A structure-based pharmacophore modelling approach to identify and design new neprilysin (NEP) inhibitors: An in silico-based investigation.

Neutral endopeptidase or neprilysin (NEP) cleaves the natriuretic peptides, bradykinin, endothelin, angiotensin II, amyloid ß protein, substance P, etc., thus modulating their effects on heart, kidney, and other organs. NEP has a proven role in hypertension, heart disease, renal disease, Alzheimer's, diabetes, and some cancers. NEP inhibitor development has been in focus since the US FDA approved a combination therapy of angiotensin II type 1 receptor inhibitor (valsartan) and NEP inhibitor (sacubitril) for use in heart failure. Considering the importance of NEP inhibitors the present work focuses on the designing of a potential lead for NEP inhibition. A structure-based pharmacophore modelling approach was employed to identify NEP inhibitors from the pool of 1140 chemical entities obtained from the ZINC database. Based on the docking score and pivotal interactions, ten molecules were selected and subjected to binding free energy calculations and ADMET predictions. The top two compounds were studied further by molecular dynamics simulations to determine the stability of the ligand-receptor complex. ZINC0000004684268, a phenylalanine derivative, showed affinity and complex stability comparable to sacubitril. However, in silico studies indicated that it may have poor pharmacokinetic parameters. Therefore, the molecule was optimized using bioisosteric replacements, keeping the phenylalanine moiety intact, to obtain five potential lead molecules with an acceptable pharmacokinetic profile. The works thus open up the scope to further corroborate the present in silico findings with the biological analysis.

Molecular insights into P2X signalling cascades in acute kidney injury.

Acute kidney injury (AKI) is a critical health issue with high mortality and morbidity rates in hospitalized individuals. The complex pathophysiology and underlying health conditions further complicate AKI management. Growing evidence suggests the pivotal role of ion channels in AKI progression, through promoting tubular cell death and altering immune cell functions. Among these channels, P2X purinergic receptors emerge as key players in AKI pathophysiology. P2X receptors gated by adenosine triphosphate (ATP), exhibit increased extracellular levels of ATP during AKI episodes. More importantly, certain P2X receptor subtypes upon activation exacerbate the situation by promoting the release of extracellular ATP. While therapeutic investigations have primarily focused on P2X4 and P2X7 subtypes in the context of AKI, while understanding about other subtypes still remains limited. Whilst some P2X antagonists show promising results against different types of kidney diseases, their role in managing AKI remains unexplored. Henceforth, understanding the intricate interplay between P2X receptors and AKI is crucial for developing targeted interventions. This review elucidates the functional alterations of all P2X receptors during normal kidney function and AKI, offering insights into their involvement in AKI. Notably, we have highlighted the current knowledge of P2X receptor antagonists and the possibilities to use them against AKI in the future. Furthermore, the review delves into the pathways influenced by activated P2X receptors during AKI, presenting potential targets for future therapeutic interventions against this critical condition.

Network pharmacology combined with molecular docking and dynamics to assess the synergism of esculetin and phloretin against acute kidney injury-diabetes comorbidity.

Acute kidney injury (AKI) is a global health concern with high incidence and mortality, where diabetes further worsens the condition. The available treatment options are not uniformly effective against the complex pathogenesis of AKI-diabetes comorbidity. Hence, combination therapies based on the multicomponent, multitarget approach can tackle more than one pathomechanism and can aid in AKI-diabetes comorbidity management. This study aimed to investigate the therapeutic potential of esculetin and phloretin combination against AKI-diabetes comorbidity by network pharmacology followed by validation by molecular docking and dynamics. The curative targets for diabetes, AKI, esculetin, and phloretin were obtained from DisGeNET, GeneCards, SwissTargetPrediction database. Further, the protein-protein interaction of the potential targets of esculetin and phloretin against AKI-diabetes comorbidity was investigated using the STRING database. Gene ontology and pathway enrichment analysis were performed with the help of the DAVID and KEGG databases, followed by network construction and analysis via Cytoscape. Molecular docking and dynamic simulations were performed to validate the targets of esculetin and phloretin against AKI-diabetes comorbidity. We obtained 6341 targets for AKI-diabetes comorbidity. Further, a total of 54 and 44 targets of esculetin and phloretin against AKI-diabetes comorbidity were retrieved. The top 10 targets for esculetin selected based on the degree value were AKR1B1, DAO, ESR1, PLK1, CA3, CA2, CCNE1, PRKN, HDAC2, and MAOA. Similarly, phloretin's 10 key targets were ACHE, CDK1, MAPK14, APP, CDK5R1, CCNE1, MAOA, MAOB, HDAC6, and PRKN. These targets were enriched in 58 pathways involved in the pathophysiology of AKI-diabetes comorbidity. Further, esculetin and phloretin showed an excellent binding affinity for these critical targets. The findings of this study suggest that esculetin and phloretin combination as a multicomponent multitarget therapy has the potential to prevent AKI-diabetes comorbidity.

