pharmaceuticals

Review
Targeting Renal Proximal Tubule Cells in
Obesity-Related Glomerulopathy
Muyao Ye 1,† , Ming Yang 1,† , Wenni Dai 1 , Hao Li 1 , Xun Zhou 1 , Yinyin Chen 2,3 and Liyu He 1, *

1 Department of Nephrology, The Second Xiangya Hospital, Central South University,

Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha 410011, China;
[email protected] (M.Y.); [email protected] (M.Y.)
2 Department of Nephrology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan
Normal University, Changsha 410081, China
3 Changsha Clinical Research, Changsha 410011, China
* Correspondence: [email protected]; Tel.: +86-73185292064
† These authors contributed equally to this work.

Abstract: As a metabolic disorder, obesity can cause secondary kidney damage, which is called
obesity-related glomerulopathy (ORG). As the incidence of obesity increases worldwide, so does
the incidence of end-stage renal disease (ESRD) caused by ORGs. However, there is still a lack of
effective strategies to prevent and delay the occurrence and development of ORG. Therefore, a deeper
understanding and elaboration of the pathogenesis of ORG is conducive to the development of
therapeutic drugs for ORG. Here, we review the characteristics of pathological lesions of ORG and
describe the roles of lipid metabolism disorders and mitochondrial oxidative stress in the development
of ORG. Finally, we summarize the current available drugs or compounds for the treatment of ORG
and suggested that ameliorating renal lipid metabolism and mitochondrial function may be potential
therapeutic targets for ORG.

Keywords: renal proximal tubule cells; obesity-related glomerulopathy; lipid metabolism; oxidative stress

Citation: Ye, M.; Yang, M.; Dai, W.; Li,

1. Introduction
H.; Zhou, X.; Chen, Y.; He, L.
Targeting Renal Proximal Tubule Kidney damage due to obesity, called obesity-related glomerulopathy (ORG), is now
Cells in Obesity-Related an important cause of chronic kidney disease and its incidence is increasing with the
Glomerulopathy. Pharmaceuticals global obesity epidemic [1,2]. ORG has various histopathological alterations, including
2023, 16, 1256. https://doi.org/ glomerular hypertrophy, focal segmental glomerulosclerosis, lipid deposition, etc. Positive
10.3390/ph16091256 oil red O lipid staining of renal biopsy tissue under a light microscope is considered the
common manifestation of ORG. Recently, multiple studies showed that tubule injury is
Academic Editor: Fedora Grande
also involved in ORG [3,4]. Altered lipid metabolism leads to ectopic lipid accumulation,
Received: 3 August 2023 especially in the kidney, which plays a key role in ORG progression. Lipids can induce
Revised: 27 August 2023 lipotoxicity in podocytes, renal proximal tubular cells (PTCs), and mesangial cells [5]. Renal
Accepted: 31 August 2023 lipotoxicity often leads to increased levels of oxidative stress, which in turn leads to renal
Published: 5 September 2023 cell apoptosis and fibrosis [6–8]. As a hypermetabolic site, renal PTCs are enriched with
a large number of mitochondria to provide energy for their reabsorption of substances [9].
In the kidney of ORG, the oxidative stress level is increased due to the increased production
of reactive oxygen species (ROS) and the suppressed FFA-induced antioxidant response in
Copyright: © 2023 by the authors.
renal PTCs [10].
Licensee MDPI, Basel, Switzerland.
With continuous intensive research, the mechanism of ORG has experienced new
This article is an open access article
advances, especially the important role of oxidative stress in proximal tubular injury.
distributed under the terms and
conditions of the Creative Commons
Since ORG is a metabolic disease, the lipid metabolism process in PTCs is similar to
Attribution (CC BY) license (https://
that of diabetic nephropathy (DN). There are more studies on renal tubular lesions in
creativecommons.org/licenses/by/ diabetes. With the gradual recognition of the importance of renal tubular injury in ORG,
4.0/). clinicians proposed ORN (obesity-related nephropathy) to highlight the injury of the

Pharmaceuticals 2023, 16, 1256. https://doi.org/10.3390/ph16091256 https://www.mdpi.com/journal/pharmaceuticals

Pharmaceuticals 2023, 16, 1256 2 of 14

tubulointerstitium, just like the conversion from DN to diabetic kidney disease (DKD). In
this review, we cover different aspects of oxidative stress-related mechanisms in PTC and
discuss the potential therapeutic target for ORG.

