Pathogenesis Of Diabetic Kidney Disease

Diabetic kidney disease (DKD) is one of the common chronic complications of diabetic patients. It refers to chronic kidney disease (DKD) caused by diabetes, manifested as elevated urinary protein levels (urinary albumin-to-creatinine ratio ≥ 30 mg/g) and ( Or) Estimated glomerular filtration rate (eGFR) <60ml. min ¯¹. (1.73m²)¯¹ and lasted for more than 3 months, while excluding other etiologies of CKD and making a clinical diagnosis.

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DKD can damage the kidney in a variety of ways. Renal blood vessels, glomeruli, and renal tubules can all be involved in the progression of the disease. The pathogenesis is complex, and the exact mechanism has not yet been clarified. Genetic factors, hemodynamic effects, inflammatory response, metabolic disorders, oxidative stress, glomerular pathological changes, and cell damage may be involved in the pathogenesis of DKD. Further research on the pathogenesis of DKD is of great significance to the clinical treatment of DKD.

The pathogenesis of DKD is very complex and is the result of the interaction of genes, epigenetics, and a social system composed of complex behavioral and environmental factors.

(1) Metabolic disorders, abnormal renal hemodynamics, activation of the renin-angiotensin-aldosterone system (RAAS), oxidative stress, and inflammation are all involved in the occurrence and development of DKD. The combined effects of the above factors cause damage to glomerular podocytes and endothelial cells, leading to the widening of the mesangial matrix and thickening of the glomerular basement membrane, atherosclerosis, tubular atrophy, and fibrosis, which can be monitored clinically proteinuria and/or decreased glomerular filtration rate (GFR).

1) Hemodynamic effects.  Hemodynamic effects play an important regulatory role in the development of DKD. Hyperglycemia increases the passage of glucose through the glomerular filtration barrier, resulting in excessive reabsorption of glucose by the proximal tubules. Increased expression of glucose transporters and a large increase in energy-dependent transport processes in proximal tubular cells combined to promote excessive reabsorption of glucose, a change that greatly increased the oxygen demand of the renal cortex and medulla, inducing renal relative ischemia and increased expression of cellular stress markers such as neutrophil gelatinase-associated lipocalin and kidney injury molecule 1. Increased loading of the proximal tubules results in hypertrophy and elongation of the proximal tubules, and hypertrophy of the kidney. Sodium-glucose cotransporter 2 in the proximal tubule transports large amounts of sodium while reabsorbing glucose, resulting in a decrease in sodium chloride concentration in the distal tubule and in the macula densa, which is subsequently sensed by the macula densa with reduced sodium ion concentrations Dilate the afferent arteriole through the feedback of the bulb, induce the granule cells to secrete renin, and generate angiotensin II through the sequential activation of the angiotensin family, and selectively contract the efferent arteriole. The above hemodynamic effects make GFR continue to rise. High, causing glomerular ultrafiltration and glomerular hypertension. With the progressive development of glomerular hypertrophy, glomerular pressure decreased, but glomerular ultrafiltration persisted. In clinical treatment, active regulation of hypertension is very important for the treatment of DKD. As one of the independent risk factors of diabetes, hypertension plays an important role in the development of DKD, and the mutual influence of the two can promote the progressive decline of GFR.

2) Disorders of glucose metabolism.

A. Hyperglycemia promotes the enhancement of the hexosamine pathway

Glucose in the body provides energy for the body through the glycolytic pathway, the tricarboxylic acid cycle, and the ATP produced by oxidative phosphorylation. In the hyperglycemic state, glucose oxidation pathways are disrupted in endothelial cells, mesangial cells, and podocytes, allowing the conversion of glucose to alternative biofuels such as fatty acids and ketones and resulting in cellular damage. Simultaneously, the glycolytic pathway, glucose aerobic and anaerobic metabolism, was increased in the proximal tubule, and the hexosamine pathway, in which fructose-6-phosphate was diverted from the glycolytic pathway, was significantly enhanced at 6 -Glucosamine 6-phosphate is generated under the action of phosphofructoyltransferase, and finally converted into uracil N-acetylglucosamine diphosphate; among them, glucosamine reduces the ATP level in the cell, thereby inhibiting the upstream of the insulin signal transduction pathway Phosphorylation of the target is activated, thereby inhibiting insulin effects and exacerbating metabolic disorders.

B. Hyperglycemia leads to enhanced polyol pathway

The polyol pathway is catalyzed by aldose reductase and sorbitol dehydrogenase, and aldose reductase is the rate-limiting enzyme of this pathway. Aldose reductase reduces glucose to sorbitol during the conversion of reduced nicotinamide adenine dinucleotide phosphate (NADPH) to nicotinamide adenine dinucleotide phosphate. Normally, aldose reductase has a low affinity for glucose and the polyol pathway is in a state of low metabolic rate. Under hyperglycemic conditions, the affinity of aldose reductase for glucose increases, and the polyol pathway is activated and metabolized to produce large amounts of sorbitol. Due to the poor permeability of kidney cells to sorbitol, its oxidized product fructose is not easily metabolized, resulting in a sharp increase in intracellular osmotic pressure, which eventually leads to edema and damage to kidney cells and affects physiological functions, thereby further aggravating kidney damage.

