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Congenital anomalies of the kidney and urinary tract (CAKUT) have been attributed to genetic and environmental factors. However, monogenic and copy number variations cannot sufficiently explain the cause of the majority of CAKUT cases. Multiple genes through various modes of inheritance may lead to CAKUT pathogenesis. We previously showed that Robo2 and Gen1 coregulated the germination of ureteral buds (UB), significantly increasing CAKUT incidence. Furthermore, MAPK/ERK pathway activation is the central mechanism of these two genes. Thus, we explored the effect of the MAPK/ERK inhibitor U0126 in the CAKUT phenotype in Robo2 PB/+ Gen1 PB/+ mice. Intraperitoneal injection of U0126 during pregnancy prevented the development of the CAKUT phenotype in Robo2 PB/+ Gen1 PB/+ mice. Additionally, a single dose of 30 mg/kg U0126 on day 10.5 embryos (E10.5) was most effective for reducing CAKUT incidence and ectopic UB outgrowth in Robo2 PB/+ Gen1 PB/+ mice. Furthermore, embryonic kidney mesenchymal levels of p-ERK were significantly decreased on day E11.5 after U0126 treatment, along with decreased cell proliferation index PHH3 and ETV5 expression. Collectively, Gen1 and Robo2 exacerbated the CAKUT phenotype in Robo2 PB/+ Gen1 PB/+ mice through the MAPK/ERK pathway, increasing proliferation and ectopic UB outgrowth. • Urinary system congenital anomalies are genetically and environmentally complex. • ROBO2 and GEN1 coregulate ureteral bud germination and influence CAKUT incidence. • U0126 treatment reduces CAKUT incidence in mice with Robo2 and Gen1 mutations. • We conclude that ROBO2 and GEN1 influence MAPK/ERK signaling to contribute to CAKUT. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) presents a substantial population health concern. Previous studies have revealed that GDM can ultimately influence nephron endowment. In this study, we established a GDM mouse model to investigate the embryological alterations and molecular mechanisms underlying the development of congenital anomalies of the kidney and urinary tract (CAKUT) affected by GDM. Our study highlights that GDM could contribute to the manifestation of CAKUT, with prevalent phenotypes characterized by isolated hydronephrosis and duplex kidney complicated with hydronephrosis in mice. Ectopic ureteric buds (UBs) and extended length of common nephric ducts (CNDs) were noted in the metanephric development stage. The expression of Ret and downstream p -ERK activity were enhanced in UBs, which indicated the alteration of RET/MAPK/ERK pathway may be one of the mechanisms contributing to the increased occurrence of CAKUT associated with GDM. • GDM could contribute to the manifestation of CAKUT in mice. • Ectopic UBs and extended length of CNDs were noted in the metanephric development stage under GDM. • GDM could alter the RET/MAPK/ERK pathway involved in metanephric development. [ABSTRACT FROM AUTHOR]