Kidney Damage Caused by Obesity and Its Feasible Treatment Drugs

Abstract

The rapid growth of obesity worldwide has made it a major health problem, while the dramatic increase in the prevalence of obesity has had a significant impact on the magnitude of chronic kidney disease (CKD), especially in developing countries. A vast amount of researchers have reported a strong relationship between obesity and chronic kidney disease, and obesity can serve as an independent risk factor for kidney disease. The histological changes of kidneys in obesity-induced renal injury include glomerular or tubular hypertrophy, focal segmental glomerulosclerosis or bulbous sclerosis. Furthermore, inflammation, renal hemodynamic changes, insulin resistance and lipid metabolism disorders are all involved in the development and progression of obesity-induced nephropathy. However, there is no targeted treatment for obesity-related kidney disease. In this review, RAS inhibitors, SGLT2 inhibitors and melatonin would be presented to treat obesity-induced kidney injury. Furthermore, we concluded that melatonin can protect the kidney damage caused by obesity by inhibiting inflammation and oxidative stress, revealing its therapeutic potential.

Keywords: inflammation; kidney damage; melatonin; obesity; oxidative stress; treatment.

Figure 1

The influence of high-fat food on the progression of renal disease. The kidney has a urinary function. Essentially, dissolved materials in the liquid fraction of blood (plasma) are formed into a filtrate by the action of the kidneys. In this way, the kidneys remove waste and recycle filtered nutrients. In addition, the kidney can affect blood pressure by regulating the urine volume and blood volume or secreting vasoactive substances. The kidney also has the function of producing some hormones with endocrine activity, such as 1,25-dihydroxycholecalciferol [1,25-(OH) 2D3], renin, renal prostaglandin and erythropoietin. The body intake of high-calorie food increases the degree of fat accumulation. When a large amount of fat accumulates in the kidney, it accelerates a series of kidney damage, such as inflammation, oxidative stress and subsequent fibrosis. Long-term fat accumulation further leads to proteinuria, glomerular and tubular diseases.

Figure 2

Pathophysiological changes of glomerulus in obesity-related nephropathy. Normal glomerular tissue consists of three parts: endothelial cells in the inner layer, glomerular basement membrane in the middle layer and podocytes in the outer layer. Glomerular hypertrophy and low glomerular density are associated with early obesity-related renal injury, followed by increased glomerular filtration rate and proteinuria. However, podocytes cannot catch up with the speed of glomerular expansion, podocyte failure, further regression and shedding, namely focal segmental glomurular selerosis (FSGS). Finally, glomerulosclerosis leads to severe renal damage.

Figure 3

The changes of renal tubules in obesity-related nephropathy. Renal tubules are tubules surrounded by monolayer epithelial cells, which can reabsorb and secrete some components in urine. Obesity-related kidney disease is characterized by tubular hypertrophy, basement membrane thickening and then interstitial inflammation and fibrosis, and it may thus set the stage for renal failure later in life. In the right picture, red indicates renal interstitial inflammation, and the line indicates renal interstitial fibrosis.

Figure 4

The mechanism by which obesity contributes to kidney injury. In obese individuals, adipose tissue secretes TNF-α, IL-6 and adiponectin. Among them, the pro-inflammatory factor TNF-α, the increase of IL-6 and the decrease of anti-inflammatory factor adiponectin promote the inflammatory response and insulin resistance, and cause the corresponding kidney injury. The lipids in the human body can be roughly divided into cholesterol and neutral fat (triglyceride, phospholipid). Free fatty acid is one of the substances decomposed from neutral fat. When the body is obese, the contents of triglyceride and FFA increase. Then, they are deposited in the kidney, causing toxicity and damage to the kidney and leading to serious lipid metabolism diseases. Similarly, RAAS can also be activated by obesity and promote macrophage infiltration, inflammation, renal vasodilation and glomerular ultrafiltration through a cascade reaction, leading to proteinuria and kidney injury. FFA, free fatty acids; IL-6, interleukin- 6; TNF-α, tumor necrosis factor-α. “↑” represents an increase, and “↓” represents a decrease.

Figure 5

The role of the RAAS system and RAAS inhibitors in obesity-related kidney injury. The renin–angiotensin–aldosterone system (RAAS) is comprised of a series of peptide hormones and corresponding enzymes and is a significant humoral regulatory system. Renin secreted by renal juxtaglomerular cells can convert the angiotensinogen in the blood into angiotensin I without physiological activity. Angiotensin I forms angiotensin II under the action of an angiotensin-converting enzyme (ACE). Adipose tissue can promote the secretion of angiotensin II, which stimulates the secretion of aldosterone and promotes the reabsorption of water and sodium in renal tubules, improves the renal filtration rate and causes proteinuria. Aldosterone stimulates NO synthesis through the mineralocorticoid receptor (MR) or Rac1, which leads to glomerular hyperfunction, renal vasodilation and renal injury. RAAS inhibitors, ARB and ACEI correct the renal filtration efficiency by inhibiting the corresponding substance level in the RAAS system, and then alleviate renal injury. ACE, angiotensin converting enzyme; ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blocker; AT1AR, angiotensin type 1A receptor; AT2AR, angiotensin type 2A receptor; NO, nitrogen oxide; Rac1, ras-related C3 botulinum toxin substrate 1. “↓” represents a decrease.

Figure 6

The mechanism of SGLTs and SGLT-2 inhibitors in obesity-related kidney injury. The reabsorption of glucose in the kidney mainly depends on sodium glucose cotransporters (SGLTs), through which glucose and Na + are transported across the membrane. SGLT-2 was mainly expressed in the kidney, while SGLT-1 was partially expressed in the kidney. About 90% of the glucose was reabsorbed by SGLT-2 in the S1 segment (the beginning of the proximal convoluted tubule and the first 1/3 of the convoluted part in the kidney) of the proximal convoluted tubule. However, SGLT-2 can also regulate inflammatory factors and lipids in proximal tubules, activate glomerular feedback and decrease the glomerular filtration rate, so as to slow down the progression of kidney disease. SGLT-1, sodium-dependent glucose transporters 1; SGLT-2, sodium-dependent glucose transporters 2. “↑” represents an increase, and “↓” represents a decrease.

Figure 7

Therapeutic effect of melatonin on obesity-related kidney injury. Melatonin acts through melatonin receptors on the cells of the kidney. Melatonin can eliminate the excessive free radicals produced by mitochondria through antioxidant enzymes, alleviate mitochondrial dysfunction and play an antioxidant role. Melatonin can down-regulate NLRP3 inflammasome, which participates in the development of renal disease associated with obesity and may be a key regulator of obesity. Melatonin can also inhibit transcription factors including NF-κB, reduce the transcription of pro-inflammatory mediators, thereby reducing the level of inflammation, and fundamentally treat the kidney damage caused by obesity. GPx, Glutathione peroxidase; IL-1β, interleukin-1β; MR, melatonin receptor; NF-κB, nuclear factor kappa-B; NLRP3, NLR Family Pyrin Domain Containing 3; NOX, NADPH oxidase; ROS, reactive oxygen species. “↓” represents a decrease.