2. Histopathology of ORG
The histopathology of ORG contains glomerular, tubulointerstitial, and vascular le-
sions. Glomerular alterations of ORG are widely recognized as glomerular hypertrophy,
focal segmental glomerulosclerosis, accompanied by segmental basement membrane thick-
ening [11]. Some showed macrophage infiltration and upregulation of proinflammatory
factors such as tumor necrosis factor α (TNF-α), monocyte chemotactic protein-1 (MCP-1),
nuclear factor kappa-B (NF-κB), and profibrotic cytokines transforming growth factor-β
(TGF-β) [5]. Lipid droplets were detected in both glomerular and PTCs, but predominantly
in PTCs [12]. The hypertrophy and apoptosis of podocytes and mesangial cells caused
glomerulomegaly [13]. Urinary alpha-1-acid glycoprotein (α1-AGP), albumin-to-creatinine
ratio, and podocyte-specific proteins mRNA were tested as biomarkers of early glomerular
damage in ORG [14].
Tubulointerstitial lesions contain tubular hypertrophy, atrophy, fibrosis, etc. Glomeru-
lar hypertrophy increases intra-glomerular pressure and drives glomerular filtration barrier
injury, resulting in proteinuria. Glomerular hyperfiltration is also associated with tubular
hypertrophy by the increased proximal tubular ultrafiltrate flow rate [15]. The majority of
plasma-free fatty acid (FFA) is carried on albumin and provides ATP for the kidney by the
mitochondrial β-oxidation of FFA. Albumin can be retrieved partly by the renal proximal
tubules, resulting in intracellular lipid droplet deposition [16]. FFA-bound albumin-related
oxidative stress is involved in the pathogenesis of PTC damage. Because the kidney is
composed largely of tubular structures, tubular hypertrophy contributes to the relatively
low glomerular density [17]. The vascular lesions are not specific in ORG, including dilation
of the capillaries and glomerular arterioles around the vascular pole of glomeruli [11].

3. Mechanisms Involved in PTC Injury in the ORG

Lipoprotein and lipid metabolism abnormalities play a crucial role in the progres-sion
of renal injury. The oxygen requirement of the kidney is very large, so the glomerular
and PTC are very sensitive to hypoxia. In particular, renal PTC is highly dependent on
aerobic metabolism [9]. Obese patients have endogenous hypoxia, which stimulates the
secretion of inflammatory molecules [18]. The aggregation of inflammatory cells leads to
increased local oxygen consumption, which in turn leads to the aggravation of hypoxia
and injury. The disorder of lipid metabolism in ORG leads to excessive fat deposition in
renal PTC and lipid metabolism ultimately also requires oxidative reaction in mitochondria
to produce ATP, so the study of mitochondrial dysfunction is gradually being carried out.
In addition, hypoxia caused by local mechanical compression caused by fat deposition has
gradually attracted attention in ORG. This review will describe the hypoxia and oxidative
stress injury of renal PTC in ORG from different aspects.

3.1. Renal Sinus Fat Compression Reduced Tubular Perfusion and Induced Renal Hypoxia
Fat deposition may occur in different areas of the kidney, including the perirenal area
outside the renal capsule, the hilum, the renal sinus, and the retroperitoneal space [19].
Recently, many studies have focused on the renal sinus because of its special location. Fat
deposition may occur in different areas of the kidney, including the perirenal area outside
the renal capsule, the hilum, the renal sinus, and the retroperitoneal space. It locates in
the center of the kidney, where fat is mostly deposited. Increased renal sinus fat (RSF)
directly compresses various renal structures, resulting in tissue perfusion and tubular flow
decrease [20]. The local ischemia and low tubular flow rate induce physical renal hypoxia.
The serum kidney injury molecule-1 (sKIM-1) was elevated by the RSF accumulation, as
a marker of renal tubular injury [21]. All the above reasons may stimulate increased renal
Pharmaceuticals 2023, 16, 1256 3 of 14

