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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.

Klotho is a transmembrane anti-ageing protein that exists in three forms, i.e. α-Klotho, β-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.

Kidney disease affects more than 10% of the worldwide population and causes significant morbidity and mortality. Epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) play a pivotal role in the progression of kidney disease. These epigenetic mechanisms are reversible and majorly involved in regulating gene expression of inflammatory, fibrotic, and apoptotic proteins. Emerging data suggest that the Toll-like receptor 2 and Toll-like receptor 4 (TLR2 and TLR4) are expressed by almost all types of kidney cells and known for promoting inflammation by recognizing damage-associated molecular proteins (DAMPs). Epigenetic mechanisms regulate TLR2 and TLR4 signaling in various forms of kidney disease where different histone modifications promote the transcription of the TLR2 and TLR4 gene and its ligand high mobility group box protein 1 (HMGB1). Moreover, numerous long non-coding RNAs (LncRNAs) and microRNAs (miRNAs) modulate TLR2 and TLR4 signaling in kidney disease. However, the precise mechanisms behind this regulation are still enigmatic. Studying the epigenetic mechanisms involved in the regulation of TLR2 and TLR4 signaling in the development of kidney disease may help in understanding and finding novel therapeutic strategies. This review discusses the intricate relationship of epigenetic mechanisms with TLR2 and TLR4 in different forms of kidney diseases. In addition, we discuss the different lncRNAs and miRNAs that regulate TLR2 and TLR4 as potential therapeutic targets in kidney disease.

Acute kidney injury (AKI) is a collection of clinical syndromes with persistent increases in morbidity and mortality rates. Hyperglycemia is a risk factor for AKI development. Renin-angiotensin-aldosterone system (RAS) disequilibrium and Klotho downregulation also play a pivotal role in the pathogenesis of AKI. Moreover, the relationship between Klotho and ACE2 (a component of non-conventional RAS) regulation in AKI remains an unexplored area of research. Hence, in this study, we investigated ACE2 and Klotho regulation in AKI using ischemic Wistar rats and NRK52E cells under normal and hyperglycemic conditions. Our findings suggested that hyperglycemia exacerbates renal ischemia-reperfusion injury (IRI)/hypoxia-reperfusion injury (HRI) induced AKI. Systemic and renal Klotho deficiency is a novel hallmark of AKI. Additionally, ACE2 is a protective component of the RAS, and its inhibition/deficiency leads to inflammation, apoptosis, Klotho downregulation, and thus AKI development. However, ACE2 activation resulted in the amelioration of AKI. Importantly, ACE2 plays an important role in Klotho upregulation, which might act as an intermediate for ACE2-mediated reno-protection. In conclusion, ACE2 activator i.e. DIZE restored endogenous ACE2-Ang-(1-7)-Klotho level, inhibited apoptosis and inflammation, and ameliorates IRI/HRI induced AKI under diabetic and non-diabetic conditions. Hence, in future, targeting ACE2-Ang-(1-7)-Klotho axis may prove a novel therapeutic strategy against AKI, where further preclinical and clinical investigations are required to verify the clinical potential of this finding.

Background and Aims In clinical settings, diabetics remain on higher risk of ischemic renal injury (IRI) than nondiabetic patients. In addition, IRI predisposes distant organs to dysfunction such as neurological impairments via activation of the pressor arm of renin-angiotensin system (RAS). In contrast, the role of depressor arm of RAS on IRI-associated neurological sequalae remains elusive. Hence, this study explored the role of angiotensin II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in IRI-associated neurological dysfunctions under nondiabetic (ND) and diabetes mellitus (DM) condition. Method Type 1 diabetes was induced by injecting streptozotocin (55 mg/kg i.p.). ND and DM rats with bilateral IRI were treated with AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator-Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) per se or in combination therapy. Behavioural, biochemical, and histopathological analysis were done to assess IRI-induced neurological impairment. Moreover, immunohistochemistry, ELISA and qRT-PCR experiments were conducted for molecular mechanism analysis. Result In ND and DM rats, IRI caused hippocampal complications as evidenced by increased MDA and nitrite levels, augmented inflammatory cytokines (granulocyte colony stimulating factor, glial fibrillary acidic protein), altered protein and mRNA expressions of Ang II, Ang-(1-7), AT1R, AT2R and MasR. In contrast, concomitant therapy of C21 and Dize effectively normalised aforementioned hippocampal alterations. The protective effect of combination therapy was exerted due to augmented protein and mRNA levels of depressor arm components. Conclusion The current study demonstrated the protective role of AT2R agonist and ACE2 activator in IRI-associated neurological dysfunction through preventing oxidative stress, inflammation and upregulating brain depressor arm of RAS under ND and DM conditions.