Targeting polo-like kinase 1 to treat kidney diseases.

Globally, ∼850 million individuals suffer from some form of kidney disease. This staggering figure underscores the importance of continued research and innovation in the field of nephrology to develop effective treatments and improve overall global kidney health. In current research, the polo-like kinase (Plk) family has emerged as a group of highly conserved enzyme kinases vital for proper cell cycle regulation. Plks are defined by their N-terminal kinase domain and C-terminal polo-box domain, which regulate their catalytic activity, subcellular localization, and substrate recognition. Among the Plk family members, Plk1 has garnered significant attention due to its pivotal role in regulating multiple mitotic processes, particularly in the kidneys. It is a crucial serine-threonine (Ser-Thr) kinase involved in cell division and genomic stability. In this review, we delve into the types and functions of Plks, focusing on Plk1's significance in processes such as cell proliferation, spindle assembly, and DNA damage repair. The review also underscores Plk1's vital contributions to maintaining kidney homeostasis, elucidating its involvement in nuclear envelope breakdown, anaphase-promoting complex/cyclosome activation, and the regulation of mRNA translation machinery. Furthermore, the review discusses how Plk1 contributes to the development and progression of kidney diseases, emphasizing its overexpression in conditions such as acute kidney injury, chronic kidney disease, and so forth. It also highlights the importance of exploring Plk1 modulators as targeted therapies for kidney diseases in future. This review will help in understanding the role of Plk1 in kidney disease development, paving the way for the discovery and development of novel therapeutic approaches to manage kidney diseases effectively.

Immunosuppressants against acute kidney injury: what to prefer or to avoid?

BACKGROUND: Acute kidney injury (AKI) is a critical global health issue associated with high mortality rates, particularly in patients undergoing renal transplants and major surgeries. These individuals often receive immunosuppressants to dampen immune responses, but the impact of these drugs on AKI remains unclear. OBJECTIVE: This review aims to provide a detailed understanding of the effects of different classes of immunosuppressants against AKI, elucidating their role in either exacerbating or mitigating the occurrence or progression of AKI. METHODS: Several preclinical and clinical reports were analyzed to evaluate the impact of various immunosuppressants on AKI. Relevant preclinical and clinical studies were reviewed through different databases such as Scopus, PubMed, Google Scholar, and ScienceDirect, and official websites like https://clinicaltrials.gov to understand the mechanisms underlying the effects of immunosuppressants on kidney function. RESULTS AND DISCUSSION: Specific immunosuppressants have been linked to the progression of AKI, while others demonstrate renoprotective effects. However, there is no consensus on the preferred or avoided immunosuppressants for AKI patients. This review outlines the classes of immunosuppressants commonly used and their impact on AKI, providing guidance for physicians in selecting appropriate drugs to prevent or ameliorate AKI. CONCLUSION: Understanding the effects of immunosuppressants on AKI is crucial for optimizing patient care. This review highlights the need for further research to determine the most suitable immunosuppressants for AKI patients, considering both their efficacy and potential side effects.

