Eleonora Tashkenbaeva
1* 
, Maftuna Abdulloeva
1 , Iroda Salieva
2 , Sabokhat Tuychieva
1 , Laziz Yorbulov
1 , Sadriddin Mukhtarov
2 , Farida Khasanjanova
1 1 Department of Internal Medicine and Cardiology №2, Samarkand State Medical University, Samarkand, Uzbekistan
2 Samarkand Branch of the Republican Specialized Scientific Practical Medical Center of Cardiology, Samarkand, Uzbekistan
Abstract
Recurrent dehydration has detected as a significant, modifiable risk factor for the development and progression of chronic kidney disease, particularly in populations exposed to occupational heat stress or limited fluid access. This overview sought to consider current findings on the molecular pathways linking episodic volume depletion to sustained renal dysfunction, emphasizing osmotic stress as the primary catalyst for tubular epithelial injury. Repeated hyperosmolar insults disrupt cellular homeostasis, provoking mitochondrial dysfunction, endoplasmic reticulum stress, and excessive reactive oxygen species production. These perturbations activate conserved signaling cascades, notably p38 MAPK, NF-κB, and the NLRP3 inflammasome, which drive pro-inflammatory cytokine release and sustained leukocyte infiltration. Concurrently, osmotic stress potently upregulates transforming growth factor-beta and connective tissue growth factor, precipitating epithelial-to-mesenchymal transition and myofibroblast differentiation. The consequent extracellular matrix accumulation, compounded by defective autophagy and maladaptive proliferative responses, establishes a self-sustaining loop of tubulointerstitial fibrosis. Recurrent dehydration further amplifies intrarenal renin-angiotensin-aldosterone system activity and endothelin-1 signaling, accelerating peritubular capillary loss and hypoxia-driven fibrogenesis. Recent data further implicate urea transporter dysregulation and tonicity-responsive enhancer-binding protein activation in exacerbating tubular cell cycle arrest and cellular senescence. Interpretation of these interconnected molecular networks reveals promising therapeutic targets that could interrupt the transition from acute osmotic injury to irreversible architectural damage. Finally, integrating mechanistic insights with clinical epidemiology reinforces the urgent need for evidence-based hydration protocols and novel antifibrotic strategies to mitigate the rising global incidence of dehydration-related chronic kidney disease.
Implication for health policy/practice/research/medical education:
Recurrent dehydration initiates a maladaptive cascade that accelerates chronic kidney disease by exposing the renal medulla to sustained hyperosmolar stress. This osmotic imbalance activates TonEBP/NFAT5 and stress-responsive kinases, driving excessive reactive oxygen species production and mitochondrial dysfunction in renal tubular epithelial cells. Persistent osmotic and oxidative insults trigger kidney tubular cell apoptosis, necrosis, and impaired regenerative capacity, creating a proinflammatory microenvironment. Damaged tubules subsequently overexpress transforming growth factor-β1, connective tissue growth factor, and pro-fibrotic cytokine networks, which promote epithelial-to-mesenchymal transition and sustained myofibroblast differentiation. Concurrently, chronic medullary hypoxia and renin-angiotensin system activation amplify extracellular matrix deposition while suppressing degradative metalloproteinase activity. Over time, these intertwined molecular pathways convert transient osmotic stress into irreversible interstitial fibrosis, progressively compromising nephron function and establishing a self-perpetuating cycle that drives the clinical transition from adaptive physiology to end-stage chronic kidney disease.
Please cite this paper as: Tashkenbaeva E, Abdulloeva M, Salieva I, Tuychieva S, Yorbulov L, Mukhtarov S, Khasanjanova F. Recurrent dehydration and chronic kidney disease; molecular pathways linking osmotic stress, tubular injury and fibrotic progression. J Nephropharmacol. 2026;x(x):e12894. DOI: 10.34172/npj.12894.