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Biomedicines
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Pathological Mechanisms of Diabetic Nephropathy
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Pathological Mechanisms of Diabetic Nephropathy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Endocrinology and Metabolism Research".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 26168

Special Issue Editor

Dr. Isha Sharma

E-Mail Website
Guest Editor
Department of Pathology, Northwestern University, Chicago, IL 60611, USA
Interests: chronic kidney disease; acute kidney injury; molecular biology; protein biochemistry; cell biology; reproductive biology

Special Issue Information

Dear Colleagues,

Diabetic nephropathy (DN) poses a monumental economic burden on any given country’s infrastructure. Therefore, it is important for investigators to come up with novel and renewed mechanisms of DN progression, which can potentially lead to the identification of new drug targets and novel therapies. In the last half a century, multiple pathways have been explored. Perturbations in these pathways lead to end-stage renal disease (ESRD) and a major cause of morbidity and mortality in both type 1 and 2 diabetic patients. For instance, a hyperglycemic or hyperlipidemic state in diabetes leads to the exacerbation of reactive oxygen species, which in turn consume the antioxidant capacity of cells, leading to oxidant stress—a common causative factor observed in the pathogenesis of diabetic nephropathy. The increase in oxidant stress is just a preliminary factor responsible for the activation of a multitude of pathological pathways such as ferroptosis, apoptosis, necroptosis, pyroptosis, and inflammation and lipid toxicity terminally leading to tubulointerstitial fibrosis. Besides these, exploring other alternate mechanisms in DN can help researchers to identify new pathways. The therapeutic usages of these pathways can substantially attenuate the progression of diabetes-mediated chronic kidney injury and ESRD.

In view of this, we welcome submissions to this Special Issue on the pathological mechanism of diabetic nephropathy. Detailed knowledge of signaling mechanisms would allow increasingly targeted therapy for DN patients. Therefore, we welcome authors to address the following themes:

  • Signaling mechanisms leading to hyperglycemia or obesity-driven tubulointerstitial fibrosis.
  • Hypertension-induced renal injury in diabetes. The cross-talk between metabolic and hemodynamic pathways in amplifying diabetes-related renal injury.
  • Lipid- or glucose-driven metabolic-sensor or post-translational perturbations that leads to renal fibrosis.
  • Glucagon-like peptide-1 receptor agonist in dampening the development and progression of diabetes-mediated renal disorders.
  • Role of various types of cell death in diabetes and obesity-driven nephropathy.

Dr. Isha Sharma
Guest Editor

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Keywords

  • oxidant stress (mitochondrial, cytosolic)
  • hyperglycemia mediated altered mitochondrial dynamics
  • apotosis, inflammation
  • tubulointerestitum injury
  • hypertension induced renal injury in diabetes
  • lipid toxicity
  • endoplasmic reticulum stress
  • ferroptosis
  • hyperglycemia induced altered hippo-pathway
  • metabolic sensors

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Published Papers (7 papers)