sodium reabsorption. So, RSF increase was considered to be positively associated with
increased renal hypertension and chronic kidney disease (CKD) development [22].
The increase in RSF is not specific in ORG; it also occurs in DN because of glucose
intolerance [23]. The blood oxygen level-dependent magnetic resonance (MR) imaging
showed that lipid accumulation in diabetic kidneys affected the renal cells’ oxygenation
and made them more susceptible to renal hypoxia [24]. RSF increases in the early stage of
diabetes and obesity and is associated with cardiovascular risk factors. This showed that
RSF may be the link between metabolic disease and associated renal disease, even serving
as an early non-invasive examination marker.
Weight loss can reduce fat deposition in the whole body, including the kidney. The
renal cells oxygenate and make them more susceptible to renal hypoxia. Weight loss in
obese and overweight people can reduce RSF [25] and further lower blood pressure and
proteinuria. The plasma creatinine concentration and glomerular filtration rate (GFR)
decreased significantly in the early stage of weight loss, but not significantly with long
observation [26]. RSF can be a target of ORG prevention and monitoring.

3.2. Lipid Metabolism in PTC

FFA is the preferred energy source for PTC, which is more effective than glucose.
Almost all plasma fatty acids are bound to albumin, with only a very small percentage
being FFA. Under normal conditions, albumin cannot pass through the glomerular filtra-
tion barrier; a small amount of FFA is reabsorbed from ultrafiltrate by receptor-mediated
endocytosis [27]. Almost all plasma fatty acids are bound to albumin, with only a very
small percentage being FFA (Figure 1). After ingestion, FFA is converted to acyl-coenzyme
A molecules and catalyzed by carnitine palmitoyl transferase-1 (CPT1) into mitochondria.
According to the energy demand of cells, intracellular fatty acids are directed to mitochon-
drial β-oxidation, or stored as triglyceride in intracellular lipid droplets if excessive. In the
process of FFA producing ATP, mitochondrial aerobic metabolism is crucial. Ischemia and
hypoxia lead to decreased FFA oxidation and the conversion of FFA to triglyceride. The FFA
in kidney is extracted from the circulation and requires more than half of the oxygen con-
sumed by the kidneys for oxidation. The mitochondrial β-oxidation of FFA provides most
of the ATP for the kidney [19]. The proximal tubules have high energy requirements and
relatively small glycolytic capacity, which makes them very sensitive to hypoxia. Almost
all plasma FFA is carried by albumin. Although weight loss is beneficial to obesity-related
diseases in long-term observation, fasting may be detrimental to serum FFA levels and
cause FFA-induced damage to renal PTC in a short period, especially on the premise of the
damaged glomerular filtration barrier and proteinuria. The physiological role of insulin
is the facilitation of glucose uptake and utilization, inhibition of FFA released by adipose
tissue, and ultimately enhancement of lipogenesis. During fasting, the decreased blood
glucose induced the decreased insulin level, thus promoting the decomposition of triacyl-
glycerol in adipocytes into FFA. So, FFA is the energy source for various tissues. In both
diabetic and non-diabetic subjects, fasting increases serum FFA levels [28]. In non-diabetic
people, serum FFA levels rapidly decrease after meals. However, FFA remains high in
diabetic and obese patients, who have impaired insulin action. Therefore, it is important
to explore the mechanism of FFA-induced damage to renal PTCs and protect them from
FFA-induced lipotoxicity.
FFAs are classified into monounsaturated, polyunsaturated, and saturated fatty acids.
Saturated FFAs are highly cytotoxic among them. The increased saturated FFAs are consid-
ered to contribute to PTC damage and podocyte injury in diabetic nephropathy. Saturated
FFAs damage PTCs via multiple mechanisms such as the TLR4-dependent pathway, DAG-
PKCθ pathway, and oxidative stress, which act on NF-κB leading to inflammation and
directly induce cell death or apoptosis [29]. In addition, the albumin-bound nonesterified
fatty acids (NEFA, also known as FFA) that passed through the damaged glomerular filtra-
tion barrier can also be reabsorbed by the proximal tubule through fatty acid transporter-2
(FATP2), causing lipid accumulation and lipoapoptosis [29].
Pharmaceuticals 2023, 16, 1256 4 of 14

Figure 1. The albumin-bound FFA is reabsorbed by PTCs. FFAs are stored as LDs in normal persons,
but increased LDs and FFAs can lead to lipotoxicity and cell death in obese patients. Abbreviation:
FA: fatty acid; FFA: free fatty acid; Alb: albumin; LDs: lipid droplets.