Coronavirus disease 19 (COVID-19) originated in Wuhan, China, in December 2019 has been declared pandemic by World Health Organization due to an exponential rise in the number of infected and deceased persons across the globe. Emerging reports suggest that susceptibility and mortality rates are higher in patients with certain comorbidities when compared to the average population. Cardiovascular diseases and diabetes are important risk factors for a lethal outcome of COVID-19. Extensive research ensuing the outbreak of coronavirus-related severe acute respiratory syndrome in the year 2003, and COVID-19 recently revealed a role of renin–angiotensin system (RAS) components in the entry of coronavirus wherein angiotensin-converting enzyme 2 (ACE2) had garnered the significant attention. This raises the question whether the use of RAS inhibitors, the backbone of treatment of cardiovascular, neurovascular, and kidney diseases could increase the susceptibility for coronavirus infection or unfortunate outcomes of COVID-19. Thus, currently, there is a lack of consensus regarding the effects of RAS inhibitors in such patients. Moreover, expert bodies like American Heart Association, American College of Cardiology, and so on have now released official statements that RAS inhibitors must be continued, unless suggested otherwise by a physician. In this brief review, we will elaborate on the role of RAS and ACE2 in pathogenesis of COVID-19. Moreover, we will discuss the potential effect of the use and disuse of RAS inhibitors in patients having COVID-19 with cardiometabolic comorbidities.

Aims LCZ696, a first-generation dual angiotensin receptor-neprilysin inhibitor (ARNi), is effective in treating heart failure patients. However, the role of ARNis in treating diabetic cardiomyopathy is poorly understood. This study evaluates the efficacy of a novel combination of telmisartan [angiotensin receptor blocker (ARB)] and thiorphan [neprilysin inhibitor (NEPi)] in ameliorating diabetic cardiomyopathy while, at the same time, exploring the relevant underlying molecular mechanism(s). Methods and results Diabetes was induced by administration of streptozotocin (55 mg/kg, i.p.) in male Wistar rats. After 4 weeks, diabetic rats were subjected to either thiorphan (0.1 mg/kg/day, p.o.) or telmisartan (10 mg/kg/day, p.o.) monotherapy, or their combination, for a period of 4 weeks. Metabolic and morphometric alterations, failing ventricular functions, and diminished baroreflex indicated development of diabetic cardiac complications. Apart from morphometric alterations, all pathological consequences were prevented by telmisartan and thiorphan combination therapy. Diabetic rats exhibited significant modulation of the natriuretic peptide system, a key haemodynamic regulator; this was normalized by combination therapy. Histopathological studies showed augmented myocardial fibrosis, demonstrated by increased % PSR-positive area, with combination therapy giving the best improvement in these indices. More importantly, the combination of thiorphan and telmisartan was superior in attenuating inflammatory (NF-κB/MCP-1), profibrotic (TGF-β/Smad7) and apoptotic (PARP/Caspase-3) cascades compared to respective monotherapies when treating rats with diabetic cardiomyopathy. In addition, diabetic heart chromatin was in a state of active transcription, indicated by increased histone acetylation (H2AK5Ac, H2BK5Ac, H3K9Ac, and H4K8Ac) and histone acetyltransferase (PCAF and Ac-CBP) levels. Interestingly, combination treatment was sufficiently potent to normalize these alterations. Conclusion The protective effect of novel ARB and NEPi combination against diabetic cardiomyopathy can be attributed to inhibition of inflammatory, profibrotic, and apoptotic cascades. Moreover, reversal of histone acetylation assists its protective effect.