Role of endoplasmic reticulum stress and autophagy in the transition from acute kidney injury to chronic kidney disease.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are global health concerns with increasing rates in morbidity and mortality. Transition from AKI-to-CKD is common and requires awareness in the management of AKI survivors. AKI-to-CKD transition is a main risk factor for the development of cardiovascular disease and progression to end-stage kidney disease. The mechanisms driving AKI-to-CKD transition are being explored to identify potential molecular and cellular targets for renoprotective drug interventions. Endoplasmic reticulum (ER) stress and autophagy are involved in the process of AKI-to-CKD transition. Excessive ER stress results in the persistent activation of unfolded protein response, which is an underneath cause of kidney cell death. Moreover, ER stress modulates autophagy and vice-versa. Autophagy is a degradation defensive mechanism protecting cells from malfunction. However, the underlying pathological mechanism involved in this interplay in the context of AKI-to-CKD transition is still unclear. In this review, we discuss the crosstalk between ER stress and autophagy in AKI, AKI-to-CKD transition, and CKD progression. In addition, we explore possible therapeutic targets that can regulate ER stress and autophagy to prevent AKI-to-CKD transition to improve the long-term prognosis of AKI survivors.

Epigenetic regulation of mitochondrial-endoplasmic reticulum dynamics in kidney diseases.

Kidney diseases are serious health problems affecting >800 million individuals worldwide. The high number of affected individuals and the severe consequences of kidney dysfunction demand an intensified effort toward more effective prevention and treatment. The pathophysiology of kidney diseases is complex and comprises diverse organelle dysfunctions including mitochondria and endoplasmic reticulum (ER). The recent findings prove interactions between the ER membrane and nearly all cell compartments and give new insights into molecular events involved in cellular mechanisms in health and disease. Interactions between the ER and mitochondrial membranes, known as the mitochondria-ER contacts regulate kidney physiology by interacting with each other via membrane contact sites (MCS). ER controls mitochondrial dynamics through ER stress sensor proteins or by direct communication via mitochondria-associated ER membrane to activate signaling pathways such as apoptosis, calcium transport, and autophagy. More importantly, these organelle dynamics are found to be regulated by several epigenetic mechanisms such as DNA methylation, histone modifications, and noncoding RNAs and can be a potential therapeutic target against kidney diseases. However, a thorough understanding of the role of epigenetic regulation of organelle dynamics and their functions is not well understood. Therefore, this review will unveil the role of epigenetic mechanisms in regulating organelle dynamics during various types of kidney diseases. Moreover, we will also shed light on different stress origins in organelles leading to kidney disease. Henceforth, by understanding this we can target epigenetic mechanisms to maintain/control organelle dynamics and serve them as a novel therapeutic approach against kidney diseases.

Potential of Renin-Angiotensin-Aldosterone System Modulations in Diabetic Kidney Disease: Old Players to New Hope!

Due to a tragic increase in the incidences of diabetes globally, diabetic kidney disease (DKD) has emerged as one of the leading causes of end-stage renal diseases (ESRD). Hyperglycaemia-mediated overactivation of the renin-angiotensin-aldosterone system (RAAS) is key to the development and progression of DKD. Consequently, RAAS inhibition by angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) is the first-line therapy for the clinical management of DKD. However, numerous clinical and preclinical evidences suggested that RAAS inhibition can only halt the progression of the DKD to a certain extent, and they are inadequate to cure DKD completely. Recent studies have improved understanding of the complexity of the RAAS. It consists of two counter-regulatory arms, the deleterious pressor arm (ACE/angiotensin II/AT1 receptor axis) and the beneficial depressor arm (ACE2/angiotensin-(1-7)/Mas receptor axis). These advances have paved the way for the development of new therapies targeting the RAAS for better treatment of DKD. In this review, we aimed to summarise the involvement of the depressor arm of the RAAS in DKD. Moreover, in modern drug discovery and development, an advance approach is the bispecific therapeutics, targeting two independent signalling pathways. Here, we discuss available reports of these bispecific drugs involving the RAAS as well as propose potential treatments based on neurohormonal balance as credible therapeutic strategies for DKD.

Toll-like receptors 2 and 4 stress signaling and sodium-glucose cotransporter-2 in kidney disease.

