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Aims/Introduction The aim of this study was to elucidate whether sodium–glucose cotransporter 2 inhibitors (SGLT2is) treatment has any renoprotective effect for type 2 diabetes mellitus patients with an estimated glomerular filtration rate (eGFR) of, Administration of sodium–glucose cotransporter 2 inhibitors slowed the annual estimated glomerular filtration rate decline in type 2 diabetes patients with an estimated glomerular filtration rate of

Aims/introduction To establish novel therapies to combat diabetic kidney disease, a human disease-relevant animal model is essential. However, a type 2 diabetic mouse model presenting progressive kidney fibrosis has not yet been established. Kidneys of streptozotocin-induced diabetic CD-1 mice showed severe fibrosis compared with other backgrounds of mice associated with the suppression of antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline. The BKS background (BKSdb / db ) is often utilized for diabetic kidney disease research; the kidney fibrosis in the BKSdb / db phenotype is minimal. Materials and methods We generated CD-1db / db mice by backcrossing the db gene into the CD-1 background, and analyzed phenotypic differences compared with BKSdb / db and CD-1db / m mice. Results Male CD-1db / db mice appeared to have elevated blood glucose levels compared with those of BKSdb / db mice. Fasting insulin levels declined in CD-1db / db mice. Plasma cystatin C levels tended to be elevated in CD-1db / db mice from 16 to 24 weeks-of-age. Male CD-1db / db mice showed significantly progressive kidney and heart fibrosis from 16 to 24 weeks-of-age when compared with that of age-matched BKSdb / db mice. The gene expression profile showed fibrogenic program-associated genes in male CD-1db / db mice. Male CD-1db / db mice displayed significantly lower urine antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline when compared to that of BKSdb / db at 24 weeks-of-age. The gene expression of prolyl oligopeptidase, the enzyme essential for antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline production from thymosin β4, was significantly lower in the CD-1 mice. Thymosin β4 levels were also lower in CD-1 mice. Conclusions These results suggest that CD-1db / db mice are a novel type 2 diabetic mouse model with progressive kidney and heart fibrosis.

Aims To investigate the effects of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors vs. dipeptidyl peptidase‐4 (DPP‐4) inhibitors on renal function preservation (RFP) using real‐world data of patients with type 2 diabetes in Japan, and to identify which subgroups of patients obtained greater RFP benefits with SGLT2 inhibitors vs. DPP‐4 inhibitors. Methods We retrospectively analysed claims data recorded in the Medical Data Vision database in Japan of patients with type 2 diabetes (aged ≥18 years) prescribed any SGLT2 inhibitor or any DPP‐4 inhibitor between May 2014 and September 2016 (identification period), in whom estimated glomerular filtration rate (eGFR) was measured at least twice (baseline, up to 6 months before the index date; follow‐up, 9 to 15 months after the index date) with continuous treatment until the follow‐up eGFR. The endpoint was the percentage of patients with RFP, defined as no change or an increase in eGFR from baseline to follow‐up. A proprietary supervised learning algorithm (Q‐Finder; Quinten, Paris, France) was used to identify the profiles of patients with an additional RFP benefit of SGLT2 inhibitors vs. DPP‐4 inhibitors. Results Data were available for 990 patients prescribed SGLT2 inhibitors and 4257 prescribed DPP‐4 inhibitors. The proportion of patients with RFP was significantly greater in the SGLT2 inhibitor group (odds ratio 1.27; P = 0.01). The Q‐Finder algorithm identified four clinically relevant subgroups showing superior RFP with SGLT2 inhibitors (P

