Renal lipid deposition and diabetic nephropathy
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Ming Yang
Ming YangDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Central South University, Changsha 410011, Hunan Province, ChinaSearch for this author in:
Abstract
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and the main cause of end-stage renal disease (ESRD). Lipid metabolism disorders are a common clinical manifestation of DN and are involved in the development of DN. Ectopic lipid deposition refers to lipids deposited in nonadipose tissue, such as liver, brain, skeletal muscle, and kidney. Recently, renal lipid deposition has been shown to play an important role in the pathological progression of DN. In this review, we summarize our understanding of the molecular mechanisms of renal lipid deposition and explore the relationship between renal lipid deposition and renal injury in DN.
1 Introduction
Diabetes is a metabolic disease characterized by hyperglycemia, and the incidence of diabetes has been increasing as living standards improve. It is estimated that there will be 642 million diabetics between the ages of 20 years and 79 years worldwide in 2040 [1]. Diabetes mellitus causes microangiopathy, and diabetic nephropathy (DN) is an important complication of diabetes [2, 3, 4]. However, preventing DN from developing into end-stage renal disease (ESRD) remains a difficult problem to solve. In this review, we systematically summarize the factors that cause renal lipid deposition in DN and discuss their role in the development of DN.
2 Glucose and Lipid Homeostasis
As the body’s main source of energy, blood glucose and lipid levels exist in a relatively stable state under normal conditions, and sustained and stable glucose and lipid levels are necessary to maintain the physiological activity of organs and cells [5,6]. Glucose and lipids can be converted to each other, and numerous factors, such as insulin, are involved in maintaining the glucose–lipid balance. Insulin plays a hypoglycemic role by accelerating the uptake of glucose, converting glucose into glycogen for storage, and inhibiting glucose production. Moreover, insulin is also involved in the regulation of lipid metabolism; it promotes the conversion of fatty acids into triglycerides (TGs) in adipose tissue. After eating, lipoprotein lipase in the vascular endothelium of adipose tissue is activated by insulin, and TGs are absorbed and hydrolyzed into nonesterified fatty acids. Subsequently, the fatty acids enter adipocytes through fatty acid transporters and are then re-esterified to form TGs, which are stored as lipid droplets [7]. Dyslipidemia is an important complication that is closely related to the progression of DN, and the severity of dyslipidemia is also correlated with the pathologic progression of DN. The Diabetic Control and Complications Trial/Epidemiology of Diabetic Interventions and Complications study group demonstrated a relationship among TG, cholesterol, and apolipoprotein B (ApoB) levels and the severity of proteinuria [8]. The incidences of high TG levels, hyper-Low-density lipoprotein cholesterolemia (high-LDL-C) levels, hypo-high-density lipoprotein chelesterolemia (low-HDL-C) levels, and a hypertriglyceridemia (high-TG)/high-density lipoprotein cholesterol (HDL-C) ratio were 64.4/1000 person-years, 83.1/1000 person-years, 14.5/1000 person-years, and 39.6/1000 person-years, respectively, among 289,462 participants with chronic kidney disease (CKD) [9]. The incidence of CKD was decreased in the high HDL-C quartile but was increased in the high TG, non-HDL-C/HDL-C, and TG/HDL-C ratio quartiles [10]. New onset of High-TG, Low-HDL-C, and High-TG/HDL-C ratios and remnant cholesterol (RC) are closely associated with glomerular filtration rate (GFR) and proteinuria [9,11,12]. High total cholesterol levels are associated with an increased risk of the development of urinary albumin excretion (UAE) [13]. Additionally, the management of TG level postmeal may prevent the progression of DN [14]. Similar results have also been observed in streptozocin (STZ)-induced DN mice; specifically, high levels of TGs and cholesterol accelerated early kidney damage [15]. Therefore, lipid metabolism disorder plays a nonnegligible role in the development of DN.
3 Renal Lipid Deposition and Renal Injury in DN
The molecular mechanisms by which high glucose causes kidney damage include advanced glycation end products (AGEs) [16], oxidative stress [17], angiotensin II, hypoxia, and interleukin-6. Many factors are involved in the development of DN, such as hyperfiltration, hypertension [18], obesity [19], and inflammation mediated by endothelin-1 [20]. Additionally, the recent role of renal lipid deposition has attracted great attention. Normally, adipose tissue is the main part of the body that stores lipids. However, in a disease state, lipids are deposited in nonadipose tissue, such as the brain [21], liver [22], skeletal muscle [23], and kidney [24], via a process known as ectopic lipid deposition.