3.3. Lipotoxicity in the PTC

The intracellular accumulation of lipids in non-adipose tissue can cause lipotoxicity,
resulting in cellular dysfunction and cell death. Most cells have limited carrying capacity
for excessive intracellular lipids. Once the threshold and storage for lipid metabolism have
been exceeded, the excessive lipid exerts lipotoxic effects. The released lipid metabolites
can lead to malfunction of proteins, aberrant lipid modification, and membrane disruption.
The ROS generation, endoplasmic reticulum (ER) stress, and transporters and signaling
enzymes are activated; then, apoptosis is increased [30]. Renal lipotoxicity occurs in
metabolism diseases, such as diabetic nephropathy and ORG. The lipids deposit mostly
in the renal tubular epithelial cells, and toxic fatty acid metabolites induce inflammatory
cytokine production, oxidative stress, ER stress, ROS generation, mitochondrial dysfunction,
and autophagy in PTCs [31,32]. In a sense, the final result of most of the above mechanisms
is to promote the oxidative stress of renal PTCs and eventually cause apoptosis (Figure 2).
There are many studies on inflammatory cytokine in renal PTC of Fas-induced renal injury,
such as interleukin 1β (IL-1β), IL-18, cluster of differentiation 36 (CD36), MCP-1, and NOD-
like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome [33,34].
With the massive recruitment of inflammatory cells, the oxygen needs to increase, leading to
the production of ROS, which causes oxidative injury to proximal tubules. The activation of
the NLRP3 inflammasome depends on oxidized low-density lipoprotein (ox-LDL)-induced
generation of ROS depending on CD36 [35].
CD36 is also called scavenger receptor B2, and can mediate the uptake of protein-
bound FAs by tissue cells in obesity and lipid metabolism [36]. In the kidney, CD36 mainly
expresses in tubular epithelial, podocytes, and mesangial cells, where lipid deposition
usually occurs, and lipid droplets can be detected by Oil Red O staining in kidney samples.
Exposure to albumin and advanced oxidation protein products promotes the expression
of CD36 in PTC. Moreover, CD36 may be regulated by peroxisome proliferator-activated
receptor (PPAR)-γ, which belongs to fatty acid oxidation adjustment factors [37]. Dysregu-
lation of PPAR activity affects the β-oxidation of FAs and is a potential cause of metabolic
syndrome-related disorders, such as hyperlipidemia and insulin resistance. In addition,
the advanced oxidation protein products (AOPPs) can induce lipotoxicity, apoptosis, and
Pharmaceuticals 2023, 16, 1256 5 of 14

fibrosis via the CD36 receptor pathway in proximal tubular epithelial cells [38]. Carnitine
palmitoyl transferase 2 (CPT2) can convert acylcarnitine to long-chain acyl-CoA and FAs
and promote β-oxidation. ER stress inhibits CPT2 and in turn promotes lipid accumulation,
leading to lipotoxicity [39]. The consequences of lipid deposition in the kidneys depend not
only on the amount of lipids deposited, but also on the characteristics of the kinds of lipids
that accumulate. Studies have shown significant increases in triglyceride and cholesterol
levels in the kidneys of high-fat diet (HFD)-treated mice [40], as well as the accumulation
of phospholipids [41]. Moreover, Lanzon et al. found significant differences in serum
metabolomics in severely obese patients with and without CKD [42]. Most lipid types
are increased in obese patients with kidney disease and serum short chain TG levels were
negatively correlated with estimated glomerular filtration rate (eGFR) [42]. In addition,
after weight-loss surgery, the renal function of CKD patients was significantly improved,
and the levels of various lipids including unsaturated phosphatidylethanolamine were also
significantly decreased [42].

