Background/Objectives: Congenital anomalies of the kidney and urinary tract (CAKUTs) represent the leading cause of pediatric chronic kidney disease, yet the molecular mechanisms underlying these malformations remain incompletely understood. While genetic studies have identified numerous CAKUT-associated genes, conventional knockout approaches often result in embryonic lethality or fail to reveal tissue-specific gene functions. This review aims to synthesize findings from conditional knockout mouse studies that have elucidated the spatiotemporal requirements of key signaling pathways during kidney development. Methods: We conducted a narrative synthesis of studies employing Cre-loxP conditional gene targeting in mouse models, identified through systematic searches of PubMed and cross-referencing of key primary research. Studies were selected based on their use of lineage-specific Cre drivers (Six2-Cre, Hoxb7-Cre, Foxd1-Cre) to investigate nephron progenitor maintenance, ureteric bud branching morphogenesis, and stromal–epithelial interactions. Results: Conditional knockout studies have redefined CAKUT pathogenesis as a disorder of dose-dependent signaling, temporal regulation, and inter-compartmental communication. WNT/β-catenin signaling operates in a biphasic, dose-dependent manner in nephron progenitors, with Six2-Cre-mediated β-catenin deletion causing premature progenitor depletion. BMP and FGF pathways demonstrate dose-dependent and context-specific functions in progenitor maintenance, while GDNF/RET signaling is essential for ureteric bud outgrowth and branching. Importantly, stromal-specific deletions have uncovered non-cell-autonomous mechanisms regulating nephron formation. Haploinsufficiency studies demonstrate that partial pathway disruption can reduce nephron endowment without overt CAKUT, predisposing to adult-onset hypertension and chronic kidney disease. Conclusions: Conditional gene targeting has mechanistically redefined CAKUT from a collection of structural malformations to a spectrum of disorders arising from quantitative perturbations in lineage-specific signaling networks. These findings establish that phenotypic severity is determined by the degree of pathway disruption, the developmental timing of insult, and the compartment affected, providing a framework for interpreting oligogenic interactions and variable penetrance in human CAKUTs.

Hip osteoarthritis (HOA) has shown the largest relative increase in prevalent cases of any osteoarthritis site, yet compartment-resolved data on the NF-κB-driven inflammatory–catabolic axis of synovitis derive mainly from the knee. We quantified nuclear factor-κB p65 (NF-κB p65), interleukin-1β (IL-1β), matrix metalloproteinase-3 (MMP-3), and the macrophage marker cluster of differentiation 68 (CD68) in the synovial intima and subintima of 19 patients undergoing hip arthroplasty for HOA and 10 controls (CTRL) without histological synovitis who underwent arthroplasty for femoral neck fracture. Immunofluorescence was quantified after blinded three-observer compartment delineation, and groups were compared by two-way analysis of variance with Tukey’s test. All four markers were increased in the HOA intima (2.6- to 3.6-fold vs. CTRL; p < 0.0001) and were higher in the intima than in the subintima of HOA synovium (p < 0.0001). In the subintima, NF-κB p65 (p < 0.0001), MMP-3 (p < 0.01), and CD68 (p < 0.05) were also increased, whereas IL-1β was not significantly increased (1.12-fold). These hypothesis-generating data show that NF-κB p65, IL-1β, MMP-3, and CD68 immunoreactivity is concentrated in the intimal lining of HOA synovium; the IL-1β increase was detected only in the intima, a distinction that bulk analysis cannot resolve.