Kidney disease is the 6th fastest-growing cause of death and a serious global health concern that urges effective therapeutic options. The inflammatory response is an initial reaction from immune and parenchymal cells in kidney diseases. Toll-like receptors (TLR) 2 and 4 are highly expressed by various kidney cells and respond to 'signaling danger' proteins, such as high mobility group box binding protein 1 (HMGB1) and prompt the progression of kidney disease by releasing inflammatory mediators. Burgeoning reports suggest that both SGLT2 and ER stress elevates TLR2/4 signaling via different axis. Moreover, SGLT2 signaling aggravates inflammation under the disease condition by promoting the NLR family pyrin domain-containing three inflammasomes and ER stress. Intriguingly, TLR2/4 downstream adaptors activate ER stress regulators. The above-discussed interactions imply that TLR2/4 does more than immune response during kidney disease. Here, we discuss in detail evidence of the roles and regulation of TLR2/4 in the context of a relationship between ER stress and SGLT2. Also, we highlighted different preclinical studies of SGLT2 inhibitors against TLR2/4 signaling in various kidney diseases. Moreover, we discuss the observational and interventional evidence about the relation between TLR2/4, ER stress, and SGLT2, which may represent the TLR2/4 as a potential therapeutic target for kidney disease.

Klotho in kidney diseases: a crosstalk between the renin-angiotensin system and endoplasmic reticulum stress.

Klotho is a transmembrane anti-ageing protein that exists in three forms, i.e. α-Klotho, ß-Klotho and γ-Klotho, with distinct organ-specific expression and functions in the body. Here we focus on α-Klotho (hereafter Klotho), abundantly expressed by the distal and proximal convoluted tubules of the kidney. A significant decline in systemic and renal Klotho levels is a new hallmark for kidney disease progression. Emerging research portrays Klotho as a promising diagnostic and therapeutic target for diabetic and non-diabetic kidney disease. Even so, the underlying mechanisms of Klotho regulation and the strategies to restore its systemic and renal levels are still lacking. Angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers are the current standard of care for kidney diseases, but the molecular mechanisms for their nephroprotective action are still ambiguous. Moreover, endoplasmic reticulum (ER) stress also plays a crucial role in kidney disease progression. Few studies have claimed that the renin-angiotensin-aldosterone system (RAAS) has a direct relation with ER stress generation and vice versa in kidney disease. Interestingly, RAAS and ER stress modulation are associated with Klotho regulation in kidney disease. Here we focus on how the RAAS and ER stress connect with Klotho regulation in kidney disease. We also discuss Klotho and ER stress in an alliance with the concept of haemodynamic and metabolic overload in kidney disease. In addition, we highlight novel approaches to implement Klotho as a therapeutic target via RAAS and ER stress modulation for the treatment of diabetic and non-diabetic kidney diseases.

Inhibition of endoplasmic reticulum stress combined with activation of angiotensin-converting enzyme 2: novel approach for the prevention of endothelial dysfunction in type 1 diabetic rats.

Persistent hyperglycemia in type 1 diabetes triggers numerous signaling pathways, which may prove deleterious to the endothelium. As hyperglycemia damages the endothelial layer via multiple signaling pathways, including enhanced oxidative stress, downregulation of angiotensin-converting enzyme 2 signaling, and exacerbation of endoplasmic reticulum (ER) stress, it becomes difficult to prevent injury using monotherapy. Thus, the present study was conceived to evaluate the combined effect of ER stress inhibition along with angiotensin-converting enzyme 2 activation, two major contributors to hyperglycemia-induced endothelial dysfunction, in preventing endothelial dysfunction associated with type 1 diabetes. Streptozotocin-induced diabetic animals were treated with either diminazene aceturate (5 mg·kg-1 per day, p.o.) or tauroursodeoxycholic acid, sodium salt (200 mg·kg-1 per day i.p.), or both for 4 weeks. Endothelial dysfunction was evaluated using vasoreactivity assay, where acetylcholine-induced relaxation was assessed in phenylephrine pre-contracted rings. Combination therapy significantly improved vascular relaxation when compared with diabetic control as well as monotherapy. Restoration of nitrite levels along with prevention of collagen led to improved vasodilatation. Moreover, there was an overall reduction in aortic oxidative stress. We conclude that by simultaneously inhibiting ER stress and activating angiotensin-converting enzyme 2 deleterious effects of hyperglycemia on endothelium were significantly alleviated. This could serve as a novel strategy for the prevention of endothelial dysfunction.

Role of dietary modifications in the management of type 2 diabetic complications.