Figure 2. Increased lipid synthesis and decreased lipid oxidation occur simultaneously in obese
patients. As mitochondria are the site of FFA undergoing β-oxidation to produce ATP, mitochondrial
dysfunction induces increased oxidative stress and eventually leads to impaired renal function.

Adenosine monophosphate-activated protein kinase (AMPK) is mostly expressed in

cortical tubular epithelial cells and may lead to renal cell dysfunction and then develop into
ORG. Since AMPK promotes fatty acid oxidation and inhibits fatty acid synthesis by phos-
phorylation of acetyl-CoA carboxylase, the decrease in AMPK inhibits the oxidation of FAs
and induces renal lipid depositions in the proximal tubule in ORG. In addition, the mark-
ers of oxidative stress, the urinary hydrogen peroxide and 8-hydroxy-20 -deoxyguanosine
(8-OHdG, a marker of oxidative damage) levels, increased in obesity [43]. HFD can activate
renal AMPK, upregulate fatty acid oxidation (FAO) enzymes, and finally induce autophagy
in the mouse PTC [44].
Macroautophagy/autophagy can protect the kidney from injury through lysosomal
degradation. Some researchers considered that autophagy deficiency can lead to renal
injury in obesity. Sustained high autophagic flux in PTC leads to metabolic syndrome, and
lipid overload-stimulated macroautophagy/autophagy is a novel mechanism of lipotoxicity
in PTC. Eicosapentaenoic acid (EPA) promoted lipid droplet formation and then migrated
from the lipid droplet to the mitochondria for β-oxidation. EPA alleviated renal lipotoxicity
via restored autophagic flux and the production of mitochondrial ROS [45,46]. Similarly,
the abnormal autophagy mediated by Mas (the G-protein coupled receptor of angiotensin)
is involved in the occurrence of lipid-induced tubular injury of obesity-related kidney
diseases [47]. Other studies about oxidative stress injury in PTC are gradually being
discovered. As mitochondria are β-oxidation sites, more studies focus on the oxidative
stress of mitochondria.
Pharmaceuticals 2023, 16, 1256 6 of 14

3.4. Mitochondrial Dysfunction in Proximal Tubular Injury

Mitochondria are the site of FAs that undergo β-oxidation to produce ATP. Insufficient
oxidation of intracellular fatty acids is a critical pathogenic factor causing renal lipotoxicity.
Lipid overload in renal PTC causes mitochondrial dysfunction, ultimately causing the
production of ROS and apoptosis. FFA-bound bovine serum albumin (BSA) stimulates
ROS accumulation and expression of MCP-1 in PTC and can be ameliorated by overex-
pression of Sirtuin 3 (SIRT3), which is localized in mitochondria [48]. FAs-induced high
levels of ROS lead to mitochondrial dysfunction in PTCs, which in turn promotes more
ROS. Damaged mitochondria decrease fatty acid β-oxidation capacity and ATP synthe-
sis, resulting in further lipid accumulation. Mitochondria-targeted antioxidant SS31 is
specifically concentrated on the inner membrane of mitochondria, which is also the site
for ROS production. SS31 reduced lipid accumulation and increased autophagy, restoring
renal AMPK activity [5,49]. In addition, calcium overload in mitochondria affects the
β-oxidation of FFA; the activation of the Mas receptor increased the protein expression of
the voltage-dependent anion channel (VDAC1), which is located on the outer membrane of
mitochondria facilitating calcium transport into mitochondria [47]. Animal studies showed
that the loss of biliverdin reductase A (BVRA) in renal PTC caused impaired mitochon-
drial respiration and β-oxidation [50]. The intracellular lipid droplets are connected to
mitochondria through a part of it, which is known as the peridroplet mitochondria [51,52].
The disorder of lipid metabolism affects the process of FA transport from lipid droplets
to mitochondria, thus affecting the β-oxidation of FA and ATP production, or causing the
overflow of FFA from lipid droplets, resulting in lipotoxicity [52]. However, the role of
peridroplet mitochondria in renal PTC of ORG needs further research to be verified.