Micro and macro vascular complications under diabetic condition are the responses to pathological stimuli exerted by up regulated renin angiotensin system (RAS) via deteriorating vascular physiology. Up-regulated RAS could influence in the adaptive mechanisms of target tissues to alter the abundance of angiotensin II type 1 receptor (AT1) and angiotensin II type 2 receptor (AT2). Such differential regulation of AT1 and AT2 have been reported to be associated with post-translational histone modifications (PTHMs). Additionally, recent evidences provide, esculetin (6,7-dihydroxycoumarin) reverses post-translational histone modifications (PTHMs) in diabetic cardiomyopathy and nephropathy. On account of these evidences, we further pursued this study to investigate the effects of esculetin on PTHMs in progressive vascular complications under insulin resistance (IR) and type 2 diabetic (T2D) conditions. Esculetin treatment in both IR and T2D conditions substantially improved vascular reactivity, increased eNos and decreased Vcam1 mRNA levels, and reduced collagen deposition in rat thoracic aorta. Further, the fold changes in At1 and At2 receptor mRNA in IR and T2D were reversed by esculetin treatment. Modifications in histone H2B lysine 120 monoubiquitination (H2BK120Ub) were also reversed in esculetin treatment group. Further, modification in the occupancy of H2BK120Ub at At1a, At2, Tgfβ and Mcp1 promoter genes was evidenced by treatment with esculetin. Taken together, our investigation concluded with the involvement of esculetin in the amelioration of vascular perturbation by modifying H2BK120Ub along with occupancy at At1, At2, Tgfβ1 and Mcp1 promoter gene.

Background and Purpose Angiotensin converting enzyme 2 (ACE2) shows its protective actions through degrading Ang II. ACE2 activity and its expression was found to be reduced in glomeruli of diabetic patients as well as in animal models of diabetes. Several recent studies have also showed the potential role of recombinant ACE2 administration in preventing diabetic nephropathy (DN). Hence, we hypothesized that ACE2 activator, diminazene aceturate (DIZE) may be beneficial in preventing DN. Experimental Approach Male Wistar rats were rendered diabetic using a single dose of Streptozotocin (55mg kg-1, i.p.). After 4 weeks, diabetic animals were grouped in to respective groups and the drug, DIZE, low dose (5mg kg-1day-1), high dose (15mg kg-1day-1) and high dose in presence of AT2 blocker (PD123319, 10mg kg-1day-1) was administered. At the end, kidneys from all the groups were collected and processed separately for glomerular isolation, protein isolation, mRNA extraction and for immunohistochemical studies. Key Results DIZE administration restored the ACE2 expression in glomeruli and increased the AT2 expression in whole kidney and isolated glomeruli of diabetic animals. DIZE administration, reduced the Ang II levels and increased Ang 1-7 levels in diabetic kidney. However, AT2 blockade, reversed all these actions of DIZE. Conclusion and Implications DIZE treatment reduced the diabetes induced renal damage through inhibiting fibrosis and apotosis. Moreover, DIZE failed to show its protective actions in presence of AT2 blocker. Taken together, these results suggest the protective role of DIZE in preventing DN through ACE2/Ang 1-7/AT2 axis.

Esculetin, a naturally occurring 6,7-dihydroxy derivative of coumarin has shown its potential role in various non-communicable diseases (NCDs) including obesity, diabetes, cardiovascular, renal failure, cancer and neurological disorders. NCDs, responsible for about 70% of the deaths occurring globally are majorly attributed to tobacco or alcohol abuse, sedentary lifestyle, and unhealthy diets. It can be managed by improving access to cost-effective treatment, care and prevention. The beneficial effects of esculetin in NCDs have been ascribed to its antioxidant, anti-proliferative and cytoprotective potential. This review attempts to summarize the beneficial effects shown by the emerging molecule and the underlying mechanisms. This may help us in improving our understanding of the molecule and may encourage the researchers to ponder over further development of esculetin as a potential therapeutic intervention in NCDs.