C. Hyperglycemia induces an increase in advanced glycation end products

AGEs are the end products of non-enzymatic catalytic reactions between proteins, fats, nucleic acids, and reducing sugars in the state of high glucose in the body, which can promote the release of transforming growth factor-β, stimulate the synthesis of collagen matrix components, and lead to GBM thickening, thereby It affects the function of the filtration membrane, eventually leading to the progressive change of GFR and the loss of glomerular function. Furthermore, the interaction of AGEs with their receptors plays an important role in the pathogenesis of DKD. AGEs receptor is a multi-ligand receptor widely present in smooth muscle cells, macrophages, endothelial cells, and astrocytes. During hyperglycemia, AGEs bind to AGEs receptors on macrophages, resulting in oxidative stress response and nuclear factor-κB (nuclear factor-κB, NF-κB) activation, and NF-κB regulates interleukin (interleukin, IL)-1α, The release of cytokines such as IL-6 and tumor necrosis factor-α activates the inflammatory response, which in turn exacerbates renal cell damage. In addition, NF-κB can also promote the expression and release of endothelin 1 and vascular endothelial growth factor. These cytokines can mediate the injury of vascular endothelial cells and the apoptosis of tissue cells, thereby aggravating the damage to glomerular function. A study of long-term diabetic patients (duration >50 years) found that non-DKD patients had higher glomerular pyruvate kinase levels than DKD patients, suggesting that maintaining glucose oxidation is important for preventing podocyte and glomerular damage.

3) Abnormal lipid metabolism is involved in the development of DKD

Abnormal lipid metabolism can be involved in the development of DKD through various pathways. Renal lipid accumulation and fatty acid oxidation changes in diabetic patients are important links in the progression of DKD. Hyperlipidemia increases the fatty acid content of albumin, and albumin-bound long-chain saturated fatty acids may play an important role in renal tubular damage. Renal tubular epithelial cells take up long-chain fatty acids through the CD36 transporter, and the expression of CD36 in diabetic patients is up-regulated, which further aggravates the accumulation of fatty acids. The accumulated fatty acids induce apoptosis of renal tubular epithelial cells by activating the p38 mitogen-activated protein kinase pathway. In addition, it has been shown that an increase in the amount of non-esterified fatty acids bound to albumin leads to mitochondrial dysfunction and superoxide production, ultimately inducing apoptosis in renal tubular epithelial cells. In addition to increased fatty acid uptake, increased lipid synthesis in the kidney is also an important cause of lipid accumulation. Sterol-regulatory element binding proteins (SREBPs) are responsible for regulating cholesterol synthesis, uptake, and fatty acid biosynthesis. Mammalian SREBPs are co-encoded by sterol regulatory element-binding transcription factor-1 and sterol regulatory element-binding transcription factor-2. The expression of SREBP1 messenger RNA is significantly increased during hyperglycemia, and the level of triacylglycerol in the kidney is significantly increased, which further aggravates the Disorders of lipid metabolism and lipid accumulation in the kidneys. Glomerular lipid deposition can also stimulate the accumulation of extracellular matrix (ECM), which eventually leads to glomerulosclerosis and progressive impairment of renal function.

4) Inflammatory response. DKD is generally regarded as an inflammatory response disease, and the level of inflammation increases with the progress of the disease, eventually leading to glomerulosclerosis. Studies have shown that renal inflammatory markers are associated with proteinuria, ECM deposition, and progressive decline in GFR. In the early stage of DKD, a large number of leukocytes accumulate in the glomerulus and tubulointerstitium, and the infiltration of inflammatory cells and the release of inflammatory factors play an important role in the development of DKD. The activation and sustained expression of inflammation-related genes and pathways play a key role in the development of DKD. Due to tissue damage, a large number of inflammatory cells gather in the kidney tissue, and a large number of inflammatory cells and their products [such as cytokines, chemokines, activated complement, and reactive oxygen species (reactive oxygen species, ROS)] induce the production of DKD. In the presence of glomerular ultrafiltration and renal fibrosis, knockout of Rag1 did not lead to diabetes-associated proteinuria. In addition, chemokine receptor inhibitors reduce proteinuria in patients with type 2 diabetes and chronic kidney disease. The degree of accumulation of inflammatory cells in the kidneys of diabetic rat models is closely related to the decline in renal function, and inhibiting the recruitment of inflammatory cells can significantly reduce kidney damage. It can be seen that inhibiting the aggregation of renal inflammatory cells can effectively prevent the production of proteinuria and reduce kidney damage. Inflammatory factors play a key role in the development of DKD. In DKD, the expression of cytokines such as chemokine 5, IL-6, tumor necrosis factor-α, and monocyte chemoattractant-1 was increased. The massive release of IL-6 and tumor necrosis factor-α enhanced the local inflammatory response of the kidney, promoted the proliferation of mesangial cells, accelerated the deposition of ECM, and aggravated the renal injury. Knockout or inhibition of monocyte chemoattractant-1 can effectively delay the progression of DKD. The activation of NF-κB and Janus kinase-signal transducer and activator of transcription signal transduction pathway is the key to cytokine production, both of which can accelerate the process of DKD by regulating the expression of stimulating adhesion molecules and pro-inflammatory factors.

