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Hypertension has been a threat to the health of people, the mechanism of which, however, remains poorly understood. It is clinically related to loss of nephron function, glomerular sclerosis, or necrosis, resulting in renal functional declines. The mechanisms underlying hypertension's development and progression to organ damage, including hypertensive renal damage, remain to be fully elucidated. As a developing approach, epigenetics has been postulated to elucidate the phenomena that otherwise cannot be explained by genetic studies. The main epigenetic hallmarks, such as DNA methylation, histone acetylation, deacetylation, noncoding RNAs, and protein N-homocysteinylation have been linked with hypertension. In addition to contributing to endothelial dysfunction and oxidative stress, biologically active gases, including NO, CO, and H 2 S, are crucial regulators contributing to vascular remodeling since their complex interplay conducts homeostatic functions in the renovascular system. Importantly, epigenetic modifications also directly contribute to the pathogenesis of kidney damage via protein N-homocysteinylation. Hence, epigenetic modulation to intervene in renovascular damage is a potential therapeutic approach to treat renal disease and dysfunction. This review illustrates some of the epigenetic hallmarks and their mediators, which have the ability to diminish the injury triggered by hypertension and renal disease. In the end, we provide potential therapeutic possibilities to treat renovascular diseases in hypertension.

The kidney is an essential excretory organ that works as a filter of toxins and metabolic by-products of the human body and maintains osmotic pressure throughout life. The kidney undergoes several physiological, morphological, and structural changes with age. As life expectancy in humans increases, cell senescence in renal aging is a growing challenge. Identifying age-related kidney disorders and their cause is one of the contemporary public health challenges. While the structural abnormalities to the extracellular matrix (ECM) occur, in part, due to changes in MMPs, EMMPRIN, and Meprin-A, a variety of epigenetic modifiers, such as DNA methylation, histone alterations, changes in small non-coding RNA, and microRNA (miRNA) expressions are proven to play pivotal roles in renal pathology. An aged kidney is vulnerable to acute injury due to ischemia-reperfusion, toxic medications, altered matrix proteins, systemic hemodynamics, etc., non-coding RNA and miRNAs play an important role in renal homeostasis, and alterations of their expressions can be considered as a good marker for AKI. Other epigenetic changes, such as histone modifications and DNA methylation, are also evident in AKI pathophysiology. The endogenous production of gaseous molecule hydrogen sulfide (H 2 S) was documented in the early 1980s, but its ameliorative effects, especially on kidney injury, still need further research to understand its molecular mode of action in detail. H 2 S donors heal fibrotic kidney tissues, attenuate oxidative stress, apoptosis, inflammation, and GFR, and also modulate the renin-angiotensin-aldosterone system (RAAS). In this review, we discuss the complex pathophysiological interplay in AKI and its available treatments along with future perspectives. The basic role of H 2 S in the kidney has been summarized, and recent references and knowledge gaps are also addressed. Finally, the healing effects of H 2 S in AKI are described with special emphasis on epigenetic regulation and matrix remodeling.

Hypertension-associated dysbiosis is linked to several clinical complications, including inflammation and possible kidney dysfunction. Inflammation and TLR4 activation during hypertension result from gut dysbiosis-related impairment of intestinal integrity. However, the contribution of TLR4 in kidney dysfunction during hypertension-induced gut dysbiosis is unclear. We designed this study to address this knowledge gap by utilizing TLR4 normal (TLR4N) and TLR4 mutant (TLR4M) mice. These mice were infused with high doses of Angiotensin-II for four weeks to induce hypertension. Results suggest that Ang-II significantly increased renal arterial resistive index (RI), decreased renal vascularity, and renal function (GFR) in TLR4N mice compared to TLR4M. 16 S rRNA sequencing analysis of gut microbiome revealed that Ang-II-induced hypertension resulted in alteration of Firmicutes: Bacteroidetes ratio in the gut of both TLR4N and TLR4M mice; however, it was not comparably rather differentially. Additionally, Ang-II-hypertension decreased the expression of tight junction proteins and increased gut permeability, which were more prominent in TLR4N mice than in TLR4M mice. Concomitant with gut hyperpermeability, an increased bacterial component translocation to the kidney was observed in TLR4N mice treated with Ang-II compared to TLR4N plus saline. Interestingly, microbiota translocation was mitigated in Ang-II-hypertensive TLR4M mice. Furthermore, Ang-II altered the expression of inflammatory (IL-1β, IL-6) and anti-inflammatory IL-10) markers, and extracellular matrix proteins, including MMP-2, -9, -14, and TIMP-2 in the kidney of TLR4N mice, which were blunted in TLR4M mice. Our data demonstrate that ablation of TLR4 attenuates hypertension-induced gut dysbiosis resulting in preventing gut hyperpermeability, bacterial translocation, mitigation of renal inflammation and alleviation of kidney dysfunction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)