This study explored the role of the depressor arm of renin-angiotensin system (RAS) on ischemic renal injury (IRI)-associated cardio-hepatic sequalae under non-diabetic (ND) and diabetes mellitus (DM) conditions. Firstly, rats were injected with Streptozotocin (55 mg/kg i.p.) to develop DM. ND and DM rats underwent Bilateral IRI followed by 24 h of reperfusion. Further, ND and DM rats were subjected to AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator- Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) per se or its combination therapy. As results, IRI caused cardio-hepatic injuries via altered oxidant/anti-oxidant levels, elevated inflammatory events, and altered protein expressions of ACE, ACE2, Ang II, Ang-(1-7) and urinary AGT. However, concomitant therapy of AT2R agonist and ACE2 activator exerts a protective effect in IRI-associated cardio-hepatic dysfunction as evidenced by inhibited oxidative stress, downregulated inflammation, and enhanced cardio-hepatic depressor arm of RAS under ND and DM conditions.

Besides assisting the maintenance of blood pressure and sodium homeostasis, the renin-angiotensin system (RAS) plays a pivotal role in pathogenesis of acute kidney injury (AKI). The RAS is equipped with two arms i) the pressor arm composed of Angiotensin II (Ang II)/Angiotensin converting enzyme (ACE)/Angiotensin II type 1 receptor (AT1R) also called conventional RAS, and ii) the depressor arm consisting of Angiotensin (1-7) (Ang 1-7)/Angiotensin converting enzyme 2 (ACE2)/MasR known as non-conventional RAS. Activation of conventional RAS triggers oxidative stress, inflammatory, hypertrophic, apoptotic, and pro-fibrotic signaling cascades which promote AKI. The preclinical and clinical studies have reported beneficial as well as deleterious effects of RAS blockage either by angiotensin receptor blocker or ACE inhibitor in AKI. On the contrary, the depressor arm opposes the conventional RAS, has beneficial effects on the kidney but has been less explored in pathogenesis of AKI. This review focuses on significance of RAS in pathogenesis of AKI and provides better understanding of novel and possible therapeutic approaches to combat AKI.

Diabetes is an enormous and ever-growing calamity and a global public health threat of the 21st century. Besides insulin and oral hypoglycaemic drugs, blockage of the renin-angiotensin system (RAS) denotes a key pharmacotherapy for the management of cardiovascular (CVD) and chronic kidney diseases (CKD), which are the leading causes of disability and death among diabetic patients. Neprilysin (NEP) inhibition, auxiliary to RAS blockage increases the bioavailability of natriuretic peptides and benefits the cardio-renal system. Omapatrilat, a dual angiotensin-converting enzyme (ACE) and NEP inhibitor has been reported to show superior anti-hypertensive, anti-atherosclerotic, insulin-sensitizing, cardiovascular and renoprotective effects to ACE inhibitors in experimental animal models for diabetes. In clinical trials on hypertensive subjects Omapatrilat increased the risk of angioedema due to which its further development as anti-hypertensive drug was hampered. This event prompted the development of angiotensin receptor neprilysin inhibitors (ARNi). The first representative of ARNi, LCZ696 (Sacubitril/ Valsartan) halted cardiovascular and renal functional decline and hence protected against CKD and CVD. Recently, LCZ696 was approved by U.S. Food and Drug Administration for the treatment of heart failure. This concise review intends to summarise the currently available reports on NEPi as a therapeutic intervention to treat CVD and CKD associated with diabetes.

