Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. During the last few years, remarkable advances have been made in the treatment of DN. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) consistently prevent or delay albuminuria and renal failure in patients with DN. Prior research from our group highlights the Janus kinase/signal transducers and activators of transcription axis as a critical target in DN. Specifically, the administration of suppression of cytokine signaling 1 (SOCS1) mimetic peptides (MiS1) modulates aberrant signaling, resulting in profound beneficial effects on renal function and structural integrity in experimental DN. The aim of this study was to evaluate the effect of empagliflozin and MiS1 on kidney damage and its associated inflammatory, oxidative stress and lipotoxic mechanisms in an advanced type 2 DN mouse model BTBR ob/ob. Mice were treated for 7 weeks with empagliflozin and MiS1, alone or in combination, and monitored for glycemia, body weight, albuminuria, histopathological damage, podocyte loss, and gene expression related to inflammation, redox balance, and lipid metabolism. Empagliflozin or MiS1 monotherapies significantly reduced albuminuria and structural renal injury, preserved podocyte number, and downregulated genes involved in inflammatory, oxidative, and mitochondrial-lipid metabolic dysregulation, with empagliflozin additionally improving metabolic parameters. Notably, the combined therapy achieved the greatest reduction in albuminuria and histological damage with enhanced suppression of pathogenic inflammatory and metabolic pathways, resulting in superior renoprotection compared with monotherapy. These findings suggested that add-on therapy with SOCS1 peptidomimetics and SGLT2i may help mitigate residual albuminuria and renal damage in type 2 DN.

The Chilean consensus on the use of SGLT-2 inhibitors (iSGLT-2) in clinical practice, jointly developed by the societies of Cardiology, Diabetes, Family Medicine, and Nephrology, strongly recommends the use of these drugs in people with heart failure with reduced ejection fraction, type 2 diabetes mellitus for prevention of cardiovascular events, and chronic kidney disease. In heart failure with preserved or mildly reduced ejection fraction, and chronic kidney disease without diabetes, the consensus suggests the use of iSGLT-2. The importance of combining iSGLT-2 with ACE inhibitors or ARBs in chronic kidney disease is highlighted, and their use is recommended to replace sulfonylureas as a second-line treatment for glycemic control in type 2 diabetes. The consensus emphasizes the need for strategies to optimize diagnosis, improve adherence, and educate about benefits beyond glycemic control. Safety and cost-effectiveness considerations for prioritized implementation according to evidence are discussed. The document highlights the importance of multidisciplinary collaboration and the generation of local evidence to maximize the potential of these drugs in the management of complex cardiometabolic conditions in Chile.

Dialysis treatment has improved the survival of patients with kidney failure. However, the hospitalization and mortality rates remain alarmingly high, primarily due to incomplete uremic toxin elimination. High-volume hemodiafiltration (HDF) has emerged as a promising approach that significantly improves patient outcomes by effectively eliminating medium and large uremic toxins, which explains its increasing adoption, particularly in Europe and Japan. Interest in this therapy has grown following the findings of the recently published CONVINCE study, as well as the need to understand the mechanisms behind the benefits. This comprehensive review aims to enhance the scientific understanding by explaining the underlying physiological mechanisms that contribute to the positive effects of HDF in terms of short-term benefits, like hemodynamic tolerance and cardiovascular disease. Additionally, it explores the rationale behind the medium-term clinical benefits, including phosphorus removal, the modulation of inflammation and oxidative stress, anemia management, immune response modulation, nutritional effects, the mitigation of bone disorders, neuropathy relief, and amyloidosis reduction. This review also analyzes the impact of HDF on patient-reported outcomes and mortality. Considering the importance of applying personalized uremic toxin removal strategies tailored to the unique needs of each patient, high-volume HDF appears to be the most effective treatment to date for patients with renal failure. This justifies the need to prioritize its application in clinical practice, initially focusing on the groups with the greatest potential benefits and subsequently extending its use to a larger number of patients.