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Research

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11 pages, 1892 KiB  
Article
Regulation of Renin Expression by Β1-Integrin in As4.1 Juxtaglomerular Line Cells
by Nobumichi Saito, Masao Toyoda, Masumi Kondo, Makiko Abe, Noriyuki Sanechika, Moritsugu Kimura, Kaichiro Sawada and Masafumi Fukagawa
Biomedicines 2023, 11(2), 501; https://doi.org/10.3390/biomedicines11020501 - 9 Feb 2023
Viewed by 2071
Abstract
(1) Background: Renal dysfunction and hypertension are mutually aggravating factors; however, the details of their interaction remain unclear. In a study using renal tissue from diabetic rats, we found that β1-integrin, a cell-substrate adhesion molecule, is specifically phosphorylated in juxtaglomerular cells that secrete [...] Read more.
(1) Background: Renal dysfunction and hypertension are mutually aggravating factors; however, the details of their interaction remain unclear. In a study using renal tissue from diabetic rats, we found that β1-integrin, a cell-substrate adhesion molecule, is specifically phosphorylated in juxtaglomerular cells that secrete renin, a blood pressure regulator. (2) Methods: A mouse juxtaglomerular cell line (As4.1 cells) was used for the following experiments: drug-induced promotion of β1-integrin phosphorylation/dephosphorylation; knockdown of β1-integrin and the cell adhesion molecule connexin-40 (a candidate for the main body of baroreceptor); and pressurization to atmospheric pressure + 100 mmHg. culture in hypotonic liquid medium. The expression of renin under these conditions was measured by qRT-PCR. (3) Results: Phosphorylation of β1-integrin suppressed the expression of renin, while dephosphorylation conversely promoted it. β1-integrin and connexin-40 knockdown both promoted the expression of renin. Pneumatic pressurization and hypotonic medium culture both decreased the expression of renin, which was restored by the knockdown of β1-integrin. (4) Conclusions: β1-integrin plays an inhibitory role in the regulation of the expression of renin, which may be controlled by phosphorylation and dephosphorylation. It is hypothesized that β1-integrin and other adhesion factors regulate the expression of renin by altering the sensitivity of baroreceptors on the plasma membrane. Full article
(This article belongs to the Special Issue Pathological Mechanisms of Diabetic Nephropathy)
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21 pages, 5564 KiB  
Article
A Cyclopentanone Compound Attenuates the Over-Accumulation of Extracellular Matrix and Fibrosis in Diabetic Nephropathy via Downregulating the TGF-β/p38MAPK Axis
by Chunyin Tang, Meng Wang, Jieting Liu, Chunlei Zhang, Luxin Li, Yan Wu, Yanhui Chu, Dan Wu, Haifeng Liu and Xiaohuan Yuan
Biomedicines 2022, 10(12), 3270; https://doi.org/10.3390/biomedicines10123270 - 16 Dec 2022
Cited by 8 | Viewed by 1929
Abstract
Excessive accumulation of the extracellular matrix (ECM) is a crucial pathological process in chronic kidney diseases, such as diabetic nephropathy, etc. The underlying mechanisms of how to decrease ECM deposition to improve diabetic nephropathy remain elusive. The present study investigated whether cyclopentanone compound [...] Read more.