4. Treatment of ORG
4.1. Weight Loss
ORG is renal damage caused by obesity, so the preferred treatment is weight loss.
The ways to lose weight include calorie restriction, physical exercise, and a good lifestyle,
and when the effects of these methods are not sufficient, another way to lose weight is
surgery [53,54]. Adequate physical exercise can stimulate muscle tissue to secrete large
amounts of myokines [55–57], and our previous review also described in detail the pro-
tective effect of myokines in delaying the progression of kidney disease [58]. In addition
to that, Rebelos et al. recruited 23 morbidly obese women and 15 age- and sex-matched
non-obese controls to measure renal volume and radiodensity by computed tomography,
and showed higher total renal blood flow and increased eGFR in the obese group than
in the control; FFA uptake in the kidneys was about 50% higher in the obese group [59].
However, after bariatric surgery, the renal FFA uptake rate decreased, the renal hemo-
dynamic changes were reversed, and the structural changes were improved in the obese
group [59]. In addition, in a study conducted by Serra et al. to determine the long-term
effects of substantial weight loss on renal function in morbidly obese patients with ORG
lesions, it was found that 92 morbidly obese patients with mild obesity-related glomeru-
lopathy who had substantial weight loss after bariatric surgery had normal renal function
confirmed by renal biopsy [60]. In addition, blood pressure decreased early after surgery
and remained stable thereafter; creatinine clearance decreased during the first 2 years,
increased slightly after 5 years, and then remained stable. Moreover, the decreases in serum
creatinine and proteinuria levels occurred throughout the follow-up period [60]. Although
bariatric surgery may preserve renal function through weight loss, the procedure carries
certain risks and complications that warrant further surgical evaluation.

4.2. RAAS Inhibitors

There is increasing evidence that abnormal glomerular filtration is one of the patho-
geneses of ORG. In the obese state, the number of functional nephrons is reduced, and com-
pensatory changes in the kidney lead to vasodilatation of afferent arterioles and increased
intraglomerular hydrostatic pressure, which eventually lead to hyperfiltration [61,62].
Pharmaceuticals 2023, 16, 1256 7 of 14

Given the central role of RAAS in the pathogenesis of ORG, another effective therapeu-
tic approach is to block the activation of the RAAS system using angiotensin-converting
enzyme inhibitors (ACEIs) or angiotensin II type I receptor blockers (ARBs). In a post
hoc analysis assessing the efficacy of ramipril in a renal disease (REIN) trial, a greater
reduction in the risk of renal events (ESRD or doubling of serum creatinine) with ramipril
was found in obese patients compared with non-obese patients [63]. Moreover, ramipril
can also increase insulin sensitivity in non-diabetic obese patients, which is a key factor in
promoting ORG [64]. Although studies specifically targeting non-diabetic obese subjects
are limited, the protective effect of RASS inhibitors in ORG is expected as it is an important
treatment for reducing urinary protein in kidney disease to delay its progression.