Introduction: The COVID-19 pandemic is a global public health problem. Patients with end-stage renal disease on hemodialysis are at a higher risk of infection and mortality than the general population. Worldwide, a vaccination campaign has been developed that has been shown to reduce severe infections and deaths in the general population. However, there are currently limited data on the clinical efficacy of vaccinations in the hemodialysis population. Methods: A national multicenter observational cohort was performed in Chile to evaluate the clinical efficacy of anti-SARS-CoV-2 vaccination in end-stage renal disease patients on chronic hemodialysis from February 2021 to August 2021. In addition, the BNT162b2 (Pfizer-BioNTech) and CoronaVac (Sinovac) vaccines were evaluated. The efficacy of vaccination in preventing SARS-CoV-2 infection, hospitalizations, and deaths associated with COVID-19 was determined. Results: A total of 12,301 patients were evaluated; 10,615 (86.3%) received a complete vaccination (2 doses), 490 (4.0%) received incomplete vaccination, and 1196 (9.7%) were not vaccinated. During followup, 1362 (11.0%) patients developed COVID-19, and 150 died (case fatality rate: 11.0%). The efficacy of the complete vaccination in preventing infection was 18.1% (95% confidence interval [CI]:11.8-23.8%), and prevention of death was 66.0% (95% CI:60.6-70.7%). When comparing both vaccines, BNT162b2 and CoronaVac were effective in reducing infection and deaths associated with COVID-19. Nevertheless, the BNT162b2 vaccine had higher efficacy in preventing infection (42.6% vs. 15.0%) and deaths (90.4% vs. 64.8%) compared to CoronaVac. Conclusion: The results of our study suggest that vaccination against SARS-CoV-2 in patients on chronic hemodialysis was effective in preventing infection and death associated with COVID-19.

The NOTCH signaling pathway is an evolutionarily conserved family of transmembrane receptors, ligands, and transcription factors. The NOTCH signaling is activated in many biological processes including nephrogenesis, tubulogenesis, and glomerulogenesis, as well as during pathological situations. Activation of Notch signaling is characterized by successive proteolytic cleavages triggered by the interaction between membrane-bound Notch receptors and ligands expressed on neighboring cells. In chronic kidney diseases, activation of the canonical NOTCH signaling pathway has been described. The following protocols will allow the direct assessment of Jagged-1/NOTCH signaling activation in biopsies of patients with chronic kidney diseases and in murine experimental models of renal damage.

Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treatment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provides limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory disorders and experimental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs could regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model resembling human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, restoring podocyte numbers. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by modulation of NOTCH pathway. JQ1 inhibited the gene expression of the NOTCH effectors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis.

Introducción: La enfermedad por coronavirus 2019 (COVID-19) en enfermos renales crónicos (ERC) en terapia de reemplazo renal (TRR), hemodiálisis (HD), diálisis peritoneal (DP) y trasplante (Tx) renal tiene elevada mortalidad, con datos clínicos y epidemiológicos en Latinoamérica aún limitados.Métodos: Estudio nacional observacional, multicéntrico, obtenido por la fuerza de tarea contra COVID-19 en Chile (FUTAC Renal), evaluando epidemiología y resultados clínicos mayores de los pacientes ERC en TRR, que desarrollaron COVID-19 en Chile el año 2020.Resultados: De 21,021 pacientes en HD, 1,498 en DP y 4,305 Tx renales, la tasa de infección acumulada a diciembre 2020 fue del 12.8, 7.0 y 5.2%, y la letalidad acumulada del 20.0, 21.9 y 16.0% respectivamente.La tasa de hospitalización por COVID-19 en cualquier TRR fue del 50%.Los predictores mayores de mortalidad en HD fueron: edad > 60 años (odds ratio [OR]: 2.69), diabetes (OR: 1.58) y vivir en Santiago (OR: 1.67).En DP: edad > 60 años, mas de cinco años en diálisis y diabetes mellitus.En Tx renal: edad > 60 años y bajo nivel socioeconómico.Conclusiones: La COVID-19 en ERC en TRR en Chile tiene un componente sindémico, junto a una elevada tasa de contagio y letalidad, datos que permitieron a FUTAC Renal sensibilizar a autoridades de salud para su vacunación prioritaria.

Cyclosporine (CsA) and tacrolimus (TAC) are immunosuppressant drugs characterized by a narrow therapeutic range and high pharmacokinetic variability. The effect of polymorphisms in genes related to the metabolism and transport of these drugs, namely CYP3A4 , CYP3A5 , MDR1 and POR genes, has been evaluated in diverse populations. However, the impact of these polymorphisms on drug disposition is not well established in Latin American populations. Using TaqMan ® probes, we determined the allelic frequency of seven variants in CYP3A4 , CYP3A5 , MDR1 and POR in 139 Chilean renal transplant recipients, of which 89 were treated with CsA and 50 with TAC. We tested associations between variants and trough and/or 2-hour concentrations, normalized by dose (C 0 /D and C 2 /D) at specific time points post-transplant. We found that CYP3A5*3/*3 carriers required lower doses of TAC. In TAC treated patients, most CYP3A5*3/*3 carriers presented higher C 0 /D and a high proportion of patients with C 0 levels outside the therapeutic range relative to other genotypes. These results reinforce the value of considering CYP3A5 genotypes alongside therapeutic drug monitoring for TAC treated Chilean kidney recipients.