5) Oxidative stress. Hyperglycemia can induce the generation of toxic intermediates, and ROS is one of the most important intermediates. ROS plays an important role in the physiological processes of proliferation, differentiation, apoptosis, and immune defense of various cells. The accumulation of ROS and the generation of superoxide are important causes of DKD in hyperglycemia, which can easily lead to ESRD. Xanthine oxidase, cytochrome P450, uncoupled endothelial nitric oxide synthase, mitochondrial respiratory chain, and NADPH oxidase all play important roles in ROS synthesis, among which mitochondrial dysfunction and NADPH oxidase are the most important. Under physiological conditions, xanthine oxidase in the kidney can generate undetectable ROS through the purine metabolic pathway. Studies by Eid et al. have shown that cytochrome P450 (especially cytochrome 4A) can induce the production of ROS by activating NADPH oxidase, causing kidney cell damage and death in diabetic mice. Uncoupled endothelial nitric oxide synthase can promote the generation of ROS and induce a decrease in the availability of nitric oxide in endothelial cells, while the accumulation of nitric oxide can lead to endothelial cell dysfunction and damage the filtration membrane function. In addition, the oxidation of mitochondrial substrates in diabetic patients is enhanced, the mitochondrial membrane potential is enhanced, and electrons are transferred through the mitochondrial electron transport chain which lead to superoxide production. Under physiological conditions, the constitutive activity of most NADPH oxidases is low, but the activity of NADPH oxidases is activated in diabetes. All NADPH oxidase subtypes are transmembrane proteins that transfer electrons from NADPH to the entire biomembrane and subsequently reduce oxygen molecules to superoxide O2-, which produces more than superoxide in vivo The processing capacity of dismutases leads to the accumulation of superoxide in the kidneys. In addition, the local inflammatory response of the kidney in the state of hyperglycemia is strengthened, a large number of inflammatory factors are released, and the generation of ROS is increased. local inflammation in the kidney tissue of DKD patients. Studies have shown that oxidative stress can also damage pancreatic β-cells, which are more susceptible to ROS due to the lower level of superoxide dismutase in pancreatic β-cells. ROS can promote apoptosis by directly destroying the DNA and protein of islet β cells, and can also be used as a signaling molecule to participate in the regulation of insulin secretion, thereby indirectly inhibiting the function of islet β cells and leading to further aggravation of glucose metabolism disorders. In addition, ROS can induce damage and apoptosis of endothelial cells and podocytes in various ways, leading to dysfunction, and the structure of the glomerular filtration membrane is subsequently destroyed, which eventually causes kidney damage and proteinuria.

(2) Glomerular hyperfiltration is more common in T1D, and its pathophysiological mechanism is not clear. The possible mechanism is speculated to be:

(1) Increased glucose reabsorption by proximal tubules through sodium-glucose cotransporter 2, which in turn induces a decrease in NaCl concentration in the macula densa, leading to weakened tubule feedback and dilation of afferent arterioles to increase glomerulus perfusion.

(2) Increased local production of angiotensin II leads to constriction of the efferent arterioles, and the overall effect is high glomerular internal pressure and high filtration.

(3) Existing research results have found that genetic factors cannot fully explain the pathogenesis of DKD, and the influence of epigenetics and environmental factors on the occurrence and development of DKD has received extensive attention.

Diabetes can lead to systemic microvascular disease, and DKD is the most common and major microvascular complication and has become the main cause of new ESRD. The pathogenic factors and pathogenesis of DKD are intricate, involving the activation of multiple cells and multiple signaling pathways. Genetic factors, hemodynamic effects, inflammatory response, metabolic disorder, oxidative stress, glomerular pathological changes, and cell damage play a crucial role in the pathogenesis of DKD, and their combined effects lead to the pathogenesis of DKD. occur and develop. Sodium-glucose cotransporter 2 has been the research focus of DKD treatment in recent years. Sodium-glucose cotransporter 2 inhibitors can effectively improve glomerular ultrafiltration and slow down the process of DKD. In addition, the use of renin-angiotensin-aldosterone system blockers can reduce the incidence of albuminuria in hypertensive patients while regulating blood pressure, but there is still a lack of specific drugs for the clinical treatment of DKD, and the pathogenesis of DKD and treatment methods still need further research.