Aims/Introduction Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (

Endothelial-mesenchymal transition (EndMT) has emerged as an essential bioprocess responsible for the development of organ fibrosis. We have previously reported that fibroblast growth factor receptor 1 (FGFR1) is involved in the anti-EndMT effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). FGFR1 is expressed on the cell membrane and performs its biological function through interaction with co-receptors, including βklotho (KLB). However, it remains unknown whether KLB is involved in the anti-EndMT effects of AcSDKP. Here, we demonstrated that AcSDKP increased KLB expression in an FGFR1-dependent manner and that KLB deficiency induced AcSDKP-resistant EndMT via the induction of the mitogen-activated protein kinase (MAPK) pathway. In cultured endothelial cells, AcSDKP increased KLB protein level in an FGFR1-dependent manner through induction of the FGFR1-KLB complex. KLB suppression by small interfering RNA transfection did not affect FGFR1 levels and resulted in the induction of EndMT. In contrast to the EndMT observed under FGFR1 deficiency, the EndMT induced by KLB suppression was not accompanied by the induction of Smad3 phosphorylation; instead, KLB-deficient cells exhibited induced activation of the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK pathways. Treatment with the specific MEK inhibitor U0126 diminished KLB deficiency-induced EndMT. Consistent with this finding, AcSDKP did not suppress either EndMT or MEK/ERK activation induced by KLB deficiency. Application of either FGF19 or FGF21 synergistically augmented the anti-EndMT effects of AcSDKP. Taken together, these results indicate that endogenous peptide AcSDKP exerts its activity through induction of the FGFR1-KLB complex in vascular endothelial cells.

Aims/Introduction The objective of the present study was to elucidate the effect of switching to teneligliptin from other dipeptidyl peptidase‐4 (DPP‐4) inhibitors on glucose control and renoprotection in type 2 diabetes mellitus patients with diabetic kidney disease. Materials and Methods The present study was a single‐arm, open‐label, observational study. A total of 23 patients, who had urinary albumin/creatinine ratios (UACR) ≥30 mg/gCr in their first urine in the early morning, and received other DPP‐4 inhibitors and renin‐angiotensin system inhibitors, switched to teneligliptin 20 mg/day. After switching to teneligliptin for 24 weeks, we evaluated changes in glycated hemoglobin (HbA1c), fasting plasma glucose levels, plasma DPP‐4 activity and UACR. Results HbA1c, fasting plasma glucose and UACR values showed no significant change after 24 weeks compared with baseline. However, plasma DPP‐4 activity was significantly reduced after 24 weeks (0.57 ± 0.26 nmol/min/mL, P = 0.012, vs baseline), compared with baseline (1.49 ± 1.73 nmol/min/mL), and there was a positive relationship between the change rate of plasma DPP‐4 activity (Δ%DPP‐4) for 24 weeks and the levels of plasma DPP‐4 activity (r = −0.5997, P = 0.0025) and fasting plasma glucose (r = −0.4235, P = 0.0440) at baseline. Additionally, the Δ%DPP‐4 for 24 weeks was significantly correlated to the change rate of UACR (r = 0.556, P = 0.0059). However, there was no relationship between Δ%DPP‐4 and ΔHbA1c (amount of HbA1c change). Conclusions Switching to teneligliptin from other DPP‐4 inhibitors for 24 weeks reduces plasma DPP‐4 activity, which is associated with a reduction in albuminuria, independent of the change in glucose levels, in type 2 diabetes mellitus patients with diabetic kidney disease.

A low-protein diet (LPD), particularly, very low-protein diet (VLPD) is expected for reno-protection in advanced chronic kidney disease, including diabetic nephropathy. We previously also demonstrated that a VLPD clearly improved advanced diabetic nephropathy in a type 2 diabetes and obesity rat. However, clinically, an everyday long-term VLPD contributes to poor adherence, which may be related to controvertial results of an LPD on the suppression for diabetic nephropathy, and has nutritional issues, such as sarcopenia or protein-energy wasting. The aim of this study is to elucidate the reno-protective effect of a cyclic and intermittent VLPD, not an everyday VLPD, against the advanced experimental diabetic nephropathy. Diabetic male Wistar fatty (fa/fa) rats (WFRs) were treated with a standard diet (STD; 23.84% protein) or a cyclic and intermittent VLPD (5.77% protein) consisting of an STD for 3 days and a VLPD for 4 days a week for 20 weeks beginning at 24 weeks of age. A cyclic and intermittent VLPD significantly improved renal hypertrophy, and significantly decreased urinary albumin and liver-type fatty acid binding protein (L-FABP) excretion without changes in body weight or exacerbation of HbA1c levels in diabetic rats. Additionally, diabetes-induced renal injuries including fibrosis, tubular cell damage and inflammation were significantly ameliorated by a cyclic and intermittent VLPD in diabetic rats. Thus, based on our experimental data, a cyclic and intermittent VLPD may be a dietary regimen that is easy to continue and has less risk of malnutrition, compared to an everyday long-term VLPD, against advanced diabetic nephropathy.

