Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice

Congenital anomalies of the kidney and urinary tract (CAKUT) are some of the most common developmental defects and have a complicated etiology, indicating an interaction of (epi-) genetic and environmental factors. Single gene mutations and copy number variations (CNVs) do not explain most cases of CAKUT, and simultaneous contributions of more than one gene (di-, oligo-, or polygenic effects; i.e., complex genetics) may lead to the pathogenesis of CAKUT. Robo2 plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations leading to supernumerary kidneys. Gen1 is a candidate gene associated with CAKUT because of its important role in early metanephric development in mice. We established a mouse model with double disruption of Robo2 and Gen1 using a piggyBac transposon and found that double gene mutation led to significantly increased CAKUT phenotypes in Robo2PB/+Gen1PB/+ mouse offspring, especially a duplicated collecting system. Increased ectopic UB formation was observed in the Robo2PB/+Gen1PB/+ mice during the embryonic period. Robo2 and Gen1 exert synergistic effects on mouse kidney development, promoting cell proliferation by activating the GDNF/RET pathway and downstream MAPK/ERK signaling. Our findings provide a disease model for CAKUT as an oligogenic disorder.

Changes of Rat Embryon Nephrogenesis during Cadmium Salt Intoxication in Pregnant Females

The purpose of the experimental study was to determine morphogenetic disorders of embryonic and fetal kidney development in chronic intragastric exposure to cadmium salts (cadmium chloride, cadmium citrate) in pregnant females. Materials and methods. Low doses of cadmium salts were selected for the study, which can be compared with the actual concentration of cadmium in the daily diets of women, including pregnant women, in industrial regions. In the experiment, female rats with a given gestational age were divided into groups as follows: Group 1 – control (number of females – n = 16, of which 8 left the experiment on the 13th day of pregnancy, and 8 on the 20th; the number of embryos – n13 = 76; n20 = 77); Group 2 – administration of cadmium chloride at a dose of 1.0 mg/kg body weight of the female (number of females – n = 16; number of embryos – n13 = 65; n20 = 62); Group 3 – administration of cadmium citrate at a dose of 1.0 mg/kg body weight of the female (number of females – n = 16; number of embryos – n13 = 69; n20 = 70). Results and discussion. New quantitative data on the effect of cadmium salts were obtained on the thickness of the cortical and cerebral layers of the kidneys, the diameter and area of the cavity of the nephron capsule in the prenatal period of development in chronic female intoxication. On the 13th day, the effect of cadmium salts on the development of embryonic kidneys was multidirectional: the effect of cadmium chloride led to an increase in the thickness of the mesonephros and mesonephric duct, and the effect of cadmium citrate reduced the studied parameters. On the 20th day of rat embryogenesis in the group exposed to cadmium chloride, the renal weights increased, and when exposed to cadmium citrate, the weight of the kidneys decreased significantly (p˂0.05) both in comparison with control values and in the group exposed to cadmium chloride. On the 20th day of development, in order to exclude an error in estimating the dynamics of changes in the weight of embryo mass and kidney mass, the nephrofetal index was calculated, i.e. the ratio of wet kidney mass to wet weight of fixed fetus. Histological parameters of nephron diameters were also compared. Conclusion. Cadmium citrate has been shown for the first time to be less non-photoxic than cadmium chloride. Calculation of the area of the cavity of the nephron capsule by the spline contour method showed a 2.6-fold decrease in the average area of the capsule cavity in the group exposed to cadmium chloride relative to the control mean values, indicating a violation of nephrogenesis. When exposed to cadmium citrate, there was also a decrease in the area of the cavity of the nephron capsule by 1.8 times, which indicates a lower level of nephrotoxic cadmium citrate compared to cadmium chloride, despite the identity of the dose of exposure

Immunohistochemical Expression of Wnt-4 Protein in Clear Cell Renal Carcinoma

Wingless binding integration site proteins (Wnt) have an important role in normal kidney development and in various kidney diseases. They are required for complete epithelial differentiation and normal nephron formation. Changes in these proteins could also have important role in carcinogenesis. This study included 185 patients with clear cell renal carcinoma (ccRCC) in whom immunohistochemical expression of Wnt-4 protein in healthy and tumorous tissue after surgery was investigated. There was higher expression of Wnt-4 in healthy than in tumor tissue. No difference between Fuhrman’s grade and Wnt-4 expression was found. A poor negative correlation between tumor size and Wnt-4 expression was found. Patients with suspected metastatic diseases had higher Wnt-4 expression. There was no difference in survival rates between Wnt-4 negative and positive groups. In our study we have shown that high Wnt-4 expression in healthy tissue decreases in low-grade tumors but then increases in high-grade tumors, suggesting that tumor progression requires Wnt-4 activation or reactivation.

