Luis Francisco Gómez-Hermosillo

Kidney transplantation (KT) remains the optimal therapy for end-stage kidney disease (ESKD), yet long-term graft survival is limited by unremitting allograft dysfunction and non-immune treatment toxicities. Sterile inflammation primarily drives graft failure. This inflammatory process releases damage-associated molecular patterns (DAMPs). DAMPs activate pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) 2 and 4, from proximal tubule epithelial cells, endothelial compartments, and infiltrating myeloid lineages. PRR signaling and the release of pro-inflammatory cytokines (IL-1β, IL-18, TNF-α) promote pro-inflammatory M1 macrophage polarization and accelerate interstitial fibrosis and tubular atrophy (IFTA). While maintenance immunosuppression prevents adaptive rejection, it causes severe metabolic, cardiovascular, and oncologic complications, including post-transplant diabetes mellitus, hypertension, and malignancies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (dapagliflozin, empagliflozin, canagliflozin) have emerged as novel disease-modifying, immunomodulatory adjuncts that act independently of glycemic control. SGLT2 inhibition reactivates tubuloglomerular feedback to relieve intraglomerular hypertension, blunts hyperfiltration, and reduces tubular transport workload. This alleviates cortical hypoxia, curtails mitochondrial ROS production, and activates AMP-activated protein kinase (AMPK) to suppress NF-κB and NLRP3 inflammasome assembly. SGLT2 inhibitors downregulate TLR expression, drive a phenotypic shift toward reparative M2 macrophages, reduce proteinuria, and provide sustained volume decongestion without triggering compensatory activation of the renin–angiotensin–aldosterone system. By targeting both upstream bioenergetic strain and downstream fibrotic remodeling (YAP/TAZ axis), SGLT2 inhibitors complement standard immunosuppression to protect allograft architecture, reduce cardiovascular morbidity, and improve long-term transplant outcomes.

Obesity affects the adaptability of adipose tissue (AT), impairing its ability to regulate energy and metabolism. Obesity is associated with many metabolic disorders, including dyslipidemia, hypertension, sleep disorders, non-alcoholic liver disease, and some types of cancer. Toll-like receptors (TLRs) are important in obesity and related metabolic disorders. TLRs are pattern-recognizing receptors (PRRs) involved in the innate immune system and recognize pathogen-associated molecular patterns (PAMPs) and endogenous ligands. TLRs, especially TLR2 and TLR4, are activated by fatty acids, endotoxins, and other ligands. TLR2 and TLR4 activation triggers inflammatory responses. Chronic inflammation driven by TLR activation is a hallmark of obesity and metabolic diseases. The inflammatory response triggered by TLR activation alters insulin signaling, contributing to insulin resistance, a key feature of metabolic syndrome and type 2 diabetes. Modulation of TLR activity through lifestyle changes (diet and exercise), obesity surgery, and pharmacological agents is under study as a possible therapeutic approach to controlling obesity and its complications.

