Functional, Structural and Molecular Alterations in the Heart and Kidney During Diabetes Mellitus

Waqar, Tehreem (2016) Functional, Structural and Molecular Alterations in the Heart and Kidney During Diabetes Mellitus. Doctoral thesis, University of Central Lancashire.

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Background: Diabetes mellitus (DM) is a major metabolic disorder leading to severe long term complications including cardiomyopathy, nephropathy, retinopathy and neuropathy that are common in type 1 DM (T1DM) and type 2 DM (T2DM). Epidemiological studies have demonstrated a role of hyperglycaemia (HG) in eliciting adverse cardiac and renal outcomes including heart failure (HF), diastolic and renal dysfunction. This study investigated the effect of HG on left ventricle (LV) and kidney structural remodelling, function and underlying molecular events associated with the two organs over a period of 2 and 4 months compared to age-matched control.
Methods: Molecular mechanisms underlying HG-induced remodelling changes including extracellular matrix (ECM) and myocyte apoptosis deposition, underlying cytokine induction, recapitulation of foetal genes, and transcriptional alterations that may influence the ECM and intracellular calcium [Ca2+]i handling in the LV and kidney of T1DM as well as T2DM were examined in this study. LV and kidney isolations following 2 and 4 months of the development of T1DM were used to assess the remodelling changes and underlying transforming growth factor β1 (TGFβ1) activity, gene expression profile of the ECM and calcium mediators using histological, immunohistochemical and quantitative gene expression analyses compared to age-matched Wistar control rats.
Results: The results show that T1DM over 4 months can elicit severe structural and molecular changes in the LV and the kidney compared to 2 months of DM. The severity of these changes was significantly less in respective healthy age-matched control animals. The isolated ventricular cardiomyocytes from T1DM rats displayed altered cellular calcium (Ca2+) homeostasis and [Ca2+]i translating to alterations in mRNA abundance of key Ca2+ handling proteins, cardiac sarcoplasmic reticulum Ca2+ATPase 2a (SERCA2a), ryanodine receptor (RyR2), Na2+/Ca2+ exchanger, phospholamban (Plb), L-type Ca2+ channel proteins (Cav1.2 and Cav1.3), calmodulin2 (Calm2) and Ca2+/calmodulin-dependant protein kinase II delta (CaMK2d) were significantly (p<0.05) altered in DM compared to age-matched control animals. The results showed LV and kidney remodelling in the T1DM rats with increased ECM deposition that translated into increased gene expressions of key components (collagen 1α, collagen 3α, fibronectin and elastin) and modulators i.e. MMP2 and MMP9 and their tissue inhibitor (TIMP4), connective tissue growth factor (CTGF), integrin 5α and connexin 43 (Cx43) of the ECM. Molecular derangements underlying this phenotype included increased TGFβ1 transcription and activity, recapitulation of foetal gene phenotype atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) with marked hypertrophy, underscored by caspase-3 mediated cell apoptosis. Electron microscopic analysis revealed ultrastructural alterations in LV highlighted by increased mitochondrial number and altered mitochondrial population, whereas the kidney presented with increase glomerular basement membrane thickness in T1DM compared to controls. These data clearly show that adult vs young adult, in combination with STZ-induced T1DM, can elicit severe changes to both the heart and the kidney, respectively in structural, functional and biochemical alterations. The final part of the study revealed exercise training after 2-3 months may have beneficial effects in T2DM animals compared to sedentary control rats. Ventricular myocyte and shortening were generally well preserved despite alterations in mRNA gene expression encoding a variety of cardiac muscle proteins in the exercised trained adult GK diabetic rat. LV remodelling in GK rat presented with marked hypertrophy of cardiomyocytes and increased ECM deposition that altogether translated into increased ECM components and regulators which were reversed by exercise training.
Conclusions: The present results have demonstrated that T1DM, if left untreated, can lead to severe changes to both the heart and the kidney. These changes seem to occur at structural and molecular levels leading to dysfunction of the heart and kidney and the severity of the damage is enhanced over time. Data suggests that diabetic cardiomyopathy (DCM) may have possible origins in pro-fibrotic and pro-hypertrophic mechanisms. Moreover, this study demonstrates that physical exercise training continues to be one of the most valuable forms of non-pharmacological therapy in DM. Data concerning molecular signalling cascades and ECM phenotype is particularly significant as targeting features of structural remodelling may delay onset and severity of myocardial and renal complications.

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