BET Proteins Regulate Expression of Osr1 in Early Kidney Development

In utero renal development is subject to maternal metabolic and environmental influences affecting long-term renal function and the risk of developing chronic kidney failure and cardiovascular disease. Epigenetic processes have been implicated in the orchestration of renal development and prenatal programming of nephron number. However, the role of many epigenetic modifiers for kidney development is still unclear. Bromodomain and extra-terminal domain (BET) proteins act as histone acetylation reader molecules and promote gene transcription. BET family members Brd2, Brd3 and Brd4 are expressed in the nephrogenic zone during kidney development. Here, the effect of the BET inhibitor JQ1 on renal development is evaluated. Inhibition of BET proteins via JQ1 leads to reduced growth of metanephric kidney cultures, loss of the nephron progenitor cell population, and premature and disturbed nephron differentiation. Gene expression of key nephron progenitor transcription factor Osr1 is downregulated after 24 h BET inhibition, while Lhx1 and Pax8 expression is increased. Mining of BRD4 ChIP-seq and gene expression data identify Osr1 as a key factor regulated by BRD4-controlled gene activation. Inhibition of BRD4 by BET inhibitor JQ1 leads to downregulation of Osr1, thereby causing a disturbance in the balance of nephron progenitor cell self-renewal and premature differentiation of the nephron, which ultimately leads to kidney hypoplasia and disturbed nephron development. This raises questions about the potential teratogenic effects of BET inhibitors for embryonic development. In summary, our work highlights the role of BET proteins for prenatal programming of nephrogenesis and identifies Osr1 as a potential target of BET proteins.

Rare anomaly of kidney development – L-shaped fusion

Within the framework of the publication, an L‑shaped fusion of the kidneys (horseshoe‑shaped) is considered, referring to the category of asymmetric fusion. The presented clinical case is an extremely rare form of congenital anomaly of renal fusion, demonstrating the difficulty of verifying the correct diagnosis. The article presents the results of a tomographic study, which, in addition to enlargement of the kidneys, recorded signs of dysplasia of the left ureter (stricture) and signs of an arterial vascular bed (aberrant artery of the upper part of the L‑shaped horseshoe).

Post-translational modifications by SIRT3 de-2-hydroxyisobutyrylase activity regulate glycolysis and enable nephrogenesis

Abnormal kidney development leads to lower nephron number, predisposing to renal diseases in adulthood. In embryonic kidneys, nephron endowment is dictated by the availability of nephron progenitors, whose self-renewal and differentiation require a relatively repressed chromatin state. More recently, NAD+-dependent deacetylase sirtuins (SIRTs) have emerged as possible regulators that link epigenetic processes to the metabolism. Here, we discovered a novel role for the NAD+-dependent deacylase SIRT3 in kidney development. In the embryonic kidney, SIRT3 was highly expressed only as a short isoform, with nuclear and extra-nuclear localisation. The nuclear SIRT3 did not act as deacetylase but exerted de-2-hydroxyisobutyrylase activity on lysine residues of histone proteins. Extra-nuclear SIRT3 regulated lysine 2-hydroxyisobutyrylation (Khib) levels of phosphofructokinase (PFK) and Sirt3 deficiency increased PFK Khib levels, inducing a glycolysis boost. This altered Khib landscape in Sirt3−/− metanephroi was associated with decreased nephron progenitors, impaired nephrogenesis and a reduced number of nephrons. These data describe an unprecedented role of SIRT3 in controlling early renal development through the regulation of epigenetics and metabolic processes.

Growth Hormone and IGF1 Actions in Kidney Development and Function

Growth hormone (GH) exerts multiple effects on different organs including the kidneys, either directly or via its main mediator, insulin-like-growth factor-1 (IGF-1). The GH/IGF1 system plays a key role in normal kidney development, glomerular hemodynamic regulation, as well as tubular water, sodium, phosphate, and calcium handling. Transgenic animal models demonstrated that GH excess (and not IGF1) may lead to hyperfiltration, albuminuria, and glomerulosclerosis. GH and IGF-1 play a significant role in the early development of diabetic nephropathy, as well as in compensatory kidney hypertrophy after unilateral nephrectomy. Chronic kidney disease (CKD) and its complications in children are associated with alterations in the GH/IGF1 axis, including growth retardation, related to a GH-resistant state, attributed to impaired kidney postreceptor GH-signaling and chronic inflammation. This may explain the safety of prolonged rhGH-treatment of short stature in CKD.

Regrow or Repair: An Update on Potential Regenerative Therapies for the Kidney

Fifteen years ago, this journal published a review outlining future options for regenerating the kidney. At that time, stem cell populations were being identified in multiple tissues, the concept of stem cell recruitment to a site of injury was of great interest, and the possibility of postnatal renal stem cells was growing in momentum. Since that time, we have seen the advent of human induced pluripotent stem cells, substantial advances in our capacity to both sequence and edit the genome, global and spatial transcriptional analysis down to the single-cell level, and a pandemic that has challenged our delivery of health care to all. This article will look back over this period of time to see how our view of kidney development, disease, repair, and regeneration has changed and envision a future for kidney regeneration and repair over the next 15 years.