophilic and caseous ureteritis associated with numerous Gram-positive coccoid bacteria occurred in three chickens. Immunohistochemistry for avian coronavirus was negative. This negative result along with the case history indicated that water restriction was the most likely cause of mortality. This condition resulted in significant economic loss for this farmer.

Surgical procedures suppress autophagic flux in the kidney

Many surgical models are used to study kidney and other diseases in mice, yet the effects of the surgical procedure itself on the kidney and other tissues have not been elucidated. In the present study, we found that both sham surgery and unilateral nephrectomy (UNX), which is used as a model of renal compensatory hypertrophy, in mice resulted in increased mammalian target of rapamycin complex 1/2 (mTORC1/2) in the remaining kidney. mTORC1 is known to regulate lysosomal biogenesis and autophagy. Genes associated with lysosomal biogenesis and function were decreased in sham surgery and UNX kidneys. In both sham surgery and UNX, there was suppressed autophagic flux in the kidney as indicated by the lack of an increase in LC3-II or autophagosomes seen on immunoblot, IF and EM after bafilomycin A1 administration and a concomitant increase in p62, a marker of autophagic cargo. There was a massive increase in pro-inflammatory cytokines, which are known to activate ERK1/2, in the serum after sham surgery and UNX. There was a large increase in ERK1/2 in sham surgery and UNX kidneys, which was blocked by the MEK1/2 inhibitor, trametinib. Trametinib also resulted in a significant decrease in p62. In summary, there was an intense systemic inflammatory response, an ERK-mediated increase in p62 and suppressed autophagic flux in the kidney after sham surgery and UNX. It is important that researchers are aware that changes in systemic pro-inflammatory cytokines, ERK1/2 and autophagy can be caused by sham surgery as well as the kidney injury/disease itself.

Compensatory renal hypertrophy following nephrectomy: When and how?

Following surgical removal of one kidney, the other enlarges and increases its function. The mechanism for the sensing of this change and the growth is incompletely understood but begins within days and compensatory renal hypertrophy (CRH) is the dominant contributor to the growth. In many individuals undergoing nephrectomy for cancer or kidney donation this produces a substantial and helpful increase in renal function. Two main mechanisms have been proposed, one in which increased activity by the remaining kidney leads to hypertrophy, the second in which there is release of a kidney specific factor in response to a unilateral nephrectomy that initiates CRH. Whilst multiple growth factors and pathways such as the mTORC pathway have been implicated in experimental studies, their roles and the precise mechanism of CRH are not defined. Unrestrained hypoxia inducible factor activation in renal cancer promotes growth and may play an important role in driving CRH.

Cross-Sectional Investigations of Pre- and Post-Operative Renal Global Function and Renal Parenchymal Volumetry in Both Partial and Radical Nephrectomy Utilizing Film-Based Technology

Objectives: To investigate pre- and post-operative renal global function and renal parenchymal volume (RPV) in both partial nephrectomy (PN) and radical nephrectomy (RN) utilizing film-based technology. Patients and Methods: The patient cohort consisted of 81 and 82 cases with T1 tumors (≤ 7 cm) treated by PN and RN, respectively. Renal global function was assessed using the estimated glomerular filtration rate (eGFR), and RPV was measured using a Synapse Vincent volumetric analyzer which creates a reconstructed image from a computed tomography scan. Renal global function and RPV were evaluated pre-operatively and 6 months post-operatively. Results: The percent eGFR decline of PN cases was significantly reduced compared with RN cases (p < 0.0001). Post-operative RPV of the contralateral side was significantly increased compared with pre-operative RPV (p < 0.0001) in RN cases. The percent change of the contralat-eral side RPV was slightly increased in RN compared with PN cases (p = 0.1881). A strong positive correlation was noted between post-operative eGFR and post-operative total RPV (r = 0.69, p < 0.0001), and a strong negative correlation was noted between percent eGFR decline and post-operative total RPV (r = -0.63, p < 0.0001). Conclusions: Prominent compensatory renal hypertrophy occurred within 6 months after RN. Post-operative renal functional outcome was closely correlated with the post-operative total RPV. In addition to RPV, further studies to unravel post-operative renal function from multifactorial aspects including surgical factors and intrinsic medical disease should be performed in the future.