Excessive accumulation of the extracellular matrix (ECM) is a crucial pathological process in chronic kidney diseases, such as diabetic nephropathy, etc. The underlying mechanisms of how to decrease ECM deposition to improve diabetic nephropathy remain elusive. The present study investigated whether cyclopentanone compound H8 alleviated ECM over-deposition and fibrosis to prevent and treat diabetic nephropathy. HK-2 cell viability after treatment with H8 was measured by an MTT assay. ECM alterations and renal fibrosis were identified in vitro and in vivo. A pharmacological antagonist was used to detect associations between H8 and the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. H8 binding was identified through computer simulation methods. Studies conducted on high glucose and transforming growth factor β1 (TGF-β1)-stimulated HK-2 cells revealed that the p38MAPK inhibitor SB 202190 and H8 had similar pharmacological effects. In addition, excessive ECM accumulation and fibrosis in diabetic nephropathy were remarkably improved after H8 administration in vivo and in vitro. Finally, the two molecular docking models further proved that H8 is a specific p38MAPK inhibitor that forms a hydrogen bond with the LYS-53 residue of p38MAPK. The cyclopentanone compound H8 alleviated the over-deposition of ECM and the development of fibrosis in diabetic nephropathy by suppressing the TGF-β/p38MAPK axis. Full article
(This article belongs to the Special Issue Pathological Mechanisms of Diabetic Nephropathy)
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17 pages, 3434 KiB  
Article
Nephroprotective Effects of Semaglutide as Mono- and Combination Treatment with Lisinopril in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease
by Louise S. Dalbøge, Michael Christensen, Martin Rønn Madsen, Thomas Secher, Nicole Endlich, Vedran Drenic’, Alba Manresa-Arraut, Henrik H. Hansen, Ida Rune, Lisbeth N. Fink and Mette V. Østergaard
Biomedicines 2022, 10(7), 1661; https://doi.org/10.3390/biomedicines10071661 - 11 Jul 2022
Cited by 17 | Viewed by 5723
Abstract
Background: Obesity, hyperglycemia and hypertension are critical risk factors for development of diabetic kidney disease (DKD). Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients. Here, we characterized the effect of the [...] Read more.
Background: Obesity, hyperglycemia and hypertension are critical risk factors for development of diabetic kidney disease (DKD). Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients. Here, we characterized the effect of the long-acting GLP-1R agonist semaglutide alone and in combination with an ACE inhibitor (lisinopril) in a model of hypertension-accelerated, advanced DKD facilitated by adeno-associated virus-mediated renin overexpression (ReninAAV) in uninephrectomized (UNx) female diabetic db/db mice. Methods: Female db/db mice received a single intravenous injection of ReninAAV 1 week prior to UNx. Six weeks post-nephrectomy, db/db UNx-ReninAAV mice were administered (q.d.) vehicle, semaglutide (30 nmol/kg, s.c.) or semaglutide (30 nmol/kg, s.c.) + lisinopril (30 mg/kg, p.o.) for 11 weeks. Endpoints included blood pressure, plasma/urine biochemistry, kidney histopathology and RNA sequencing. Results: Vehicle-dosed db/db UNx-ReninAAV mice developed hallmarks of DKD characterized by severe albuminuria and advanced glomerulosclerosis. Semaglutide robustly reduced hyperglycemia, hypertension and albuminuria concurrent with notable improvements in glomerulosclerosis severity, podocyte filtration slit density, urine/renal kidney injury molecule-1 (KIM-1) levels and gene expression markers of inflammation and fibrogenesis in db/db UNx-ReninAAV mice. Co-administration of lisinopril further ameliorated hypertension and glomerulosclerosis. Conclusions: Semaglutide improves disease hallmarks in the db/db UNx-ReninAAV mouse model of advanced DKD. Further benefits on renal outcomes were obtained by adjunctive antihypertensive standard of care. Collectively, our study supports the development of semaglutide for management of DKD. Full article
(This article belongs to the Special Issue Pathological Mechanisms of Diabetic Nephropathy)
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Review