Diabetic kidney disease is a leading cause of end stage kidney disease requiring renal transplantation or dialysis in not only Asian but also western countries. Recent data has also implicated that the prevalence of diabetic kidney disease was similar between 1988 and 2014 in cross-sectional studies of adults aged 20 years or older with diabetes mellitus participating in National Health and Nutrition Examination Surveys 1), although newly introduced treatments such as renin-angiotensin-aldosterone system inhibitors did affect the prevalence and clinical manifestations of diabetic kidney disease. Moreover, the prevalence of type 2 diabetes is still increasing strikingly all the world 2), thereby increasing the prevalence of diabetic kidney disease in future if we will not be able to discover new therapeutic strategies for high risk diabetic patients to develop and progress kidney disease. This article is protected by copyright. All rights reserved.

Diabetic nephropathy is a life-threatening complication in patients with diabetes mellitus; it is the leading cause of end-stage renal disease worldwide, and is associated with higher cardiovascular morbidity and mortality. Although the intensive control of glucose and blood pressure by blocking the renin–angiotensin system has been shown to prevent the development and progression of diabetic nephropathy as well as cardiovascular events to some extent, the residual risk for the progression of diabetic nephropathy is still high1. Thus, active investigations to understand the underlying mechanisms by which diabetes predisposes patients to the development and progression of diabetic nephropathy have implicated a variety of causal factors, such as altered intracellular signaling, the accumulation of advanced glycation end products and the overproduction of inflammatory cytokines2,3. Of these, the crucial role of transforming growth factor (TGF)-β action in mediating progressive glomerulosclerosis and tubulointerstitial fibrosis has been intensively investigated4. We have recently reported that inhibiting dipeptidyl peptidase-4 (DPP-4) activity with the DPP-4 inhibitor, linagliptin, ameliorated diabetes-induced glomerulosclerosis and tubulointerstitial fibrosis through the inhibition of endothelial mesenchymal transition by blocking TGF-β2/DPP-4/miR29s cross-talk in streptozotocin (STZ)-induced diabetic mice5. Recently, Chen et al.6 implicated the role of epidermal growth factor receptor (EGFR) phosphorylation in mediating TGF-β-induced renal fibrosis and its inhibition by the EGFR inhibitor, erlotinib, in STZ-induced diabetic mice. To extend their findings, Zang et al.7 reported that EGFR inhibition with erlotinib treatment slowed the progression of diabetic nephropathy in association with a decrease in endoplasmic reticulum (ER) stress and an increase in autophagy in STZ-induced diabetic endothelial nitric oxide synthase (eNOS) knockout mice. The findings here support the results of Zang et al.7 in that the EGFR inhibitor, erlotinib, clearly inhibited renal ER stress based on the expression of C/EBP homologous protein, protein kinase ribonucleic acid-like endoplasmic reticulum kinase and binding immunoglobulin protein, and enhanced autophagy based on the increased expression of autophagy-related protein 12, beclin and microtubule-associated protein light chain 3 AII and the decreased expression of sequestosome 1/p62 in the kidney of STZ-induced diabetic eNOS knockout mice. Because both enhanced ER stress and decreased autophagy are coordinately associated with the pathogenesis of diabetic nephropathy and because preventing these changes have recently been the focus as new therapeutic targets8,9, the current findings by Zang et al.7 suggest a strong therapeutic potency of EGFR inhibition in diabetic nephropathy (Figure ​(Figure11). Figure 1 Diabetes mellitus-related endoplasmic reticulum (ER) stress is a potent pathogenic factor of diabetic nephropathy. Healthy kidney cells have the ability to induce autophagy to overcome prolonged ER stress conditions, leading to kidney protection (blue ... The upstream signaling regulation of autophagy is mainly by two intracellular nutrient-sensing kinases, adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1). Autophagy is activated by the AMPK-mediated phosphorylation of UNC-51-like kinase 1 (ser317), and is suppressed by the mTORC1-mediated phosphorylation of UNC-51-like kinase 1 (ser757)10. Previous reports have shown that AMPK activity is decreased, whereas mTORC1 activity is increased in the kidneys of diabetic mice compared with non-diabetic mice11–14, suggesting that both kinases might be involved in the upregulation of autophagy in erlotinib-treated STZ-induced diabetic eNOS−/− mice. Indeed, Zang et al.7 showed that EGFR inhibition with erlotinib increased AMPK activity based on the increased phosphorylation of AMPK-α and AMPK-β, whereas it decreased mTORC1 activity based on the decreased phosphorylation of phosphorylated p70 ribosomal protein S6 kinase (p70S6K) and eukaryotic translation initiation factor 4B. Thus, they concluded that EGFR inhibition modifies the intracellular nutrient-sensing signals and subsequently activates autophagy, resulting in the amelioration of diabetic nephropathy. However, the detailed molecular mechanisms underlying the interaction between EGFR signaling and two nutrient-sensing signals remain unclear. The cross-talk between mTORC1 and ER stress has recently highlighted their possible pathogenic roles in diabetic nephropathy. For instance, Inoki et al.13 reported that the interaction between mTORC1 and ER stress in glomerular podocytes plays a pivotal role in mediating the development and progression of diabetic nephropathy. Briefly, Inoki et al.13 found that binding immunoglobulin protein induced by ER stress was overexpressed, and its accumulation was significantly reduced by treatment with an mTORC1-specific inhibitor, rapamycin, in podocyte-specific mTORC1-activated mice, which suggested that the elevated ER stress is induced by mTORC1 activation. Interestingly, Zang et al.7 provided the first evidence that altered bidirectional interaction between ER stress and mTORC1 is involved not in only podocyte damage, but also in tubular epithelial cell damage in the progression of diabetic nephropathy. Collectively, the cross-talk between mTORC1 and ER stress could be involved in the pathogenesis of both podocyte and tubular cell damage in diabetic nephropathy, and might become a potential therapeutic target. More recently, Chen et al.15 reported that podocyte-specific EGFR knockout mice were resistant to the progression of diabetes-related podocyte damage, although the relationship between EFGR signaling, nutrient-sensing signals and autophagy was not shown in the study. A recent study by Fang et al.16 showed that autophagy activity was suppressed in a mTORC1-dependent manner in podocytes of diabetic mice. Therefore, I am curious about how podocyte-specific EGFR gene deletion in mice affects diabetes-related hyperactivation of mTORC1 and the inhibition of autophagy in podocytes, which could provide further evidence that EGFR-mediated regulation of intracellular nutrient-sensing is involved in the pathogenesis of diabetic nephropathy. In summary, the current understanding based on a series of EGFR research studies might shed light on a potential therapeutic implication of EGFR inhibition in diabetic nephropathy. Further studies are required of cross-talk between EGFR and intracellular nutrient-sensing signals.

