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Renal developmental genes are differentially regulated after unilateral ureteral obstruction in neonatal and adult mice.

ABSTRACT: Congenital obstructive nephropathy hinders normal kidney development. The severity and the duration of obstruction determine the compensatory growth of the contralateral, intact opposite kidney. We investigated the regulation of renal developmental genes, that are relevant in congenital anomalies of the kidney and urinary tract (CAKUT) in obstructed and contralateral (intact opposite) kidneys after unilateral ureteral obstruction (UUO) in neonatal and adult mice. Newborn and adult mice were subjected to complete UUO or sham-operation, and were sacrificed 1, 5, 12 and 19 days later. Quantitative RT-PCR was performed in obstructed, intact opposite kidneys and sham controls for Gdnf, Pax2, Six4, Six2, Dach1, Eya1, Bmp4, and Hnf-1?. Neonatal UUO induced an early and strong upregulation of all genes. In contrast, adult UUO kidneys showed a delayed and less pronounced upregulation. Intact opposite kidneys of neonatal mice revealed a strong upregulation of all developmental genes, whereas intact opposite kidneys of adult mice demonstrated only a weak response. Only neonatal mice exhibited an increase in BMP4 protein expression whereas adult kidneys strongly upregulated phosphatidylinositol 3 kinase class III, essential for compensatory hypertrophy. In conclusion, gene regulation differs in neonatal and adult mice with UUO. Repair and compensatory hypertrophy involve different genetic programs in developing and adult obstructed kidneys.

SUBMITTER: Kubik MJ

PROVIDER: S-EPMC7653944 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Renal developmental genes are differentially regulated after unilateral ureteral obstruction in neonatal and adult mice.

Kubik Melanie J MJ Wyczanska Maja M Gasparitsch Mojca M Keller Ursula U Weber Stefanie S Schaefer Franz F Lange-Sperandio Bärbel B

Scientific reports 20201109 1

Congenital obstructive nephropathy hinders normal kidney development. The severity and the duration of obstruction determine the compensatory growth of the contralateral, intact opposite kidney. We investigated the regulation of renal developmental genes, that are relevant in congenital anomalies of the kidney and urinary tract (CAKUT) in obstructed and contralateral (intact opposite) kidneys after unilateral ureteral obstruction (UUO) in neonatal and adult mice. Newborn and adult mice were subj ...[more]

PMID: 33168884

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Project description:Renal scintigraphy using 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) is widely used for the assessment of renal function in humans. However, the application of this method to animal models of renal disease is currently limited, especially in rodents. Here, we have applied 99mTc-MAG3 renal scintigraphy to a mouse model of unilateral ureteral obstruction (UUO) and evaluated its utility in studying obstructive renal disease.UUO mice were generated by complete ligation of the left ureter. Sham-operated mice were used as a control. Renal function was investigated on days 0, 1, 3, and 6 post-surgery using dynamic planar imaging of 99mTc-MAG3 activity following retro-orbital injection. Time-activity curves (TACs) were produced for individual kidneys and renal function was assessed by 1) the slope of initial 99mTc-MAG3 uptake (SIU), which is related to renal perfusion; 2) peak activity; and 3) the time-to-peak (TTP). The parameters of tubular excretion were not evaluated in this study as 99mTc-MAG3 is not excreted from UUO kidneys.Compared to sham-operated mice, SIU was remarkably (>60%) reduced in UUO kidneys at day 1 post surgery and the TACs plateaued, indicating that 99mTc-MAG3 is not excreted in these kidneys. The plateau activity in UUO kidneys was relatively low (~40% of sham kidney's peak activity) as early as day1 post surgery, demonstrating that uptake of 99mTc-MAG3 is rapidly reduced in UUO kidneys. The time to plateau in UUO kidneys exceeded 200 sec, suggesting that 99mTc-MAG3 is slowly up-taken in these kidneys. These changes advanced as the disease progressed. SIU, peak activity and TTPs were minimally changed in contra-lateral kidneys during the study period.Our data demonstrate that renal uptake of 99mTc-MAG3 is remarkably and rapidly reduced in UUO kidneys, while the changes are minimal in contra-lateral kidneys. The parametric analysis of TACs suggested that renal perfusion as well as tubular uptake is reduced in UUO kidneys. This imaging technique should allow non-invasive assessments of UUO renal injury and enable a more rapid interrogation of novel therapeutic agents and protocols.

Project description:BackgroundIt is controversial to evaluate the function of hydronephrotic kidneys by renal dynamic imaging (RDI). Our aim was to study the features of renal dynamic imaging (RDI) at different stages after unilateral ureteral obstruction (UUO) and to investigate a method that could be reasonably used to evaluate renal function and predict renal functional recoverability.MethodsWe made UUO models using fifteen adult New Zealand white rabbits and systematically observed the changes in kidney morphology, blood flow, radiotracer distribution and function by RDI. We then compared the differences in terms of imaging features between different periods and analyzed the relationship between blood flow and function in obstructed kidneys.Results1) Obstructed kidneys gradually became larger than preoperative kidneys and contralateral kidneys (P<0.05) and reached their peak size between days 42 and 56, after which they gradually got smaller in size. 2)The correlation between the blood perfusion of the obstructed kidney and the obstruction duration (r = 0.125, P = 0.045) was very weak. In the initial period of obstruction, the perfusion of the obstructed kidney significantly decreased, followed by a sharp rebound in later days, and then the perfusion declined again. The peak in blood perfusion was on day 7. 3) The uptake rate of the obstructed kidney drastically decreased in the early stage and became lower than that of the contralateral kidney and the kidney before the operation (P<0.05), after which uptake increased gradually; the peak was on day 28. After that, uptake gradually decreased. 4) The grading of the radiotracer distribution in obstructed kidneys was positively correlated with the obstruction duration (r = 0.975, P = 0.000), and a uniform renal distribution was an early feature of obstruction. 5) The blood perfusion of the obstructed kidney and its functioning frequently increased or decreased simultaneously, but sometimes there was also a mismatch. The peak of renal blood perfusion recovery occurred prior to the peak of renal function recovery.ConclusionIn different periods of severe UUO, the imaged features of obstructed kidneys were different. These features are beneficial for determining the degree of hydronephrosis and renal function and predicting renal functional recoverability.

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Renal developmental genes are differentially regulated after unilateral ureteral obstruction in neonatal and adult mice.

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Renal developmental genes are differentially regulated after unilateral ureteral obstruction in neonatal and adult mice.

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