Comprehensive Analyses of Factors Associated with Postoperative Renal Global Function in Patients Treated by Partial Nephrectomy

<i>Study aim:</i> To characterize the associated factors of postoperative renal global functional deterioration after partial nephrectomy (PN), comprehensive analyses were performed using multiple factors categorized as data from pre, intra and postoperative periods. <i>Methods:</i> Ninety-three patients underwent PN. Estimated glomerular filtration rate (eGFR) and computed tomography (CT) scans were examined pre- and 6 months postoperatively. Renal global functional deterioration after PN was assessed by postoperative percent of eGFR decline. Pre- and postoperative renal parenchymal volume (RPV) was measured by the Synapse Vincent volumetric analyzer which creates a reconstructed image from a CT scan. Additional factors that were analyzed included patient demographics, comorbidities, surgical factors and tumor pathology. All factors demonstrating statistical tendencies (P < 0.1) in univariate analyses were subjected to multivariate logistic regression analysis. Two groups were categorized according to the degree of eGFR decline. Groups A and B were categorized as less than 15% and greater than 15% declines, respectively. <i>Results:</i> The case distributions of hypertension (HTN) and male gender were significantly shifted in group B. Significant compensatory renal hypertrophy of the contralateral side occurred postoperatively. The percent increment of RPV in the contralateral side in group B was significantly lower than that in group A. In multivariate analysis, HTN was the sole independent associated factor in group B. <i>Conclusions:</i> Host factors, rather than surgical factors, may be associated with postoperative renal global functional deterioration in PN. Surgeons should consider medical problems in addition to surgical skills especially in HTN patients.

MPS 01-08 CYCLIC GMP DEPENDENT PROTEIN KINASE-AKT PATHWAY IS ESSENTIAL FOR COMPENSATORY RENAL HYPERTROPHY AND MAINTENANCE RENAL FUNCTION AFTER UNILATERAL NEPHRECTOMY

Objective: Renal hypertrophy as an early compensatory mechanism to replace the loss of functioning tissue ultimately turns into a maladaptive process leading to progressive deterioration of renal function. We previously reported that nitric oxide (NO) production in the kidney is increased in the early phase after nephrectomy. However, the precise mechanism of increased NO production and its role in compensatory renal hypertrophy following nephrectomy remain unclear. We therefore hypothesize that the eNOS-soluble guanylate cyclase (sGC)-protein kinase G (PKG) pathway plays a crucial role in compensatory renal hypertrophy following unilateral nephrectomy. Design and Method: We used the following three groups of mice (male; background: C57BL6;): wild-type (WT), eNOS knockout (eNOS-KO) and endothelial specific eNOS transgenic (ECeNOS-TG) mice. These mice underwent left unilateral nephrectomy (i.e., WT-Nx, eNOS-KO-Nx and ECeNOS-TG-Nx), and their right kidney and serum were obtained for examination 2 weeks after nephrectomy. Next, we investigated the mechanism of NO-induced hypertrophy in vitro using human proximal tubular epithelial cells (hPTECs). hPTECs were stimulated with sGC stimulator BAY 41-2272 (Bay), and the activity of PKG and the downstream pathway were examined. In addition, we examined the effects of BAY in vivo by treating eNOS-KO mice with BAY (eNOS-KO-Nx-BAY) after unilateral nephrectomy. Results: Two weeks after nephrectomy, compensatory renal hypertrophy was markedly suppressed in the eNOS-KO-Nx group compared with the WT-Nx group. And serum CRN was increased in eNOSKO mice after nephrectomy compared with WT mice. Furthermore eNOS-KO-Nx also was increased excretion of albunuria after uni-nephrectomy. On the other hand, the ECeNOS-TG-Nx group exhibited enhanced compensatory renal hypertrophy than the other two groups. Treatment with BAY significantly enhanced compensatory renal hypertrophy in the eNOS-KO-Nx mice. Conclusions: Reduction of eNOS-NO bioavailability, as a endothelial dysfunction, may induce failure of compensatory hypertrophy and accelerate progressive renal dysfuction.

Compensatory Renal Hypertrophy and the Uptake of Cysteine S-Conjugates of Hg2+ in Isolated S2 Proximal Tubular Segments.