Diabetes is a chronic metabolic disorder with a high rate of morbidity and mortality. Insufficient insulin secretion and insulin action are two major causes for the development of diabetes, which is characterized by a persistent increase in blood glucose level. Diet and sedentary life style play pivotal role in development of vascular complications in type 2 diabetes. Dietary modification is associated with a reprogramming of nutrient intake, which are proven to be effective for the management of diabetes and associated complications. Dietary modifications modulate various molecular key players linked with the functions of nutrient signalling, regulation of autophagy, and energy metabolism. It activates silent mating type information regulation 2 homolog1 (SIRT1) and AMP-activated protein kinase (AMPK). AMPK mainly acts as an energy sensor and inhibits autophagy repressor Mammalian target of rapamycin (mTOR) under nutritional deprivation. Under calorie restriction (CR), SIRT1 gets activated directly or indirectly and plays a central role in autophagy via the regulation of protein acetylation. Dietary modification is also effective in controlling inflammation and apoptosis by decreasing the level of pro-inflammatory cytokines like nuclear factor kappa- beta (NF-kß), tissue growth factor-beta (TGF-ß), tissue necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). It also improves glucose homeostasis and insulin secretion through beta cell regeneration. This indicates calorie intake plays a crucial role in the pathogenesis of type 2 diabetes-associated complications. The present review, emphasizes the role of dietary modifications in diabetes and associated complications.

Role of SET7/9 in the progression of ischemic renal injury in diabetic and non-diabetic rats.

SET domain with lysine methyltransferase 7/9 (Set7/9), a histone lysine methyltransferase (HMT), recently suggested to exert a critical role among kidney disorders, whereas its role in diabetes associated IRI co-morbidity remains complete elusive. The present study aimed to understand the role of SET7/9 and histone methylation in regulation of inflammatory signaling under IRI in diabetes mellitus and non-diabetic rats. Our results demonstrated that IRI caused renal dysfunction via increased blood urea nitrogen (BUN) levels in ND and DM rats. The NF-κB mediated inflammatory cascade like increased p-NF-κB, reduced IκBα levels followed by enhanced leukocyte infiltration as shown by increased MCP-1 expressions. IRI results in increased histone H3 methylation at lysine 4 and 36 (H3K4Me2, H3K36Me2), and decreased histone H3 methylation at lysine 9. Additionally, IRI increased the protein and mRNA expression of H3K4Me2 specific histone methyltransferase-SET7/9 in DM and ND rats. The abovementioned results remain prominent in DM rats compared to ND rats followed by IRI. Further, treatment with a novel SET7/9 inhibitor; cyproheptadine, significantly improved renal functioning via reducing the BUN levels in ND and DM rats. Hence, this study demonstrated the role of SET7/9 in mediating active transcription via H3K4Me2, ultimately regulated the NFκB-mediated inflammatory cascade. Therefore, SET7/9 can be explored as novel target for drug development against IRI under DM and ND conditions.

Diabetic nephropathy: The regulatory interplay between epigenetics and microRNAs.

Diabetic nephropathy (DN) is still one of the leading causes of end-stage renal disease despite the emergence of different therapies to counter the metabolic, hemodynamic and fibrotic pathways, implicating a prominent role of genetic and epigenetic factors in its progression. Epigenetics is the study of changes in the expression of genes which may be inheritable and does not involve a change in the genome sequence. Thrust areas of epigenetic research are DNA methylation and histone modifications. Noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs) control the expression of genes via post-transcriptional mechanisms. However, the regulation by epigenetic mechanisms and miRNAs are not completely distinct. A number of emerging reports have revealed the interplay between epigenetic machinery and miRNA expression, particularly in cancer. Further research has proved that a feedback loop exists between miRNA expression and epigenetic regulation in disorders including DN. Studies showed that different miRNAs (miR-200, miR-29 etc.) were found to be regulated by epigenetic mechanisms viz. DNA methylation and histone modifications. Conversely, miRNAs (miR-301, miR-449 etc.) themselves modulated levels of DNA methyltranferases (DNMTs) and Histone deacetylases (HDACs), enzymes vital to epigenetic modifications. With already few FDA approved epigenetic -modulating drugs (Vorinostat, Decitabine) in the market and miRNA therapeutic drugs under clinical trial it becomes imperative to analyze the possible interaction between the two classes of drugs in the modulation of a disease process. The purpose of this review is to articulate the interplay between miRNA expression and epigenetic modifications with a particular focus on its impact on the development and progression of DN.