Renal involvement is an important cause of morbidity and mortality in systemic lupus erythematosus (SLE). The present study included patients with recently diagnosed Class III and Class IV lupus nephritis (LN) treated by Rheumatology who, upon the detection of alterations in their kidney function, were referred to Nephrology for the joint management of both medical specialties. The purpose of this study was to compare the plasma expression of Toll-Like Receptor 7 (TLR7) and TLR9 in healthy control (HC) subjects and newly diagnosed Class III and Class IV LN patients with 12-month follow-ups. The plasma expression of TLR7 and TLR9 proteins was determined by the ELISA method. A significant increase in the expression of TLR7 protein was found in Class III LN in the basal determination compared to the expression in the HC (p = 0.002) and at 12 months of follow-up (p = 0.03) vs. HC. The expression of TLR9 showed a behavior opposite to that of TLR7. TLR9 showed decreased protein expression in LN Class III patients’ baseline and final measurements. The result was similar in the basal and final determinations of LN Class IV compared to the expression in HC. A significant decrease in SLEDAI -2K was observed at 12 months of follow-up in patients in Class III (p = 0.01) and Class IV (p = 0.0001) of LN. Complement C3 levels improved significantly at 12-month follow-up in Class IV patients (p = 0.0001). Complement C4 levels decreased significantly at 12-month follow-up in LN Class III compared to baseline (p = 0.01). Anti-DNA antibodies decreased significantly at 12 months of follow-up in Class IV LN (p = 0.01). A significant increase in proteinuria was found at 12 months of follow-up in Class III LN, compared to the baseline determination (p = 0.02). In LN Class IV, proteinuria decreased at 12 months of follow-up compared to baseline (p = 0.0001). Albuminuria decreased at 12 months of follow-up in LN Class IV (p = 0.006). Class IV LN, albuminuria also decreased at 12 months of follow-up (p = 0.009). Hematuria persisted in all patients and the glomerular filtration rate did not change. Three Class IV patients died before 12 months of follow-up from various causes. In conclusion, although the rheumatologic data appeared to improve, the renal function data remained inconsistent. Decreased expression of TLR9 and increased expression of TLR7 could be useful in the early diagnosis of Class III and Class IV LN is correct.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) and is considered one of the leading causes of mortality. Multiple immunological pathways are involved in the pathogenesis of SLE, which makes it imperative to deepen our knowledge about this disease’s immune-pathological complexity and explore new therapeutic targets. Since an altered redox state contributes to immune system dysregulation, this document briefly addresses the roles of oxidative stress (OS), oxidative DNA damage, antioxidant enzymes, mitochondrial function, and mitophagy in SLE and LN. Although adaptive immunity’s participation in the development of autoimmunity is undeniable, increasing data emphasize the importance of innate immunity elements, particularly the Toll-like receptors (TLRs) that recognize nucleic acid ligands, in inflammatory and autoimmune diseases. Here, we discuss the intriguing roles of TLR7 and TLR9 in developing SLE and LN. Also included are the essential characteristics of conventional treatments and some other novel and little-explored alternatives that offer options to improve renal function in LN.

Obesity and hypertension are health problems of increasing prevalence in developed countries. The link between obesity and hypertension is not yet fully determined. Oxidative stress (OS) and mitochondrial function may play a role in obesity-associated hypertension. A cross-sectional study with 175 subjects with normal weight, overweight, or obese who attended a medical check-up was included. The subjects were divided according to the body mass index (BMI) into normal-weight (n-53), overweight (n-84), and obesity (n-38). Hypertension was also evaluated. To measure mitochondrial function, ATP hydrolysis and ATP synthesis in platelets and serum, respectively, were determined. Superoxide dismutase (SOD), catalase, lipohydroperoxides, 8-isoprostanes, carbonyl groups in proteins, nitric oxide (NO) metabolites, 8-hydroxy-2′-deoxyguanosine (8-OHG), 8-oxoguanine glycosylase (hOGG1), tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) were measured by standard colorimetric or immunoassay methods. Obese subjects showed lower ATP hydrolysis activity than normal weight and overweight subjects (p < 0.01). No differences between those groups were found in ATP synthase and catalase activities, lipid hydroperoxides, carbonyl groups in proteins, 8-isoprostanes, and NO metabolites. In the obesity group, SOD activity (p < 0.01) was decreased while 8-OHG (p < 0.01) was increased. Subjects with hypertension showed increased 8-OHG (p < 0.01) and less reparative enzyme (hOGG1 p = 0.04) than subjects with normal weight. Moreover, we found a decrease of SOD (p < 0.01), catalase activities (p = 0.04), NO metabolites (p < 0.01), and increases of carbonyl groups in proteins (p = 0.01), TNF-α (p < 0.01) and IL-6 (p < 0.01 in hypertensive subjects. Obese subjects show a decrease in ATP hydrolysis. The decrease in ATP hydrolysis rate and ATP synthesis and an increase in OS and inflammation markers were associated with the hypertensive state.