Aims/Introduction: Activation of the renin-angiotensin system (RAS) in the kidney plays an important role in renal function. The aim of this study was to investigate whether plasma and urinary angiotensinogen levels were associated with renal and cardiovascular prognosis in type 2 diabetic patients. Materials and Methods: We measured plasma and urinary angiotensinogen levels in the observational follow-up cohort of 234 Japanese type 2 diabetic patients (144 with normoalbuminuria, 90 with albuminuria) enrolled between 1998 and 1999 and followed them up until the end of 2008. The associations of these markers with the annual decline in the estimated glomerular filtration rate (eGFR) and incidence of renal and cardiovascular composite endpoints (chronic hemodialysis, myocardial infarction, angina pectoris, stroke and cerebral hemorrhage) were evaluated. Results: At baseline, urinary angiotensinogen levels correlated with urinary albumin-creatinine ratio, urinary β2-microglobulin and inversely with eGFR. In contrast, plasma angiotensinogen levels correlated neither with these renal factors nor with urinary angiotensinogen levels. In the follow-up study (median duration: 9 years), urinary angiotensinogen, but not plasma angiotensinogen, correlated inversely with the annual change in eGFR (r = −0.51, P

Anti-diabetic agent-related hypoglycemia is a serious complication in type 2 diabetic patients on hemodialysis. Therefore, we assessed the efficacy and tolerability of 24 weeks of monotherapy with vildagliptin, a dipeptidyl peptidase four inhibitor, which is a new class of antidiabetic agent. This open-label, single-arm clinical trial was performed on 26 patients on hemodialysis. The primary assessments were changes in postprandial glucose level and glycated albumin (GA). During the study, three patients dropped out, and data from 23 patients were analyzed. Significant reductions were seen in postprandial glucose (−2.60 ± 3.80 mmol/L, P

