Department of Pharmacy
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Item Significance of LncRNAs in AKI-to-CKD transition: a therapeutic and diagnostic viewpoint(Elsevier, 2024-04) Gaikwad, Anil Bhanudas; Majumder, SyamantakAcute 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.Item Immunosuppressants against acute kidney injury: what to prefer or to avoid?(Taylor & Francis, 2024-03) Gaikwad, Anil BhanudasAcute 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.Item Apelinergic system in acute kidney injury: mechanistic insights and therapeutic potential(Elsevier, 2024-11) Gaikwad, Anil BhanudasAcute kidney injury (AKI) has emerged as a global health crisis, surpassing mortality rates associated with several cancers and heart failure. The lack of effective therapies, coupled with challenges in diagnosis and the high cost of kidney transplantation, underscores the urgent need to explore novel therapeutic targets and strategies for AKI. Understanding the intricate pathophysiology of AKI is paramount in this endeavor. The components of the apelinergic system—namely, apelin and elabela/toddler, along with their receptor—are prominently expressed in various kidney cells and have garnered significant attention in renal research. Recent studies have highlighted the renoprotective role of the apelinergic system in AKI. This system exerts its protective effects by modulating several pathophysiological processes, including reducing endoplasmic reticulum (ER) stress, improving mitochondrial dynamics, inhibiting inflammation and apoptosis, promoting diuresis through vasodilation of renal vasculature, and counteracting the effects of reactive oxygen species (ROS). Despite these advancements, the precise involvement of the apelinergic system in the progression of AKI remains unclear. Furthermore, the therapeutic potential of apelin-13 in AKI is not fully understood. This review aims to elucidate the role of the apelinergic system in AKI and its interactions with key pathomechanisms involved in the progression of AKI. Additionally, we discuss the current clinical status of exogenous apelin-13 therapy, providing insights that will guide future research on apelin against AKI.Item Molecular insights into P2X signalling cascades in acute kidney injury(Springer, 2024-01) Gaikwad, Anil BhanudasAcute 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.Item Hinokitiol prevents diabetic acute kidney injury by mitigating er stress(Wiley, 2025-02) Gaikwad, Anil BhanudasAcute kidney injury (AKI) in diabetic conditions often advances to chronic kidney disease (CKD), exacerbated by ischemia–reperfusion injury (IRI) through pathomechanisms such as endoplasmic reticulum (ER) stress and inflammation. Currently, available treatment options for diabetic AKI are not uniformly effective, highlighting the need for novel interventions. This study aimed to examine the renoprotective effects of hinokitiol, a natural tropolone compound, against diabetic AKI with its capability to decrease ER stress and inflammation, along with apoptosis. This study involved NRK-52E cells grown in-vitro under high-glucose conditions subjected to 10 mM sodium azide to elicit hypoxia/reperfusion injury (HRI). The expression of key ER stress markers like binding immunoglobulin binding protein (BiP), R/PKR-like ER kinase (PERK), and eukaryotic initiation factor-2 (eIF2α) as well as inflammatory proteins was markedly diminished by hinokitiol pretreatment (50 μM). Hinokitiol further reduced apoptosis in the NRK-52E cells. Similarly, in the in-vivo study, male Wistar rats with STZ-induced Type 1 diabetes (55 mg/kg, i.p.) were treated with hinokitiol 50 and 100 mg/kg/day i.p. for 5 days, followed by AKI induction via bilateral IRI. Hinokitiol pretreatment significantly reduced the elevated plasma blood urea nitrogen (BUN), creatinine, and urinary kidney injury molecule-1 (KIM-1) levels and tubular damage in diabetic AKI rats. Hinokitiol also reduced the respective ER stress protein expressions in diabetic AKI rats, as demonstrated by immunohistochemical analysis and immunoblotting. These findings suggest that hinokitiol alleviates diabetic AKI by modulating the PERK/CHOP/NF-κB axis, highlighting the likeliness of hinokitiol as a viable therapeutic technique for alleviating diabetic AKI.Item Renoprotective effect of esculetin against ischemic acute kidney injury-diabetic comorbidity(Taylor & Francis, 2024-02) Gaikwad, Anil Bhanudas; Jadhav, Hemant R.Mitophagy maintains cellular homeostasis by eliminating damaged mitochondria. Accumulated damaged mitochondria can lead to oxidative stress and cell death. Induction of the PINK1/Parkin-mediated mitophagy is reported to be renoprotective in acute kidney injury (AKI). Esculetin, a naturally available coumarin, has shown protective action against diabetic complications. However, its effect on AKI-diabetes comorbidity has not been explored yet. Therefore, we aimed to investigate the renoprotective effect of esculetin against AKI under diabetic conditions via regulating PINK1/Parkin-mediated mitophagy. For this, type 1 diabetic male Wistar rats were treated with two doses of esculetin (50 and 100 mg/kg/day orally) for five days followed by AKI induction by bilateral ischemic-reperfusion injury (IRI). NRK-52E cells grown in high glucose were exposed to sodium azide (10 mM) for induction of hypoxia/reperfusion injury (HRI) in-vitro. Esculetin (50 µM) treatment for 24 h was given to the cells before HRI. The in-vitro samples were utilized for cell viability and ΔΨm assay, immunoblotting, and immunofluorescence. Rats’ plasma, urine, and kidney samples were collected for biochemical analysis, histopathology, and western blotting. Our results showed a significant decrease in kidney injury-specific markers and increased expression of mitophagy markers (PINK1 and Parkin) with esculetin treatment. Moreover, esculetin prevented the HRI and hyperglycemia-induced decrease in ΔΨm and autophagosome marker. Also, esculetin therapy reduced oxidative stress via increased Nrf2 and Keap1 expression. Esculetin attenuated AKI under diabetic condition by preventing mitochondrial dysfunction via inducing PINK1/Parkin-mediated mitophagy, suggesting its potential as an effective therapy for preventing AKI-diabetes comorbidity.Item Network pharmacology combined with molecular docking and dynamics to assess the synergism of esculetin and phloretin against acute kidney injury-diabetes comorbidity(Springer, 2024-04) Jadhav, Hemant R.; Gaikwad, Anil BhanudasAcute 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.