Renal lipid deposition is a common pathological change in DN, and the degree of renal lipid deposition is closely related to kidney damage. Kimmelstiel and Wilson [25] performed a Sudan III staining of the renal tissue at autopsy and observed lipid deposition in the renal tissue of DN patients. Additionally, Herman-Edelstein et al. [26] demonstrated that compared with the control group, increased renal lipid accumulation and the deregulation of lipid metabolism genes were observed in DN patients diagnosed by kidney biopsies. Subsequently, a large number of in vivo and in vitro studies have demonstrated the presence of lipid deposition in the renal tissue of DN. Through high-density microarrays, Mishra et al. [27] reported that the expression of adipose differentiation-related protein (ADRP) mRNA (the marker protein of lipid droplets) was increased 5.4-fold in the kidneys of 16-week-old db/db mice compared to the control group, and the upregulation of ADRP was confirmed by immunohistochemistry and western blotting. Similar results were observed in the kidneys of mice with STZ-induced DN, as oil red O staining demonstrated increased lipid deposition [28]. Based on the above findings, renal lipid deposition is an important pathological change in DN. Renal lipid deposition in DN further aggravates renal damage by promoting the production of reactive oxygen species (ROS) and inflammatory cytokines [16,29]. Thus, the remission of renal ectopic deposition represents a new potential target in the treatment of DN. However, the mechanisms underlying renal lipid deposition in DN remain unclear. A number of molecules have been implicated in the development of lipid deposition in the kidney, such as sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs). We provide a systematic summary below.
3.1 SREBPs
SREBPs are members of the family of membrane-bound transport factors that activate genes that encode enzymes needed for the synthesis of cholesterol and unsaturated fatty acids [30]. Among them, SREBP-1 mainly promotes the synthesis of fatty acids, whereas SREBP-2 promotes the synthesis of cholesterol [30,31]. Therefore, its expression is closely related to lipid metabolic balance, and the abnormal expression of SREBPs causes lipid damage in the kidneys (Figure 1). Upregulation of SREBP expression in the kidney was found to increase the level of proteinuria [32,33]. Additionally, overexpression of SREBP1c in mice significantly increased proteinuria [34]. In rats with STZ-induced DN, increased expression of SREBP-1 was observed, which resulted in the accumulation of TG in the kidney [32]. To further investigate the role of SREBPs in renal lipid deposition, transgenic mice overexpressing SREBP in the kidneys were generated. SREBP-1 expression in the kidney is increased in DN and promotes the expression of transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF), which results in lipid deposition and lipid damage in the kidney [32]. Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily that plays an important role in metabolism and inflammation [35,36]. In the kidneys of DN mice, FXR agonists can inhibit the expression of SREBP-1 and reduce glomerulosclerosis, tubulointerstitial fibrosis, and the level of proteinuria [37]. Curcumin is a natural nutrient extracted from turmeric and exhibits significant pharmacological effects [38]. Curcumin can improve renal lipid deposition by activating adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation, thereby inhibiting the expression of SREBP1c, acetyl-CoA carboxylase, and fatty acid synthase in rats with STZ-induced DN [39]. Curcumin also increases the expression of heme oxygenase 1 by activating nuclear factor erythroid 2-related factor 2 (Nrf2), thus inhibiting oxidative stress in DN mice [40]. Therefore, inhibition of SREBP expression in the kidney may be a potential target for reducing renal lipid deposition and ameliorating renal injury in DN.
Mechanism of renal lipid deposition in DN. In the state of DN, abnormal expression of key proteins in lipid regulation leads to increased renal lipid synthesis, decreased lipid oxidation, and increased renal ectopic lipid deposition. Furthermore, lipotoxicity induces inflammation, apoptosis, and fibrosis, thereby aggravating kidney injury. DN, diabetic nephropathy; SREBPs, sterol regulatory element-binding proteins; PPARs, peroxisome proliferator-activated receptors.
3.2 PPARs
PPARs are a family of nuclear transcription factors that control the transcription of specific genes by binding to regulatory DNA sequences [41, 42, 43]. PPARs play an important role in maintaining glucose and lipid homeostasis. Three known subtypes, PPAR-α, PPAR-δ, and PPAR-γ, play distinct physiological roles in different tissues. In general, PPARs perform their biological functions as metabolic sensors by binding to dietary metabolites. PPARα is mainly expressed in the heart and liver and is involved in the regulation of catabolism. PPARδ is highly expressed in skeletal muscle and regulates fatty acid transport and oxidation. PPARγ is involved in anabolism in adipose tissue [44,45]. In addition to lipid metabolism, PPARγ is also involved in other physiological activities, such as cell differentiation, insulin action, and cancer [46].