One of the protective actions of angiotensin converting enzyme-2 (ACE2) is the inactivation of angiotensin II. Expression and activity of ACE2 was reduced in glomeruli of diabetic patients and in animal models of diabetes. Recently the potential role of recombinant ACE2 administration in preventing diabetic nephropathy (DN) has been shown. Here we have tested the effects of the ACE2 activator, diminazene aceturate (DIZE), in a model of DN.Male Wistar rats were rendered diabetic using a single dose of streptozotocin (55 mg·kgTreatment with DIZE restored ACE2 expression in glomeruli and increased expression of ATDIZE treatment reduced diabetes-induced renal damage as shown by reduction of fibrosis and apoptosis. These protective actions of DIZE were blocked by the AT

Background. Distinct histone modifications regulate gene expression in certain diseases but little is known about histone epigenetics in diabetic nephropathy. The current study examined the role of histone epigenetics in development and progression of nephropathy in db/db mice. Methods. We studied kidney damage in 6-month-old nondiabetic mice and type 2 diabetic db/db mice that underwent either sham surgery or uninephrectomy at 6 weeks of age which accelerates glomerulosclerosis in db/db mice via glomerular hyperfiltration. Histone H3K9 and H3K23 acetylation, H3K4 and H3K9 dimethylation and H3 phosphorylation at serine 10 was explored by western blotting of renal histone extracts. Results. Uninephrectomy in C57BL/6 mice or onset of diabetes in type 2 diabetes reduced renal H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10. In contrast, H3K9 and H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10 were significantly increased in uninephrectomized db/db mice. The disease pattern of these mice is characterized by an increased glomerular cell proliferation, severe glomerulosclerosis, albuminuria and glomerular filtration rate reduction. Treating uninephrectomized db/db mice with a Mcp-1/Ccl2 antagonist prevented the histopathological damage and the aforementioned histone modification abnormalities of advanced diabetic glomerulosclerosis. Conclusion. We conclude that advanced diabetic nephropathy is associated with increased renal H3K9 and H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10 that enhance chromatin unfolding and gene expression.

Background and purpose: Curcumin has been used to treat cancer, diabetes and other pathologies. However, little is known regarding its role in altering post-translational modifications of histone H3. A recent report suggests that acute hyperglycaemia induces a global down-regulation of gene expression in human tissues and epigenetic regulation of gene expression could be a novel mechanism underlying the pathological processes of hyperglycaemia. The present study was undertaken to examine changes in histone modification by curcumin treatment which prevents development of type I diabetic nephropathy. Experimental approach: Male Sprague-Dawley rats were rendered diabetic using a single dose of streptozotocin (55 mg kg−1, i.p.). Diabetic nephropathy was assessed by measurements of blood urea nitrogen, albumin and creatinine levels. Post-translational modifications of histone H3, heat shock protein-27 (HSP-27) and mitogen-activated protein (MAP) kinase p38 expression were examined by western blotting. Key results: Treatment of diabetic rats with curcumin significantly decreased blood urea nitrogen and creatinine and increased albumin; variables associated with the development of diabetic nephropathy. There were also increased levels of HSP-27 and MAP kinase (p38) in diabetic kidney. However, curcumin treatment prevented this increase in HSP-27 and p38 expression. Moreover, at nuclear level curcumin prevented the decrease in dephosphorylation and increases acetylation of histone H3. Conclusions and implications: Our results suggested that protection against development of diabetic nephropathy by curcumin treatment involved changes in post-translational modifications of histone H3, expression of HSP-27 and MAP kinase p38 in diabetic kidney. British Journal of Pharmacology (2008) 153, 1225–1231; doi:10.1038/sj.bjp.0707666; published online 21 January 2008