During the past 10 years, a global pandemic of end-stage renal disease (ESRD) attributed to diabetes mellitus has changed the therapeutic strategies based on landmark trials that have shown that diabetic micro- and macrovascular complications might be preventable. However, the remaining risk of the progression of diabetic kidney disease to ESRD is still high, despite newly introduced anti-diabetic, antihypertensive and dyslipidemic drugs in the 21st century. Here, we show the importance of targeting remission and regression of microalbuminuria in type 2 diabetic patients. To achieve the remission and regression of microalbuminuria, physicians have revised the management strategy of diabetic patients and have to act immediately. Early detection of microalbuminuria with continuous screening, the use of renin–angiotensin system blockades, and targets for HbA1c of

Legumain/asparaginyl endopeptidase (EC 3.4.22.34) is a novel cysteine protease that is abundantly expressed in the late endosomes and lysosomes of renal proximal tubular cells. Recently, emerging evidence has indicated that legumain might play an important role in control of extracellular matrix turnover in various pathological conditions such as tumor growth/metastasis and progression of atherosclerosis. We initially found that purified legumain can directly degrade fibronectin, one of the main components of the extracellular matrix, in vitro. Therefore, we examined the effect of legumain on fibronectin degradation in cultured mouse renal proximal tubular cells. Fibronectin processing can be inhibited by chloroquine, an inhibitor of lysosomal degradation, and can be enhanced by the overexpression of legumain, indicating that fibronectin degradation occurs in the presence of legumain in lysosomes from renal proximal tubular cells. Furthermore, in legumain-deficient mice, unilateral ureteral obstruction (UUO)-induced renal interstitial protein accumulation of fibronectin and renal interstitial fibrosis were markedly enhanced. These findings indicate that legumain might have an important role in extracellular matrix remodeling via the degradation of fibronectin in renal proximal tubular cells.

Dipeptidyl peptidase (DPP)‐4 inhibitors are a new class of antidiabetic drugs that increase incretin hormone levels to enhance blood sugar level‐dependent insulinotropic effects, suppress glucagon action, and reduce bowel motility. These incretin effects are ideal for blood sugar control. However, the safety profile of DPP‐4 inhibitors is not yet established. Herein, we present three cases of ileus, considered to be closely related to the use of DPP‐4 inhibitors, in diabetic patients. Each of the three patients exhibited some risk of a deficiency in bowel movement; the onset of ileus was within 40 days after strengthened inhibition of DPP‐4. The use of a DPP‐4 inhibitor could be safe, although the cases presented herein enable us to inform the scientific community to some of the potential adverse effects of the use of DPP‐4 inhibitors in select populations.

Since diabetes now accounts for 35% of all new cases of end-stage renal disease in the United States, it is really important to prevent the onset of diabetic nephropathy. Activation of protein kinase C (PKC) is implicated to be one of the causal factors in the development of renal dysfunctions in diabetes. In this study, we have demonstrated that total diacylglycerol (DAG) contents and PKC activity in glomeruli were significantly increased in diabetic rats as compared to control rats, but intraperitoneal injection of d-alpha-tocopherol prevented these biochemical abnormalities in parallel with normalization of glomerular dysfunction such as increased glomerular filtration rate (GFR) in diabetic rats. Albuminuria in diabetic rats was also significantly increased as compared to control rats, whereas d-alpha-tocopherol treatment again ameriolated increased albuminuria in parallel with the inhibition of glomerular PKC activation by diabetes. Moreover, we have observed that the activity of DAG kinase, which metabolizes DAG to phosphatidic acid and acts as an attenuator for the DAG-PKC pathway, was enhanced by d-alpha-tocopherol treatment. These results suggest that the increase in the DAG-PKC pathway might play an important role for the development of glomerular dysfunctions in diabetes and d-alpha-tocopherol treatment could be helpful in diabetic nephropathy.