In the kidney, PPARs also play a central role in maintaining lipid homeostasis, and the abnormal expression of PPARs is closely related to the occurrence and development of lipid deposition in DN. Notably decreased PPARα expression and increased lipid deposition were observed in the kidneys of DN patients compared with control individuals [26]. Moreover, Heidari et al. [47] also demonstrated that coenzyme Q10, an antioxidant, upregulates PPARγ gene expression and downregulates the expression of inflammatory factor genes, such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α). These findings suggest that PPARs play an important role in the development of DN. Similar results have been demonstrated in animal models. In PPAR-α gene knockout mice with STZ-induced DN, the levels of serum free fatty acids and TGs were notably increased compared with those in wild-type mice with DN, and this effect was accompanied by an increase in mesangial matrix, glomerulosclerosis, and proteinuria [48]. When fenofibrate (an activator of PPAR) was used, the increase in type IV collagen expression caused by high glucose could be alleviated in mesangial cells [48]. Additionally, many other studies have found that fenofibrate reduces blood lipids, improves insulin resistance, reduces the UAE rate, and relieves glomerular hypertrophy and mesangial matrix expansion [49, 50, 51]. Further, the novel PPAR-γ agonist, RB394, alleviates insulin resistance and hyperlipidemia and ameliorates renal interstitial fibrosis and tubular cell damage in obese diabetic zucker spontaneously hypertensive fatty (ZSF1) rats [52]. These findings suggested that the abnormal expression of PPARs aggravates lipid metabolism disorders in DN. However, the restoration of normal expression relieves diabetic lipid disorders and improves the pathological damage of DN.
3.3 Adiponectin
Adiponectin is a protein that is specifically secreted by adipocytes and plays a strong role in insulin sensitization and hypoglycemic and lipid catabolism in peripheral tissue [53, 54, 55]. Insulin promotes the uptake of serum glucose in muscle and adipose tissue through glucose transporter type 4 (GLUT4) and inhibits hepatic gluconeogenesis, and it also stimulates the synthesis of fats in adipose tissue [56]. These biological processes promote the reduction of blood glucose and energy storage. Interestingly, one of the biological roles of adiponectin involves promoting the absorption of glucose in muscle and adipose tissue through GLUT4 and inhibiting gluconeogenesis in the liver, thereby lowering blood glucose levels [56]. Three forms of adiponectin are found in circulation, namely trimers, low molecular weight multimers, and high-molecular weight (HMW) oligomers [57]. Two types of receptors have been identified, namely adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2). AdipoR1 activates the AMPK pathway, whereas AdipoR2 activates the PPAR pathway to exert the physiological effects of adiponectin [58].
Aleidi et al. [59] demonstrated that adiponectin serum levels were significantly lower in patients with diabetes than in individuals in the control group and were negatively correlated with insulin resistance. Additionally, Kacso et al. [60] demonstrated that low adiponectin levels in plasma can predict the progression of renal disease in patients with diabetes; adiponectin levels were negatively correlated with the rate of decline in GFR and the rate of increase in the urinary albumin/creatinine ratio (UACR). Similar results were observed in early-stage DN patients; specifically, AdipoR1 and AdipoR2 expression was notably decreased compared to that in individuals in the control group [61]. These findings suggest that adiponectin plays a protective role in the progression of DN. Supportive results have also been observed in animal models. In db/db mice, reduced AdipoR expression and aggravated tubulointerstitial fibrosis were observed in the kidney, whereas AdipoRon treatments alleviated renal changes caused by diabetes. Mechanistically, adiponectin exerts its biological effects by activating AdipoR1 and AdipoR2 in the kidney directly. Activated AdipoR1 and AdipoR2 increase the expression of Ca2+/calmodulin-dependent protein kinase kinase-β (CaMKKβ), phosphorylated Ser431 liver kinase B1 (LKB1), and phosphorylated Thr172 AMPK. They also promote the expression of PPAR and thus relieve lipid deposition and endothelial dysfunction [61]. Additionally, adiponectin also inhibits the necrotic apoptosis pathway by activating the p38 mitogen-activated protein kinase (MAPK) pathway and further improving renal inflammation in the kidneys of DN rats [62]. Resveratrol is a natural plant polyphenol that regulates inflammation and oxidative stress. Park et al. [63] demonstrated that resveratrol increases the levels of serum adiponectin and decreases albuminuria, inflammation, and apoptosis in db/ db mice. Mechanistically, resveratrol increased AdipoR1 and AdipoR2 expression in the renal cortex. Moreover, AMPK phosphorylation and silent information regulator T1 (SIRT1) expression were increased, and the phosphorylation of the downstream molecules forkhead box class O (FoxO) 1 and FoxO3a was decreased. Additionally, PPARγ was also activated, and the levels of nonesterified fatty acids and triacylglycerol in the kidney were decreased. Conversely, it seems that the opposite result has been observed; namely, serum adiponectin levels were increased in patients with type 1 diabetes with nephropathy compared to individuals in the control group [64]. This result may be due to a compensatory mechanism. Moreover, adiponectin is also involved in the regulation of lipid metabolic processes. It can reduce lipid deposition by promoting the protein expression levels of ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) [65]. Our previous studies have also shown that adiponectin receptor activator (AdipoRon) could activate AMPK by promoting the activation of the adiponectin receptor, thereby promoting the level of renal lipophagy and reducing renal lipid deposition in DN [66].
