Determination of the molecular-genetic mechanisms of cellular plasticity and pancreatic tissue remodeling in SHR rats

Abstract

Essential arterial hypertension is accompanied by systemic neurohumoral and microcirculatory disturbances, oxidative stress, and metabolic alterations that may affect the endocrine compartment of the pancreas and promote its remodelling. A key component of these changes is endocrine cell plasticity, which is mediated by reprogramming of transcriptional networks and may contribute to the development of islet dysfunction. In spontaneously hypertensive rats, a model relevant to essential arterial hypertension, the molecular and genetic mechanisms underlying these processes remain insufficiently defined, which justifies analysing the expression profile of key genes associated with cellular plasticity and pancreatic tissue remodelling.

The aim of the work: To determine the molecular mechanisms of cellular plasticity and pancreatic remodelling under conditions of essential arterial hypertension by analysing the expression profile of key genes.

Materials and methods. For the analysis of gene expression, the real-time reverse transcription polymerase chain reaction method was used using the PARN-405Z RT² Profiler™ PCR Array Rat Stem Cell kit (QIAGEN, Germany), where the pancreas was the object of the study in experimental animals.

Results. In rats SHR, pancreatic gene expression demonstrates coordinated suppression of regulators of epigenetic and transcriptional control and endocrine cell maturity (Hdac1 12.25-fold; Foxa2 2.12-fold; Sox2 3.11-fold; Neurog2 14.37-fold; 2⁻ΔΔCt), together with reduced mitochondrial proteostasis (Hspa9 14.87-fold) and trophic fibroblast growth factor signalling (Fgfr1 11.51-fold; Fgf1 4.91-fold). Concomitant downregulation of Notch and Wnt pathway components (Dtx2 7.26-fold; Numb 4.17-fold; Axin1 3.60-fold) and adhesion and matrix-related genes (Cdh1 2.39-fold; Catna1 3.44-fold; Col2a1 2.12-fold), along with decreased cell-cycle regulators (Ccne1 9.06-fold; Ccnd2 2.47-fold), indicates microenvironmental disorganisation and limited compensatory renewal. Overall, this profile supports a mechanistic shift toward reduced regenerative reserves, metabolic vulnerability, and functional exhaustion of the endocrine compartment under chronic hypertensive stress.

Conclusions: 1. In SHR rats, the pancreatic transcriptional profile is characterised by a predominant decrease in gene expression, reflecting dysregulatory remodelling of the endocrine compartment under chronic hypertensive stress.

1. Suppression of key regulators of epigenetic and transcriptional control and endocrine cell maturity (Hdac1, Foxa2, Sox2, Neurog2) is observed, which is consistent with reduced plasticity and diminished functional reserve of the endocrine compartment.
2. The most pronounced shifts involve mitochondrial resilience and trophic support (Hspa9; Fgfr1, Fgf1), indicating energy and trophic insufficiency as major components of the SHR phenotype.
3. Downregulation of Notch and Wnt components and adhesion and matrix-related genes (Dtx2, Numb, Axin1; Cdh1, Catna1, Col2a1), together with reduced cell-cycle reserves (Ccne1, Ccnd2), supports microenvironmental disorganisation and limited compensatory renewal, thereby favouring functional exhaustion of the endocrine compartment.