Compound 21 and Telmisartan combination mitigates type 2 diabetic nephropathy through amelioration of caspase mediated apoptosis.

The current study aimed to understand the role of novel, highly selective, orally active, non-peptide Angiotensin II type 2 receptor (AT2R) agonist, Compound 21 and its potential additive effect with Telmisartan on apoptosis and underlying posttranslational modifications in a non-genetic murine model for type 2 diabetic nephropathy (T2DN). An experimental model for T2DN was developed by administering low dose Streptozotocin in high fat diet fed male Wistar rats, followed by their treatment with Telmisartan, C21 or their combination. Our results demonstrated that C21 and Telmisartan combination attenuated metabolic and renal dysfunction, renal morphological and micro-architectural aberrations and hemodynamic disturbances in type 2 diabetic rats. The anti-apoptotic and anti-inflammatory effects of Telmisartan were significantly accentuated by C21 indicated by expression of apoptotic markers (Parp1, Caspase 8, Caspase 7, cleaved PARP and cleaved Caspase 3) and NF-κB mediated inflammatory molecules like interleukin 6, tumour necrosis factor alpha; monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1. C21 was found to improve Telmisartan mediated reversal of histone H3 acetylation at lysine 14 and 27 and expression of histone acetyl transferase, p300/CBP-associated factor also known to regulate NF-κB activity and DNA damage response. C21 in combination with Telmisartan markedly mitigates caspase mediated apoptosis and NF-κB signalling in T2D kidney, which could be partially attributed to its influence on PCAF mediated histone H3 acetylation. Hence further research should be done to develop this combination to treat T2DN.

Hidden targets of ubiquitin proteasome system: To prevent diabetic nephropathy.

Diabetic nephropathy (DN) is the major cause of end stage renal failure. Although, several therapeutic targets have emerged to prevent the progression of DN, the number of people with DN still continues to rise worldwide, suggesting an urgent need of novel targets to prevent DN completely. Currently, the role of ubiquitin proteasome system (UPS) has been highlighted in the pathogenesis and progression of various diseases like obesity, insulin resistance, atherosclerosis, cancers, neurodegerative disorders and including secondary complications of diabetes. UPS mainly involves in protein homeostatis through ubiquitination (post translational modification) and proteasomal degradation of various proteins. Ubiquitination, not only involves in proteasomal degradation, but also directs the substrate proteins to participate in multitude of cell signalling pathways. However, very little is known about ubiquitination and UPS in the progression of DN. This review mainly focuses on UPS and its components including E2 conjugating enzymes, E3 ligases and deubiquitinases (DUBs) in the development of DN and thus may help us to find novel therapeutic targets with in UPS to prevent DN completely in future.

Histone H2AK119 and H2BK120 mono-ubiquitination modulate SET7/9 and SUV39H1 in type 1 diabetes-induced renal fibrosis.

Hyperglycaemia-induced expression of extracellular matrix (ECM) components plays a major role in the development of diabetic nephropathy (DN). The epigenetic mechanisms that modulate ECM gene expression in DN remain unclear. Therefore, we examined the role of histone H2A and H2B monoubiquitination on epigenetic chromatin marks, such as histone H3 lysine dimethylation (H3K4Me2, H3K9Me2 and H3K79Me2) in type 1 diabetic rat kidney. Hyperglycaemia increased collagen deposition and Col1a1 gene expression. In whole kidney of diabetic animals, both H2AK119 mono-ubiquitination (H2AK119Ub) and H2BK120 mono-ubiquitination (H2BK120Ub) were found to be increased, whereas, in glomeruli of diabetic animals, expression of both H2AK119Ub and H2BK120Ub was reduced. Changes in ubiquitin proteasome system components like increased Rnf2 (H2A-specific E3 ligase) and decreased H2A- and H2B-specific deubiquitinases (ubiquitin-specific proteases 7, 16, 21 and 22) were also observed. Globally increased levels of chromatin marks associated with active genes (H3K4Me2 and H3K79Me2) and decreased levels of repressive marks (H3K9Me2) were also observed. Hyperglycaemia also increased the protein expression of SET7/9 and decreased the expression of SUV39H1. We also showed the decreased occupancy of H2AK119Ub and H2BK120Ub on the promoters of Set7/9 and Suv39h1 in diabetic kidney. In addition, methylation marks regulated by H2AK119Ub (H3K27Me2 and H3K36Me2) and H2BK120Ub (H3K4Me2 and H3K79Me2) were also found to be altered on the promoters of Set7/9 and Suv39h1 Taken together, these results show the functional role of H2AK119Ub and H2BK120Ub in regulating histone H3K4Me2 and H3K9Me2 through modulating the expression of SET7/9 and SUV39H1 in the development of diabetic renal fibrosis.