Moreover, leptin is also an adipokine that can regulate carbohydrate and lipid metabolism [67]. Nehus et al. [68] showed that leptin levels were positively related to TG levels and negatively related to HDL-c concentrations. In the kidney, leptin intervention could activate AMPK, reduce the expression of ADRP and SREBP1c, and ultimately reduce renal lipid deposition in the DN state [69]. In addition to the key proteins involved in the regulation of lipid anabolism described above, abnormal fatty acid mitochondrial β-oxidation is also closely related to the occurrence and development of DN [70]. Overall, increased renal fatty acid synthesis, decreased oxidative metabolism, and altered expression of lipid regulatory proteins contribute to renal lipid deposition in the DN state, and lipid deposition in the kidney aggravates renal injury through different signaling pathways.
4 Adverse Events Caused by Lipid Deposition
4.1 Insulin resistance
Insulin resistance is present in type 2 diabetes, and previous studies have demonstrated that ectopic fat deposition can lead to insulin resistance through multiple pathways. Fatty acids deposited in the liver or skeletal muscles activate protein kinase C theta (PKC-θ), and the activity of insulin receptor substrate 1 (IRS-1)-associated PI3K is subsequently inhibited [71]. Additionally, lipid deposition in pancreatic β-cells reduces the secretion of insulin stimulated by glucose and induces pancreatic islet cell apoptosis, which ultimately leads to the decline of pancreatic islet function and insulin resistance [72]. Numerous studies have demonstrated that insulin resistance is closely related to proteinuria and abnormal renal function. In a study of 1456 Asian individuals over the age of 65 years with an average follow-up of 3.15 years, the incidence of proteinuria, CKD GFR < 60 mL/min/1.73m2, and decreased renal function in insulin-resistant patients were increased by 1.278-, 1.312-, and 1.16-fold, respectively, compared with the control group [73]. Hyperinsulinemia in circulation caused by insulin resistance could activate the local renin angiotensin aldosterone system (RAAS), leading to the proliferation of vascular smooth muscle cells (VSMCs) and hypertrophy [74]. Additionally, insulin resistance also increases the expression of TGF-β. This stimulates the hyperplasia of the mesangial matrix and thickening of the basement membrane of renal glomeruli, eventually leading to proteinuria [75].
4.2 Perirenal and renal sinus lipid deposition
Lipid deposition in the perirenal and renal sinuses can be diagnosed by multislice computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound. In a cross-sectional study of 151 patients with type 2 diabetes, measurements of para- and perirenal fat thickness from the inner side of abdominal muscle tissue to the surface of the kidney were performed. Para- and perirenal fat thickness were identified as independent risk factors for renal injury and directly affect renal function in type 2 diabetes [76]. Additionally, in 146 patients at risk for diabetes, lipid deposition in the renal sinus was identified as an independent risk factor for exerciseinduced proteinuria [77]. Moreover, a study of 205 participants between the ages of 55 years and 85 years who were at risk for cardiovascular events demonstrated that increased renal sinus fat compresses the renal lymphatic system and obstructs renal outflow tract venous reflux. Additionally, it increases renal intrarenal hydrostatic pressure, activates the RAAS system, and further aggravates insulin resistance and hypertension [78]. The above evidence suggests that lipid deposition in the perirenal and renal sinuses will further aggravate the progression of DN.