Interleukin-17A (IL-17A) is a proinflammatory cytokine produced by cells of the immune system, predominantly Th17 and γδ lymphocytes. In this paper, we review the role of IL-17A in the pathogenesis of hypertension and in target organ damage. Preclinical studies in mice have shown that systemic adminstration of IL-17A increases blood pressure, probably by acting on multiple levels. Furthermore, IL-17A plasma concentrations are already elevated in patients with mild or moderate hypertension. Many studies in hypertensive mice models have detected IL-17A-producing cells in target organs such as the heart, vessels and kidneys. Patients with hypertensive nephrosclerosis show kidney infiltration by Th17 lymphocytes and γδ lymphocytes that express IL-17A. In addition, in experimental models of hypertension, the blockade of IL-17A by genetic strategies or using neutralizing antibodies, disminished blood pressure, probablyby acting on the small mesenteric arteries as well as in the regulation of tubule sodium transport. Moreover, IL-17A inhibition reduces end-organs damage. As a whole, the data presented in this review suggest that IL-17A participates in the regulation of blood pressure and in the genesis and maintenance of arterial hypertension, and may constitute a therapeutic target of hypertension-related pathologies in the future.

La interleuquina 17A (IL-17A) es una citoquina proinflamatoria producida por células del sistema inmune, sobre todo por los linfocitos Th17 y los linfocitos γδ. En este trabajo, revisamos el papel de IL-17A en la patogenia de la hipertensión y de la lesión en órganos diana. Estudios en ratones han demostrado que la IL-17A aumenta la presión arterial, probablemente por acciones a varios niveles. Además, las concentraciones plasmáticas de IL-17A están ya aumentadas en pacientes con hipertensión arterial ligera o moderada. Estudios preclínicos sobre hipertensión arterial han detectado células productoras de IL-17A en órganos diana, como corazón, vasos y riñón. En pacientes con nefroesclerosis hipertensiva existe infiltración del riñón por linfocitos Th17 y linfocitos γδ que expresan IL-17A. Además, en modelos experimentales de hipertensión el bloqueo de IL-17A, mediante estrategias génicas, o utilizando anticuerpos neutralizantes, disminuye la presión arterial por acciones sobre la pared vascular y el transporte tubular de sodio y disminuye la lesión en órganos diana. En conjunto, los datos presentados en esta revisión sugieren que la IL-17A participa en la regulación de la presión arterial y en la génesis y mantenimiento de la hipertensión arterial, pudiendo constituir una diana terapéutica en el futuro.

Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta-like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1-null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey-1 expression compared to wild-type (WT) littermates. NOTCH1 over-activation in Dlk1-null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL-17A and other related-inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non-canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17-mediated inflammatory response.

BACKGROUND:We performed a multicenter study to assess the association between secondary antibody deficiency (immunoglobulin G [IgG] hypogammaglobulinemia combined with low levels of specific antibodies) and development of infection in kidney transplantation.METHODS:We prospectively analyzed 250 adult kidney recipients at four centers. The assessment points were before transplantation and 7 and 30 days after transplantation. The immune parameters were as follows: IgG, IgA, and IgM and complement factors C3 and C4 tested by nephelometry; specific IgG antibodies to cytomegalovirus (CMV) and IgG and IgG2 antibodies to pneumococcal polysaccharide (anti-PPS) determined using enzyme-linked immunosorbent assay. The clinical follow-up period lasted 6 months. The clinical outcomes were CMV disease and recurrent bacterial infections requiring antimicrobial therapy.STATISTICS:Multivariate logistic regression.RESULTS:At day 7, IgG hypogammaglobulinemia (IgG levels < 700 mg/dL) combined with low IgG anti-CMV antibody titers (defined as levels < 10 000 units) was present in 12% of kidney recipients. IgG hypogammaglobulinemia combined with low IgG anti-PPS antibody titers (defined as levels < 10 mg/dL) at 1 month after kidney transplantation were recorded in 16% of patients. At day 7 the combination of IgG hypogammaglobulinemia and low anti-CMV titers was independently associated with the development of CMV disease (odds ratio [OR], 6.95; 95% confidence interval [CI], 1.17-41.31; P = .033). At day 30 after transplantation, the combination of IgG < 700 mg/dL and IgG anti-PPS < 10 mg/dL, was independently associated with recurrent bacterial infection (OR, 5.942; 95% CI, 1.943-18.172; P = .002).CONCLUSION:In a prospective multicenter study, early immunologic monitoring of secondary antibody deficiency proved useful for the identification of kidney recipients who developed severe infection.