Cisplatin is one of the most common chemotherapeutic drugs used against various solid, tumours. Despite of its therapeutic benefits, its use in clinical practice is often limited because of dose, related toxicity. The nephrotoxic potential of cisplatin has been ascribed to its accumulation in the, renal tubular cells generating reactive oxygen species (ROS), activation of Bax, increased secretion of, TNFα and activation of certain inflammatory mediators like cytokines. The present investigation was, undertaken with an objective to study the effect of rosiglitazone against cisplatin induced, nephrotoxicity. Pretreatment of rosiglitazone prevents cisplatin induced nephrotoxicity which was, clearly evident from the renal biochemical parameters like reduced BUN, creatinine and TNFα levels, and increased albumin levels, which was also supported by histopathological studies of the kidneys. In contrast, posttreatment of rosiglitazone was not able to protect the renal damage in cisplatin induced, renal toxicity. These results showed the variation of pre & posttreatment effects of rosiglitazone, against the cisplatin induced nephrotoxicity.

The combination of diabetes and renal failure is associated with accelerated cardiomyopathy, but the molecular mechanisms of how renal failure drives diabetic heart disease remain elusive. We speculated that the metabolic abnormalities of renal failure will affect the epigenetic control of cardiac gene transcription and sought to determine the histone H3 modification pattern in hearts of type 2 diabetic mice with several degrees of renal dysfunction. We studied the histone H3 modifications and gene expression in the heart of 6-month-old nondiabetic mice and type 2 diabetic db/db mice that underwent either sham surgery or uninephrectomy at 6 weeks of age, which accelerates glomerulosclerosis in db/db mice via glomerular hyperfiltration. Western blotting of hearts from uninephrectomized db/db mice with glomerulosclerosis, albuminuria, and reduced glomerular filtration rate revealed increased acetylation (K23 and 9), phosphorylation (Ser 10), dimethylation (K4), and reduced dimethylation of (K9) of cardiac histone H3 as compared with db/db mice with normal renal function or nondiabetic wild-type mice. This pattern suggests alterations in chromatin structure that favor gene transcription. In fact, hearts from uninephrectomized db/db mice revealed increased mRNA expression of multiple cardiomyopathy-related genes together with cardiomyocyte hypertrophy. These data suggest that renal failure alters cardiac histone H3 epigenetics, which foster cardiomyocyte hypertrophy in type 2 diabetes.

Cisplatin is a widely used antineoplastic drug. Major drawback of cisplatin therapy is its nephrotoxicity. The objective of this study was to check the effect of tannic acid on cisplatin induced nephrotoxicity. Post-treatment of tannic acid prevents cisplatin (5mg/kg) induced nephrotoxicity and decreases poly(ADP-ribose) polymerase cleavage, phosphorylation of p38 and hypoacetylation of histone H4. In contrast, co-treatment of tannic acid potentiates the nephrotoxicity. Comparative nephrotoxicity studies show that co-treatment of tannic acid with reduced dose of cisplatin (1.5mg/kg) developed almost similar nephrotoxicity. MALDI protein profiling of plasma samples provides indirect evidence that tannic acid co-treatment increases bioavailability of cisplatin.

Diabetic nephropathy (DN) is one of the main causes of end stage renal disease (ESRD) and a leading cause of diabetes mellitus related morbidity and mortality. Recently, sirtuin are reported to have emerging pathogenetic roles in cancer, muscle differentiation, heart failure, neurodegeneration, diabetes and aging. The aim of the present study was to study the role of intermittent fasting (IF) on DN and studying the expression of Sir2 and p53. At biochemical level, we found that IF causes significant improvement in blood urea nitrogen (BUN), creatinine, albumin and HDL cholesterol, parameters that are associated with the development of DN. Diabetic rats on IF also show significant improvement in onset of hypertension. Interestingly, the expression of Sir2, a NAD dependent histone deacetylase, decreases in diabetic rat kidney and this decrease is overcome by IF. Moreover, we provide evidence for involvement of mitogen activated protein kinases (MAPK) cascade in mediating the effects of IF as there is reduction in the expression of p38 which gets induced under diabetic condition. This was further accompanied by the concomitant decrease in cleavage of caspase3 and p53 expression. These findings suggest that IF significantly improves biochemical parameters associated with development of DN and changes the expression of Sir2 and p53.