E3 ubiquitin ligases as novel targets for inflammatory diseases.

Ubiquitination is one of the post translational modifications which decide the fate of various proteins in the cells, by either directing them towards proteasomal degradation or participation in several cell signalling pathways. Recently, the role of ubiquitination has been unravelled in pathogenesis and progression of various diseases, where inflammation is critical, like obesity, insulin resistance, atherosclerosis, angiotensin-II induced cardiac inflammation and asthma. E3 ligases are known to be instrumental in regulation of the inflammatory cascade. This review focuses on the role of different E3 ligases in the development of inflammatory diseases and thus may help us to target these E3 ligases in future drug discovery to prevent inflammation.

Esculetin attenuates alterations in Ang II and acetylcholine mediated vascular reactivity associated with hyperinsulinemia and hyperglycemia.

Esculetin (6, 7- dihydroxycoumarin) was found to be protective against hepatic and renal damage associated with Streptozotocin (STZ) induced type 1 diabetes, because of its radical scavenging property. However, there are no reports regarding its effect on vascular dysfunction under hyperinsulinemic and hyperglycemic conditions. Hence, the present study aimed to investigate the effect of esculetin on vascular dysfunction under these conditions. Non-genetic model of hyperinsulinemia and hyperglycemia were developed by high fat diet (HFD) feeding and HFD + Streptozotocin (STZ, 35 mg/kg, I.P) treatment in Wistar rats, respectively. Esculetin was administered at 50 and 100 mg/kg/day (P.O, 2 weeks) doses and biochemical, vascular reactivity and immunohistochemical experiments were performed to assess the effect of esculetin on vascular dysfunctions. Esculetin treatment significantly attenuates metabolic perturbations, alleviates insulin levels in hyperinsulinemic condition. Thoracic aorta of hyperinsulinemic and hyperglycemic rats showed hyper-responsiveness to Ang II mediated contraction and impaired acetylcholine mediated relaxation, and esculetin attenuates alterations in vascular reactivity to Ang II and acetylcholine challenges. In addition, immunohistochemical evaluations revealed that esculetin prevents increase in AT1R, AT2R, Keap1, TGF-ß, and decrease in ACE2 expression in aorta of hyperinsulinemic and hyperglycemic rats.

Significance of LncRNAs in AKI-to-CKD transition: A therapeutic and diagnostic viewpoint.

Acute kidney injury to chronic kidney disease (AKI-to-CKD) transition is a complex intermingling of characteristics of both AKI and CKD. Pathophysiologically, the transition lasts seven days after the AKI episode and thereafter silently progresses towards CKD. Growing reports confirm that the AKI-to-CKD transition is heavily regulated by epigenetic modifiers. Long non-coding RNAs (lncRNAs) share a diverse role in gene regulation at transcriptional and translational levels and have been reported to be involved in the regulation and progression of AKI-to-CKD transition. Several lncRNAs have been considered potential biomarkers for diagnosing kidney disease, including AKI and CKD. Targeting lncRNAs gives a promising therapeutic strategy against kidney diseases. The primitive role of lncRNA in the progression of the AKI-to-CKD transition is yet to be fully understood. As known, the lncRNAs could be used as a biomarker and a therapeutic target to halt the CKD development and progression after AKI. This review aims to deepen our understanding of the current knowledge regarding the involvement of lncRNAs in the AKI-to-CKD transition. This review primarily discusses the role of lncRNAs and the change in their mechanisms during different stages of kidney disease, such as in AKI, AKI-to-CKD transition, and CKD. Further, we have discussed the potential diagnostic and pharmacological outcomes of targeting lncRNAs to prevent or slow the progression of AKI-to-CKD transition.