4.3. Maintenance of Lipid Metabolic Homeostasis

Lipid metabolism disorder is also an important risk factor for ORG. Therefore, lipid-
lowering is a therapeutic modality to relieve ORG. Chen et al. have demonstrated more
severe lipid accumulation and inflammation and aggravated kidney injury in angiotensin-
converting enzyme 2 (ACE2) knockout ORG mouse model, while ACE2 overexpression
activated the NF-E2-related factor 2 (Nrf2) pathway and alleviated kidney pathological
injury by reducing lipid deposition and inflammatory response [65]. Statins are a class of
lipid-lowering drugs commonly used in the clinic. Studies have shown that simvastatin
intervention effectively reduces the levels of tissue factor (TF) and plasminogen activator
inhibitor-1 (PAI-1) in mesangial cells [66]. This means that simvastatin plays a kidney-
protective role by inhibiting the formation of microthrombus in hypercholesterolemic
conditions. Similarly, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are
also a class of effective lipid-lowering drugs and side effects are less common in patients
with CKD [67]. In the future, it may also serve as a therapeutic target for maintaining
lipid homeostasis in ORG patients. Resveratrol is an anticancer hormone mainly found
in mulberry, peanut, grape, and other plants. It has a variety of biological activities such
as antioxidant, anti-inflammatory, cardiovascular protection, and anti-aging [68]. It was
reported that resveratrol could reduce renal lipid deposition by regulating the junctional
adhesion molecule-like (JAML)/sirtuin 1 (Sirt1) lipid synthesis pathway, thereby reducing
renal injury in diabetic nephropathy state [69]. What is more, resveratrol also increased the
expression of adiponectin receptor 1 (AdipoR1) and AdipoR2 in renal PTC [70]. Han et al.
reported that when renal AdipoR1 is activated, it can activate the AMPK/lipophagy
signaling pathway in cells, thereby alleviating lipid deposition in DN [71]. Moreover,
pterostilbene, a methylated derivative of pterostilbene, also showed lipid-regulating effects.
Gu et al. have shown that pterostilbene could inhibit the expression of sterol regulatory
element binding transcription factor 1 (SREBP-1) and FAS protein and downregulate TGF-
β1 and p-smad3 expression, and finally relieve ectopic lipid deposition, and reduce renal
tubular injury and fibrosis in the kidney of high-fat-diet-fed mice [72]. In addition to
these compounds, it has also been shown that mitochondria-associated ER membranes
(MAMs) are indispensable for the maintenance of cellular lipid metabolism. MAMs are
the subcellular structure that mediates the exchange of signals and substances between
mitochondria and ER [73,74]. One of its major functions is to participate in intracellular
lipid metabolism and synthesis [75]. Abnormality of its structure and function can lead
to a disorder of intracellular lipid metabolism. In terms of kidney disease, the degree of
its structural destruction is also closely related to renal lipid deposition in patients with
DN [76]. However, there is no study on the structure and function of MAMs in ORG, but
MAMs may be a potential research direction for lipid kidney injury in ORG in the future
due to their importance in lipid metabolism.

4.4. Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i)

SGLT2i is a new class of oral hypoglycemic drug that has received great attention
in recent years; it can inhibit the reabsorption of glucose by the kidney and promote the
excretion of glucose in urine [77,78]. Several SGLT2 inhibitors, including empagliflozin,
Pharmaceuticals 2023, 16, 1256 8 of 14

dapagliflozin, and canagliflozin, have been approved for clinical use [79–81]. Several
studies have confirmed that SGLT2i plays a protective role in delaying the progression of
kidney diseases [82–84]. In addition to its direct reno-protective effects, SGLT2i has also
been shown to significantly reduce body weight, potentially in part by increasing energy
expenditure and enhancing fatty acid oxidation [85]. Moreover, it may also alleviate ORG
kidney injury by reducing renal lipid deposition, inflammation, and oxidative stress [86].

4.5. Adipokines
Excessive and unhealthy obesity is the main onset factor of ORG. Under these condi-
tions, there is an unhealthy expansion of adipose tissue, and both structure and function
are affected to some extent. In the human body, adipose tissue not only serves as a storage
site for fat but also secretes a series of proteins called adipokines that affect distal tissues
or organs through endocrine action [87,88]. Leptin was discovered in 1994 and is mainly
released by white adipose tissue [89]. After it is synthesized and secreted by adipose tissue,
it circulates to the hypothalamus through the blood and binds to specific receptors, then pro-
motes the anorexigenic neuropeptide circuits and inhibits orexigenic neuropeptide circuits
and leads to a decrease in food intake and an increase in energy expenditure [90–92]. Leptin
knockout mice are commonly used as an obesity mouse model (ob/ob mice) [93,94]. In ad-
dition to leptin, adiponectin is also an adipokine secreted mainly by adipose tissue [95,96].
Xu et al. found decreased adiponectin expression in serum samples from HFD-fed mice,
accompanied by downregulation of podocyte markers and increased levels of inflammation
and apoptosis [97]. The intervention of adiponectin significantly alleviated renal injury,
while inhibition of adiponectin expression aggravated renal inflammation, oxidative stress,
and apoptosis [97]. To date, more than one hundred adipokines have been characterized,
and their functions in kidney disease have been described in detail in our previous re-
view [98]. Although the current research on adipokines is still in its infancy, the deepening
of research on their role in the progression of kidney disease, especially ORG, is worth
looking forward to.