Diabetic kidney disease is the primary cause of chronic kidney disease worldwide, which can progress to end‐stage renal disease that requires chronic dialysis therapy or renal transplantation1. An improved therapeutic strategy to combat diabetic kidney disease might include blocking the mechanisms by which diabetes leads to renal injury; for example, activation of protein kinase C (PKC). The PKC family comprises a group of related serine/threonine kinases that are ubiquitously expressed and participate in a variety of intracellular signaling pathways. The PKC family is divided into classical (α, β I, β II, γ), novel (δ, e, η, θ) and atypical (ζ, ι/λ) isoforms on the basis of the biochemical properties of the isoforms2. In diabetics, PKC activity is upregulated in vascular tissue including the retina and the renal glomeruli. Of the 10 PKC isoforms, the α, β I, β II, δ, and ζ isoforms have been reported to be activated in glomeruli and renal cells exposed to high concentrations of glucose3. In previous preclinical studies, we showed the beneficial effects of oral treatment with the selective PKCβ inhibitor, ruboxistaurin, on diabetic kidney and eye diseases.Treatment with ruboxistaurin improved albuminuria, glomerular filtration rate and retinal circulation in diabetic rats when administered orally for 2–8 weeks. In a longer study in the db/db mouse, treatment with ruboxistaurin ameliorated albuminuria and mesangial expansion by reducing the expression of transforming growth factor (TGF)‐β, fibronectin and type IV collagen5. Subsequently, in a study in diabetic transgenic Ren‐2 rats, inhibition of PKCβ with ruboxistaurin resulted in amelioration of albuminuria, structural injury and TGF‐β expression, despite continued hyperglycemia and hypertension. In short‐term clinical trials, ruboxistaurin was shown to be effective in the treatment of diabetic kidney disease and advanced retinopathy, consistent with preclinical studies. However, the results of long‐term clinical studies in patients with diabetic eye disease have been disappointing, despite some modest effect on albuminuria6, and further clinical trials of ruboxistaurin or other PKC β inhibitors are therefore warranted. Although a number of researchers have implicated PKCβ activation in the development and progression of diabetic kidney disease, other studies have implicated PKCα as a major underlying mechanism of diabetes‐induced albuminuria. Specifically for streptozotocin (STZ)‐induced diabetes, Kang et al.7 showed activation of PKCα and e isoforms in the kidney without significant increase in PKCβ isoforms, in contrast to our findings. Using PKCα and β knockout mice, Haller et al.8 showed that PKCβ activation was involved in transforming growth factor (TGF)‐β1‐mediated renal hypertrophy and extracellular matrix expansion, whereas PKCα activation mediated the expression of perlecan, vascular endothelial growth factor (VEGF) and nephrin, resulting in albuminuria. Similarly, King et al.9 presented a longer study in diabetic PKCβ knockout mice carried out over 24 weeks that showed reduced glomerular and renal hypertrophy, although only a modest reduction in albuminuria was observed. A recent report in Diabetes clearly showed that deletion of both PKCα and β isoforms inhibits the development of diabetic kidney disease in STZ‐induced diabetic mice, although albuminuria was not completely prevented as compared with exclusively PKCα knockout diabetic mice9. As further evidence for these findings, pharmacological inhibition of PKCα and β with {"type":"entrez-protein","attrs":{"text":"CGP41252","term_id":"812271292","term_text":"CGP41252"}}CGP41252, an agent utilized as the classical PKC inhibitor in several cancer trials, ameliorated albuminuria, but failed to significantly reduce renal hypertrophy in the STZ‐induced 129/SV and the db/db mice. Interpretation of these findings implicated {"type":"entrez-protein","attrs":{"text":"CGP41252","term_id":"812271292","term_text":"CGP41252"}}CGP41252 as a broad‐PKC inhibitor as opposed to a specific inhibitor of PKCα and β. Such an agent might inhibit novel PKC isoforms, such as PKCe. Deletion of the PKCe signaling pathway induces glomerulosclerosis and tubulointerstitial fibrosis in vivo, suggesting a protective role against diabetic kidney disease10. Diabetic kidney disease continues to be a major complication of type 1 and type 2 diabetes, and represents the major cause of end‐stage renal disease globally. There is an urgent need for new therapeutic drugs, although intensified blood glucose and blood pressure control with inhibition of the renin–angiotensin system are critical for reducing albuminuria, and preserving or slowing decline of renal function in diabetics. However, this new study highlights the need for further development of isoform‐specific PKC inhibitors specifically targeting both PKCα and β action without inhibition of other PKC isoforms (Figure 1). Discovery of such inhibitors could have potential use in the future treatment of diabetic kidney disease. Figure 1 Diabetes induces activation of protein kinase C (PKC) isoforms (α, β, e, δ and ζ) in renal tissue through hyperglycemia, high blood pressure and dyslipidemia, resulting in development and progression of ...