4.3 Other factors
In the kidney, different renal innate cells have different responses to high glucose stimulation. As an important part of the kidney that plays a reabsorption function, renal tubular cells are very active in metabolism. Lipiduria is considered to be a manifestation secondary to hyperlipidemia, which is mainly due to the filtration of high-density lipoprotein particles [79]. The increased levels of lipiduria expose the renal tubules to large amounts of lipids. Increased lipids in the urine (long-chain acyl-CoA [LC-CoA]) competitively disrupt the binding of the Na+/H+ exchanger (NHE1) to phosphatidylinositol 4,5-bisphosphate in renal tubular cells, thereby promoting renal tubular cell apoptosis. However, inhibition of LC-CoA preserves NHE1 activity and prevents apoptosis in the proximal tubule cells [80]. Moreover, in DN, the decreased expression of Annexin A1 (ANXA1) in tubular cells accelerates renal lipid accumulation. However, ANXA1 overexpression can alleviate renal lipid deposition, thereby inhibiting renal tubular cell apoptosis and fibrosis [81]. Moreover, our group also observed increased lipid deposition accompanied by decreased expression of Disulfide-bond-A oxidoreductase-like protein (DsbA-L) and aggravated fibrosis in tubular cells in the kidneys of STZ-induced DN mice. However, DsbA-L overexpression alleviated lipid deposition and fibrosis in the kidney. Another study demonstrated that the effect of DsbA-L on lipid protection is achieved by activating the AMPK signaling pathway [28].
In addition to tubular cells, Ang II also promotes the accumulation of lipids in human renal mesangial cells (HMCs), and low-density lipoprotein receptor (LDLr), SREBP-cleavage activating protein (SCAP), and SREBP-2 mRNA, and protein expression were increased after Ang II treatment. Furthermore, lipid loading promoted the expression of fibrosis factors such as collagen I, α-smooth muscle actin, and fibronectin [82]. Similarly, there is also a large amount of lipid deposition in HMCs in rats with a high-fat diet and STZ-induced DN. Treatment with astragaloside IV significantly inhibited renal lipid deposition and downregulates the expression of fibrosis proteins to delay kidney injury [83]. Similar results were also observed in podocytes. In vitro and in vivo studies have shown that inflammation causes podocyte lipid accumulation through the dysregulation of the LDLr pathway in DN, leading to podocyte injury and accelerating the progression of DN [84].
5 Conclusion
Lipid metabolism disorders are closely related to the occurrence and development of DN. In a diabetic state, the abnormal expression of lipid metabolic proteins in the kidney, excessive synthesis of lipids, and reduced fatty acid oxidation result in lipid deposition in the kidney. The deposition of lipids in the kidney exacerbates the pathological progression of DN by promoting the activation of the RAAS system and increasing the expression of profibrotic factors. Treatment with lipid-lowering agents can alleviate the pathological damage of DN. There are still many aspects to be revealed in the future, such as the molecular mechanism of renal lipid deposition in DN. Additionally, compounds that specifically inhibit renal lipid deposition also need to be identified. However, renal lipid deposition provides a new theoretical basis for studying the pathogenesis of DN and is expected to provide new therapeutic targets and approaches for the prevention and treatment of DN.
Funding statement: This work was supported by the Natural Science Foundation of Hunan Province (No. 2021JC0003), the National Key R&D Program of China (No. 2018YFC1314002), and the National Natural Science Foundation of China (No. 81730018).
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Author Contribution
Yang M: Conceptualization, Methodology, Software. Liu Y: Data curation, Writing-Original draft preparation. Luo S: Visualization, Investigation. Xiao Y: Supervision. Zhao C: Software, Validation. Sun L: Writing-Reviewing and Editing. All authors have read and approve the final manuscript.
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Conflict of Interest
Lin Sun is the Associate Editor of the journal. The article was subject to the journal’s standard procedures, with peer review handled independently of this editor and his research groups.
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Data Sharing
Not applicable.
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© 2023 Ming Yang, Yan Liu, Shilu Luo, Ying Xiao, Chanyue Zhao, Lin Sun, published by De Gruyter on behalf of the SMP
This work is licensed under the Creative Commons Attribution 4.0 International License.
Articles in the same Issue
- Commentary
- One organ’s antidote is another organ’s poison
- Review
- Renal lipid deposition and diabetic nephropathy
- Mini Review
- The burden of diabetic nephropathy in India: Need for prevention
- Original Article
- Efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system in diabetic kidney disease: A meta-analysis
Articles in the same Issue
- Commentary
- One organ’s antidote is another organ’s poison
- Review
- Renal lipid deposition and diabetic nephropathy
- Mini Review
- The burden of diabetic nephropathy in India: Need for prevention
- Original Article
- Efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system in diabetic kidney disease: A meta-analysis