Chronic kidney disease is characterized by a progressive and permanent loss of functioning nephrons. In order to compensate for this loss, the remaining functional nephrons undergo significant structural and functional changes. We hypothesize that luminal uptake of inorganic mercury (Hg2+), as a conjugate of cysteine (Cys; Cys-S-Hg-S-Cys), is enhanced in S2 segments of proximal tubules from the remnant kidney of uninephrectomized (NPX) rabbits. To test this hypothesis, we measured uptake and accumulation of Cys-S-Hg-S-Cys in isolated perfused S2 segments of proximal tubules from normal (control) and NPX rabbits. The remnant kidney in NPX rabbits undergoes significant hypertrophy during the initial 3 weeks following surgery. Tubules isolated from NPX rabbits were significantly larger in diameter and volume than those from control rabbits. Moreover, real-time PCR analyses of proximal tubules indicated that the expression of selected membrane transporters was greater in kidneys of NPX animals than in kidneys of control animals. When S2 segments from control and NPX rabbits were perfused with cystine or Cys-S-Hg-S-Cys, we found that the rates of luminal disappearance and tubular accumulation of Hg2+ were greater in tubules from NPX animals. These increases were inhibited by the addition of various amino acids to the perfusate. Taken together, our data suggest that hypertrophic changes in proximal tubules lead to an enhanced ability of these tubules to take up and accumulate Hg2.

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

Loss of functional nephrons induces compensatory glomerular hyperfiltration and hypertrophy, leading to the progression of chronic kidney disease. Krüppel-like factor 2 (KLF2), a shear-stress-inducible transcription factor, confers protection against endothelial injury. Because glomerular hyperfiltration is associated with shear stress, we hypothesized that KLF2 may be an important factor in the compensatory response to unilateral nephrectomy (UNX). To test this hypothesis, endothelial cell-specific Klf2 heterozygous knockout mice (KO) and their wild-type littermate control (WT) underwent either UNX or sham-operation. WT-UNX mice developed compensatory renal hypertrophy as expected, whereas KO-UNX mice did not. KO-UNX mice exhibited higher blood pressure, reduced glomerular filtration rate, and significant increase in proteinuria and glomerulosclerosis compared to WT-UNX. Expression of endothelial nitric oxide synthase (official name Nos3), a known transcriptional target gene of KLF2, was significantly reduced and dysregulation of other endothelial genes was also observed in the glomeruli of KO-UNX when compared to WT-UNX and sham-operated mice. Furthermore, both podocyte number andexpression of podocyte markers were also significantly reduced in KO-UNX glomeruli, indicating a potential cross talk between glomerular endothelial cells and podocytes. Finally, decreased renal expression of KLF2 in nephrectomy patients was associated with the progression of kidney disease. Taken together, our data demonstrate a protective role of KLF2 against glomerular endothelial cell injury and progression of chronic kidney disease in the model of compensatory renal hypertrophy.

ZO-2 silencing induces renal hypertrophy through a cell cycle mechanism and the activation of YAP and the mTOR pathway.

Renal compensatory hypertrophy (RCH) restores normal kidney function after disease or loss of kidney tissue and is characterized by an increase in organ size due to cell enlargement and not to cell proliferation. In MDCK renal epithelial cells, silencing of the tight junction protein zona occludens 2 (ZO-2 KD) induces cell hypertrophy by two mechanisms: prolonging the time that cells spend at the G1 phase of the cell cycle due to an increase in cyclin D1 level, and augmenting the rate of protein synthesis. The latter is triggered by the nuclear accumulation and increased transcriptional activity of Yes-associated protein (YAP), the main target of the Hippo pathway, which results in decreased expression of phosphatase and tensin homologue. This in turn increased the level of phosphatidylinositol (3,4,5)-triphosphate, which transactivates the Akt/mammalian target of rapamycin pathway, leading to activation of the kinase S6K1 and increased synthesis of proteins and cell size. In agreement, in a rat model of uninephrectomy, RCH is accompanied by decreased expression of ZO-2 and nuclear expression of YAP. Our results reveal a novel role of ZO-2 as a modulator of cell size.

