The kidney’s intricate physiology relies on finely tuned gene regulatory networks that coordinate cellular responses to metabolic, inflammatory, and fibrotic stress. Beyond protein-coding transcripts, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators of renal biology. By modulating transcriptional, post-transcriptional, and epigenetic pathways, ncRNAs govern podocyte integrity, tubular adaptation, intercellular signaling, and immune activation. Dysregulation of these networks is now recognized as a hallmark of major kidney diseases, ranging from diabetic nephropathy and acute kidney injury to chronic kidney disease, glomerulopathies, and polycystic kidney disease. Mechanistic studies have revealed how pathogenic ncRNAs drive apoptosis, inflammation, fibrosis, and cystic remodeling, while protective ncRNAs mitigate these processes, highlighting their dual roles as both disease mediators and therapeutic targets. The exceptional stability of ncRNAs in urine, plasma, and exosomes further positions them as minimally invasive biomarkers with diagnostic and prognostic value. Translational advances include anti-miR and mimic-based therapies (e.g., lademirsen targeting miR-21, miR-29 mimics, anti-miR-17 oligonucleotides), alongside lncRNA silencing strategies, although challenges in delivery, safety, and redundancy remain significant. This review integrates molecular mechanisms with translational perspectives, providing a comprehensive synthesis of how ncRNAs shape renal pathophysiology. By bridging mechanistic insights with emerging diagnostic and therapeutic applications, we highlight the potential of ncRNAs to transform nephrology, paving the way for biomarker-driven precision medicine and novel interventions aimed at intercepting kidney injury at its regulatory roots. In clinical terms, ncRNA-based biomarkers and therapeutics promise earlier detection, more precise risk stratification, and individualized treatment selection within precision nephrology.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric renal failure, but the molecular mechanisms driving these conditions are not yet fully understood. Fibroblast Growth Factor 23 (FGF23) and its co-receptor α-KLOTHO play crucial roles in regulating calcium and phosphate homeostasis in adult kidneys, but their roles in kidney development and the pathogenesis of CAKUT remain unclear. Because of that, we analyzed the spatial and temporal expression of FGF23 and α-KLOTHO in normal fetal kidney development and CAKUT using an immunofluorescence technique. Our results demonstrate a dynamic pattern of FGF23 and α-KLOTHO expression in healthy kidney development, with FGF23 levels decreasing and α-KLOTHO levels increasing with gestational age. Also, we showed that FGF23 expression was significantly reduced in horseshoe (HKs) and duplex kidneys (DKs), while α-KLOTHO expression remained unchanged across all CAKUT conditions. Based on our results, we suggest that altered FGF23 expression in CAKUT contributes to disease pathogenesis and may represent a potential therapeutic target.

Background/Objectives: Chronic synovitis is a hallmark of osteoarthritis (OA) progression, driving cartilage degradation via inflammatory mediators. While the MAPK signaling pathway is implicated in OA pathogenesis its activation patterns in hip synovium remain poorly characterized, and regional differences within the synovial membrane have not been systematically examined. This research aims to determine the expression of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and the Epidermal Growth Factor Receptor (EGFR) in the MAPK signaling pathway in the synovial membrane of osteoarthritic hips. Methods: We compared synovial immunofluorescence expression of the aforementioned proteins in a control (CTRL) group of subjects with femoral neck fractures and a group with hip OA. Results: Higher ERK1/2 immunoexpression was detected in the intima compared with the subintima in the CTRL group (p < 0.05), and a similar distribution was observed in the OA group (p < 0.0001). The intima of the OA group exhibited a considerably greater area percentage of positive signal than the intima of the CTRL group (p < 0.01). In all groups examined, we observed that p38 MAPK expression was markedly more positive in the intima than in the subintima (p < 0.0001), but without statistically significant differences between groups. JNK and EGFR immunoexpression were higher in the intima than in the subintima across all analyzed groups, but the difference did not reach statistical significance (p > 0.05). No differences in the expression of these two markers were detected between the CTRL and OA groups (p > 0.05). Differential analysis of the GEO dataset revealed no significant differences in expression between the OA and CTRL groups in the expression of MAPK1, MAPK3, MAPK8, MAPK9, MAPK10, and MAPK11. EGFR was significantly elevated in OA compared to CTRLs in the differential analysis of the GEO dataset. Conclusions: This study provides the first comprehensive analysis of MAPK pathway activation in hip OA synovium, revealing ERK1/2 as a key player with region-specific upregulation in the synovial intima. Combined with elevated EGFR expression, these findings suggest potential therapeutic targets for hip OA synovitis. The discordance between protein and mRNA levels for ERK1/2 indicates post-transcriptional regulation, warranting further investigation into phosphorylation status and functional activation. Our results support the development of targeted interventions for hip OA, a condition with limited treatment options beyond joint replacement.