The absence of optimal treatments for Diabetic Nephropathy (DN) highlights the importance of the search for novel therapeutic targets. The vascular endothelial growth factor receptor 2 (VEGFR2) pathway is activated in experimental and human DN, but the effects of its blockade in experimental models of DN is still controversial. Here, we test the effects of a therapeutic anti-VEGFR2 treatment, using a VEGFR2 kinase inhibitor, on the progression of renal damage in the BTBR ob/ob (leptin deficiency mutation) mice. This experimental diabetic model develops histological characteristics mimicking the key features of advanced human DN. A VEGFR2 pathway-activation blockade using the VEGFR2 kinase inhibitor SU5416, starting after kidney disease development, improves renal function, glomerular damage (mesangial matrix expansion and basement membrane thickening), tubulointerstitial inflammation and tubular atrophy, compared to untreated diabetic mice. The downstream mechanisms involved in these beneficial effects of VEGFR2 blockade include gene expression restoration of podocyte markers and downregulation of renal injury biomarkers and pro-inflammatory mediators. Several ligands can activate VEGFR2, including the canonical ligands VEGFs and GREMLIN. Activation of a GREMLIN/VEGFR2 pathway, but not other ligands, is correlated with renal damage progression in BTBR ob/ob diabetic mice. RNA sequencing analysis of GREMLIN-regulated genes confirm the modulation of proinflammatory genes and related-molecular pathways. Overall, these data show that a GREMLIN/VEGFR2 pathway activation is involved in diabetic kidney disease and could potentially be a novel therapeutic target in this clinical condition.

Gremlin is a member of the TGF-beta superfamily that can act as a BMP antagonist, and recently, has been described as a ligand of the vascular endothelial growth factor receptor 2 (VEGFR2). Gremlin shares properties with the Notch signaling pathway. Both participate in embryonic development and are reactivated in pathological conditions. Gremlin is emerging as a potential therapeutic target and biomarker of renal diseases. Here we review the role of the Gremlin-VEGFR2 axis in renal damage and downstream signaling mechanisms, such as Notch pathway.

Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NFκB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawal.

INTRODUCTION:Diabetic nephropathy (DN) is the leading cause of chronic kidney disease worldwide. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway participates in the development and progression of DN. Among the different mechanisms involved in JAK/STAT negative regulation, the family of suppressor of cytokine signaling (SOCS) proteins has been proposed as a new target for DN. Our aim was to evaluate the effect of SOCS1 mimetic peptide in a mouse model of obesity and type 2 diabetes (T2D) with progressive DN.RESEARCH DESIGN AND METHODS:Six-week-old BTBR (black and tan brachyuric) mice with the ob/ob (obese/obese) leptin-deficiency mutation were treated for 7 weeks with two different doses of active SOCS1 peptide (MiS1 2 and 4 µg/g body weight), using inactive mutant peptide (Mut 4 µg) and vehicle as control groups. At the end of the study, the animals were sacrificed to obtain blood, urine and kidney tissue for further analysis.RESULTS:Treatment of diabetic mice with active peptide significantly decreased urine albumin to creatinine ratio by up to 50%, reduced renal weight, glomerular and tubulointerstitial damage, and restored podocyte numbers. Kidneys from treated mice exhibited lower inflammatory infiltrate, proinflammatory gene expression and STAT activation. Concomitantly, active peptide administration modulated redox balance markers and reduced lipid peroxidation and cholesterol transporter gene expression in diabetic kidneys.CONCLUSION:Targeting SOCS proteins by mimetic peptides to control JAK/STAT signaling pathway ameliorates albuminuria, morphological renal lesions, inflammation, oxidative stress and lipotoxicity, and could be a therapeutic approach to T2D kidney disease.

Diabetic nephropathy (DN) is a multifactorial disease characterized by hyperglycemia and close interaction of hemodynamic, metabolic and inflammatory factors. Nuclear factor-κB (NF-κB) is a principal matchmaker linking hyperglycemia and inflammation. The present work investigates the cell-permeable peptide containing the inhibitor of kappa B kinase γ (IKKγ)/NF-κB essential modulator (NEMO)-binding domain (NBD) as therapeutic option to modulate inflammation in a preclinical model of type 2 diabetes (T2D) with DN. Black and tan, brachyuric obese/obese mice were randomized into 4 interventions groups: Active NBD peptide (10 and 6 µg/g body weight); Inactive mutant peptide (10 µg/g); and vehicle control. In vivo/ex vivo fluorescence imaging revealed efficient delivery of NBD peptide, systemic biodistribution and selective renal metabolization. In vivo administration of active NBD peptide improved albuminuria (>40% reduction on average) and kidney damage, decreased podocyte loss and basement membrane thickness, and modulated the expression of proinflammatory and oxidative stress markers. In vitro, NBD blocked IKK-mediated NF-κB induction and target gene expression in mesangial cells exposed to diabetic-like milieu. These results constitute the first nephroprotective effect of NBD peptide in a T2D mouse model that recapitulates the kidney lesions observed in DN patients. Targeting IKK-dependent NF-κB activation could be a therapeutic strategy to combat kidney inflammation in DN.

Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several anti-inflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury.

Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.