Compensatory renal hypertrophy and the handling of an acute nephrotoxicant in a model of aging

Aging often results in progressive losses of functioning nephrons, which can lead to a significant reduction in overall renal function. Because of age-related pathological changes, the remaining functional nephrons within aged kidneys may be unable to fully counteract physiological and/or toxicological challenges. We hypothesized that when the total functional renal mass of aged rats is reduced by 50%, the nephrons within the remnant kidney do not fully undergo the functional and physiological changes that are necessary to maintain normal fluid and solute homeostasis. We also tested the hypothesis that the disposition and handling of a nephrotoxicant are altered significantly in aged kidneys following an acute, 50% reduction in functional renal mass. To test these hypotheses, we examined molecular indices of renal cellular hypertrophy and the disposition of inorganic mercury (Hg2+), a model nephrotoxicant, in young control, young uninephrectomized (NPX), aged control and aged NPX Wistar rats. We found that the process of aging reduces the ability of the remnant kidney to undergo compensatory renal growth. In addition, we found that an additional reduction in renal mass in aged animals alters the disposition of Hg2+ and potentially alters the risk of renal intoxication by this nephrotoxicant. To our knowledge, this study represents the first report of the handling of a nephrotoxicant in an aged animal following a 50% reduction in functional renal mass.

Long-Term Structural and Functional Myocardial Adaptations in Healthy Living Kidney Donors: A Pilot Study.

Background and AimsCompensatory renal hypertrophy following unilateral nephrectomy (UNX) occurs in the remaining kidney. However, the long-term cardiac adaptive process to UNX remains poorly defined in humans. Our goal was to characterize myocardial structure and function in living kidney donors (LKDs), approximately 12 years after UNX.Methods and ResultsCardiac function and structure in 15 Italian LKDs, at least 5 years after UNX (median time from donation = 8.4 years) was investigated and compared to those of age and sex matched U.S. citizens healthy controls (n = 15). Standard and speckle tracking echocardiography (STE) was performed in both LKDs and controls. Plasma angiotensin II, aldosterone, atrial natriuretic peptide (ANP), N terminus pro B-type natriuretic peptide (NT-proBNP), cyclic guanylyl monophosphate (cGMP), and amino-terminal peptide of procollagen III (PIIINP) were also collected. Median follow-up was 11.9 years. In LKDs, LV geometry and function by STE were similar to controls, wall thickness and volumes were within normal limits also by CMR. In LKDs, CMR was negative for myocardial fibrosis, but apical rotation and LV torsion obtained by STE were impaired as compared to controls (21.4 ± 7.8 vs 32.7 ± 8.9 degrees, p = 0.04). Serum creatinine and PIIINP levels were increased [1.1 (0.9–1.3) mg/dL, and 5.8 (5.4–7.6)] μg/L, respectively), while urinary cGMP was reduced [270 (250–355) vs 581 (437–698) pmol/mL] in LKDs. No LKD developed cardiovascular or renal events during follow-up.ConclusionsLong-term kidney donors have no apparent structural myocardial abnormalities as assessed by contrast enhanced CMR. However, myocardial deformation of the apical segments, as well as apical rotation, and LV torsion are reduced. The concomitant increase in circulating PIIINP level is suggestive of fibrosis. Further studies, focused on US and EU patients are warranted to evaluate whether these early functional modifications will progress to a more compromised cardiac function and structure at a later time.

Novel roles of cardiac natriuretic peptides in renal compensatory hypertrophy

Background Loss of renal tissue and renal function results in an increase in function and mass of the remaining intact kidney tissue. A prominent example for this so called renal compensatory hypertrophy is the removal of one kidney (uninephrectomy, UNx) for instance in living kidney donors. Although it is well established that kidney size and function of the remaining kidney markedly increase in these patients and that these adaptations are a prerequisite for living kidney donation, several open questions regarding the regulation of the compensatory mechanisms remain. For instance the initial signals inducing the increase in glomerular filtration rate (GFR) are largely unknown. Based on previous studies demonstrating that I. the rapid increase in GFR post-UNx is mediated by a circulating factor and II. the cardiac natriuretic peptides ANP and BNP both are capable of increasing the GFR, we speculated that natriuretic peptides might be the long sought factor mediating the functional adaptation of kidney function in response to a loss of kidney tissue.