We studied the expression of connexin 43 (Cx43) and pannexin 1 (PANX1) in different cellular populations of the kidneys of diabetic mice and diabetic and non-diabetic patients, to evaluate their role as potential therapeutic targets in diabetic kidney disease (DKD). A combination of a low dose of streptozotocin and a high-fat diet (HFD) was used to induce a type 2 diabetes model (DM2) in mice. Kidney tissues from diabetic (n = 9) and control patients (n = 11) who underwent nephrectomy were collected. Tissues from mice and humans were processed for double immunofluorescence, using antibodies against Cx43, phosphorylated Cx43 (pCx43) or PANX1 and markers for specific cell populations: endothelium (CD31/PECAM1); pericytes/mesangium (PDGFRB); podocytes (nephrin/synaptopodin); proximal tubules and collecting ducts (aquaporin 2). The results showed a significant decrease in the expression of pCx43 in PDGFRB-immunoreactive mesangium in diabetic patients compared to the control group (p < 0.0001). This contrasted with an increase in pCx43 in pericytes of diabetic mice (p = 0.1). However, we found a general decrease in Cx43 protein expression in diabetic mouse kidneys (p < 0.05). We also found a decrease in the expression of PANX1 in endothelial cells of diabetic patients (p < 0.05) and a significant increase in PANX1 expression in cells expressing PDGFRB (p < 0.05). Expression of PANX1 in endothelium (r = −0.50; p < 0.05) and pCx43 in the mesangium (r = −0.65; p < 0.01) correlated negatively with the percentage of sclerotic glomeruli. The expression and activation of Cx43 and the expression of PANX1 are altered in distinct populations of renal cells during long-term type 2 diabetes mellitus, especially cells of the vascular wall. This may indicate their role in the pathophysiological processes of DKD. Therefore, connexin and pannexin channels could be considered as possible therapeutic targets in the prevention and treatment of diabetic kidney disease.

Background and Objectives: Mitogen-activated protein kinases (p38, JNK, ERK1/2) regulate key cellular processes essential for kidney development. Disruptions in these signaling pathways can lead to congenital anomalies of the kidney and urinary tract (CAKUT), a major cause of pediatric kidney disease. This study investigates and compares the expression of these molecules in normal fetal kidneys and CAKUT-affected tissues. Materials and Methods: Forty-three human fetal kidney samples, including controls and specimens with horseshoe, hypoplastic, and dysplastic kidneys, were analyzed across developmental phases 2–4 using immunofluorescence. Quantitative image analysis and statistical comparisons were performed between developmental stages and phenotypes. Results: ERK1/2 expression increased during late development in control kidneys but was significantly reduced in hypoplastic kidneys. p38 showed phase-dependent alterations, with early upregulation in dysplastic kidneys and late elevation in horseshoe kidneys. JNK exhibited significant phase-dependent upregulation in horseshoe kidneys. P38 displayed dynamic expression associated with nephron maturation. Conclusions: MAPK pathways show distinct developmental and phenotype-specific expression patterns in human fetal kidneys. These differences reflect divergent pathogenic mechanisms in CAKUT and may support improved molecular characterization of congenital renal anomalies.

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.