4.6. Mitochondrial Homeostasis

Given the importance of mitochondrial disorders in ORG, maintaining the func-
tion of mitochondria is also a potential treatment for ORG therapy. Intervention with
1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-(polyethylene glycol)-ss31 (SS-31) (a mi-
tochondrial protective peptide) improved the mitochondrial structure of renal cells, upregu-
lated AMPK activity, and reduced intracellular lipid accumulation, endoplasmic reticulum
stress, and apoptosis in the kidney of mice fed an HFD [5]. A similar result was also ob-
served that INT-777 could induce mitochondrial biogenesis, reduce oxidative stress levels,
and increase fatty acid β-oxidation to relieve obesity-related kidney injury [99]. In the
future, more specific mitochondrial protective agents need to be sought to further elucidate
the importance of mitochondria in the development of ORG.

4.7. Others
In addition to the treatments mentioned above, some drugs have also been reported
to prevent or delay the progression of ORG. Glucagon-like peptide-1 receptor agonists
(GLP-1 RAs) could also slow the progress of ORG in different ways. On the one hand,
GLP-1 RAs can promote urinary sodium excretion by inhibiting Na/H exchange 3 in the
proximal renal tubules, and thus inhibit the activation of RAAS [100]. On the other hand,
it can also effectively reduce the weight of obese patients, whether they have diabetes
or not [101,102]. These characteristics suggest its feasibility in the treatment of ORG. Sul-
foraphane is a bioactive ingredient found in abundance in cauliflower, kale, and other
cruciferous plants. It could ameliorate insulin resistance and glucose intolerance in HFD-
induced obese mice [103]. Moreover, it also could inhibit malondialdehyde protein (MDA)
accumulation induced by obesity and increase superoxide dismutase (SOD) levels, thus
reducing obesity-related injury [104]. A recent study also showed that sulforaphane inter-
Pharmaceuticals 2023, 16, 1256 9 of 14

vention reduced body weight, organ-associated fat weight, and urinary albumin/creatinine
ratio in obese mice [105]. Furthermore, sulforaphane also upregulated the specific protein
expression level of the podocyte and improved the podocyte function [105]. Moreover,
other compounds, such as eicosapentaenoic acid [45], Coptidis Rhizoma [106], and lipoxin
A4 [107] may also be potential targets for ORG therapy (Table 1).

Table 1. Potential treatments or drugs for obesity-related glomerulopathy.

Measures/Compounds Categories Ref.

Exercise [54]
Weight loss
Bariatric surgery [60]
RAAS inhibitors Ramipril [63]
Simvastatin [66]
PCSK9i [67]
Lipid regulation
Resveratrol [69]
Pterostilbene [72]
Dapagliflozin [86]
SGLT2i
Empagliflozin [86]
SS-31 [5]
INT-777 [99]
Sulforaphane [105]
Others
Eicosapentaenoic acid [45]
Coptidis Rhizoma [106]
Lipoxin A4 [107]

5. Conclusions and Perspectives

As the number of obese people worldwide increases, the prevalence of ORG will
gradually increase. Many factors are involved in the occurrence and development of ORG,
while lipid metabolism disorder plays a major role in this process. In this review, we sum-
marize the pathogenesis of ORG and current treatment options. Although a comprehensive
understanding of the pathogenesis of ORG has been achieved, there are still many problems
that need to be solved in the future for more effective prevention and treatment of ORG.
At present, there is still a lack of early diagnostic markers for ORG, which makes the early
diagnosis of ORG difficult. In addition, the effectiveness and feasibility of bariatric surgery
in ORG remain to be validated. Once these outstanding issues are resolved, ORG can be
effectively prevented and treated.

Author Contributions: Writing—original draft preparation, M.Y. (Muyao Ye), M.Y. (Ming Yang) and
W.D.; writing—review and editing, H.L., X.Z., Y.C. and L.H. All authors have read and agreed to the
published version of the manuscript.
Funding: This work was supported by the Hunan Provincial Natural Science Foundation for Out-
standing Youth [No. 2022JJ10093], Scientific Research Project of Hunan Provincial Health Commission
[No. B202303056777], Natural Science Foundation of Hunan Province [No. 2019JJ50889].
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data sharing is not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Pharmaceuticals 2023, 16, 1256 10 of 14

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