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19 pages, 2068 KiB  
Review
Glycation-Associated Diabetic Nephropathy and the Role of Long Noncoding RNAs
by Ankita Durge, Isha Sharma and Rashmi Santosh Tupe
Biomedicines 2022, 10(10), 2623; https://doi.org/10.3390/biomedicines10102623 - 19 Oct 2022
Cited by 3 | Viewed by 2581
Abstract
The glycation of various biomolecules is the root cause of many pathological conditions associated with diabetic nephropathy and end-stage kidney disease. Glycation imbalances metabolism and increases renal cell injury. Numerous therapeutic measures have narrowed down the adverse effects of endogenous glycation, but efficient [...] Read more.
The glycation of various biomolecules is the root cause of many pathological conditions associated with diabetic nephropathy and end-stage kidney disease. Glycation imbalances metabolism and increases renal cell injury. Numerous therapeutic measures have narrowed down the adverse effects of endogenous glycation, but efficient and potent measures are miles away. Recent advances in the identification and characterization of noncoding RNAs, especially the long noncoding RNAs (lncRNAs), have opened a mammon of new biology to explore the mitigations for glycation-associated diabetic nephropathy. Furthermore, tissue-specific distribution and condition-specific expression make lncRNA a promising key for second-generation therapeutic interventions. Though the techniques to identify and exemplify noncoding RNAs are rapidly evolving, the lncRNA study encounters multiple methodological constraints. This review will discuss lncRNAs and their possible involvement in glycation and advanced glycation end products (AGEs) signaling pathways. We further highlight the possible approaches for lncRNA-based therapeutics and their working mechanism for perturbing glycation and conclude our review with lncRNAs biology-related future opportunities. Full article
(This article belongs to the Special Issue Pathological Mechanisms of Diabetic Nephropathy)
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17 pages, 1619 KiB  
Review
Nephroprotective Properties of the Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) Receptor Agonists
by Tomislav Bulum
Biomedicines 2022, 10(10), 2586; https://doi.org/10.3390/biomedicines10102586 - 15 Oct 2022
Cited by 11 | Viewed by 3928
Abstract
Diabetes mellitus is the leading cause of chronic kidney disease, and about 30–40% of patients with diabetes will develop kidney disease. Incretin hormones have received attention during the past three decades not only as a pharmacotherapy for the treatment of type 2 diabetes, [...] Read more.
Diabetes mellitus is the leading cause of chronic kidney disease, and about 30–40% of patients with diabetes will develop kidney disease. Incretin hormones have received attention during the past three decades not only as a pharmacotherapy for the treatment of type 2 diabetes, but also for their cardiorenometabolic effects. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Additional to the pancreas, receptors for GLP-1 are widely distributed in various organs, causing positive effects on endothelial function and vascular atherogenesis. Along with glycemic control and weight reduction, GLP-1 receptor agonists also strongly improve cardiovascular and renal outcomes in patients with type 2 diabetes. Recently, a dual GIP and GLP-1 receptor agonist has been approved for the treatment of type 2 diabetes. Compared to GLP-1 receptor agonist semaglutide, dual GIP and GLP-1 receptor agonist tirzepatide showed a superior reduction in hemoglobin A1c and body weight. Preliminary results also suggest that tirzepatide improves kidney outcomes in adults with type 2 diabetes with increased cardiovascular risk. In this review, we present the nephroprotective properties of dual GIP and GLP-1 receptor agonists as a new drug to treat type 2 diabetes. Full article
(This article belongs to the Special Issue Pathological Mechanisms of Diabetic Nephropathy)
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14 pages, 745 KiB  
Review
Atherosclerosis Specific Features in Chronic Kidney Disease (CKD)
by Anastasia V. Poznyak, Nikolay K. Sadykhov, Andrey G. Kartuesov, Evgeny E. Borisov, Vasily N. Sukhorukov and Alexander N. Orekhov
Biomedicines 2022, 10(9), 2094; https://doi.org/10.3390/biomedicines10092094 - 27 Aug 2022
Cited by 21 | Viewed by 4031
Abstract
Atherosclerosis is the major cause of cardiovascular disease, leading to a high mortality rate worldwide. Several risk factors are known to favor atherogenesis, among which are high blood pressure, smoking, diabetes mellitus, and others. Chronic kidney disease is another serious health problem associated [...] Read more.
Atherosclerosis is the major cause of cardiovascular disease, leading to a high mortality rate worldwide. Several risk factors are known to favor atherogenesis, among which are high blood pressure, smoking, diabetes mellitus, and others. Chronic kidney disease is another serious health problem associated with significant health care costs, morbidity, and mortality. Chronic kidney disease shares several risk factors with atherosclerosis and cardiovascular diseases, such as hypertension and diabetes mellitus. Additional risk factors for cardiovascular disease development should be considered in patients with chronic kidney disease. Interestingly, patients suffering from chronic kidney disease are more prone to cardiovascular problems than the general population. Moreover, chronic kidney disease is characterized by an increased atherosclerotic burden from the very early stages. The purpose of this review was to summarize data on atherosclerosis in chronic kidney disease, highlighting the specific features of the disease combination. Full article
(This article belongs to the Special Issue Pathological Mechanisms of Diabetic Nephropathy)
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17 pages, 1426 KiB  
Review
New Approaches to Diabetic Nephropathy from Bed to Bench
by Jun-Li Tsai, Cheng-Hsu Chen, Ming-Ju Wu and Shang-Feng Tsai
Biomedicines 2022, 10(4), 876; https://doi.org/10.3390/biomedicines10040876 - 9 Apr 2022
Cited by 13 | Viewed by 4503
Abstract
Diabetic nephropathy (DN) is the main cause of end-stage kidney disease (ESKD). DN-related ESKD has the worst prognosis for survival compared with other causes. Due to the complex mechanisms of DN and the heterogeneous presentations, unmet needs exist for the renal outcome of [...] Read more.
Diabetic nephropathy (DN) is the main cause of end-stage kidney disease (ESKD). DN-related ESKD has the worst prognosis for survival compared with other causes. Due to the complex mechanisms of DN and the heterogeneous presentations, unmet needs exist for the renal outcome of diabetes mellitus. Clinical evidence for treating DN is rather solid. For example, the first Kidney Disease: Improving Global Outcomes (KDIGO) guideline was published in October 2020: KDIGO Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. In December of 2020, the International Society of Nephrology published 60 (+1) breakthrough discoveries in nephrology. Among these breakthroughs, four important ones after 1980 were recognized, including glomerular hyperfiltration theory, renal protection by renin-angiotensin system inhibition, hypoxia-inducible factor, and sodium-glucose cotransporter 2 inhibitors. Here, we present a review on the pivotal and new mechanisms of DN from the implications of clinical studies and medications. Full article
(This article belongs to the Special Issue Pathological Mechanisms of Diabetic Nephropathy)
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