Biphasic regulation of Na+-HCO3- cotransporter by angiotensin II type 1A receptor

Although angiotensin (Ang) II is known to regulate renal proximal transport in a biphasic way, the receptor subtype(s) mediating these Ang II effects remained to be established. To clarify this issue, we compared the effects of Ang II in wild-type mice (WT) and Ang II type 1A receptor-deficient mice (AT(1A) KO). The Na+-HCO3- cotransporter (NBC) activity, analyzed in isolated nonperfused tubules with a fluorescent probe, was stimulated by 10(-10) mol/L Ang II but was inhibited by 10(-6) mol/L Ang II in WT. Although valsartan (AT1 antagonist) blocked both stimulation and inhibition by Ang II, PD 123,319 (AT2 antagonist) did not modify these effects of Ang II. In AT1A KO, in contrast, this biphasic regulation was lost, and only stimulation of NBC activity by 10(-6) mol/L Ang II was observed. This stimulation was blocked by valsartan but not by PD 123,319. More than 10(-8) mol/L Ang II induced a transient increase in cell Ca2+ concentrations in WT, which was again blocked by valsartan but not by PD 123,319. However, up to 10(-5) mol/L Ang II did not increase cell Ca2+ concentrations in AT1A KO. Finally, the addition of arachidonic acid inhibited the NBC activity similarly in WT and AT(1A) KO, suggesting that the inhibitory pathway involving P-450 metabolites is preserved in AT(1A) KO. These results indicate that AT(1A) mediates the biphasic regulation of NBC. Although low-level expression of AT(1B) could be responsible for the stimulation by 10(-6) mol/L Ang II in AT1A KO, no evidence was obtained for AT2 involvement.     

Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process

Pseudohypoaldosteronism type II is a salt-sensitive form of hypertension with hyperkalemia in humans caused by mutations in the with-no-lysine kinase 4 (WNK4). Several studies have shown that WNK4 modulates the activity of the renal Na(+)Cl(-) cotransporter, NCC. Because the renal consequences of WNK4 carrying pseudoaldosteronism type II mutations resemble the response to intravascular volume depletion (promotion of salt reabsorption without K(+) secretion), a condition that is associated with high angiotensin II (AngII) levels, it has been proposed that AngII signaling might affect WNK4 modulation of the NCC. In Xenopus laevis oocytes, WNK4 is required for modulation of NCC activity by AngII. To demonstrate that WNK4 is required in the AngII-mediated regulation of NCC in vivo, we used a total WNK4-knockout mouse strain (WNK4(-/-)). WNK4 mRNA and protein expression were absent in WNK4(-/-) mice, which exhibited a mild Gitelman-like syndrome, with normal blood pressure, increased plasma renin activity, and reduced NCC expression and phosphorylation at T-58. Immunohistochemistry revealed normal morphology of the distal convoluted tubule with reduced NCC expression. Low-salt diet or infusion of AngII for 4 d induced phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and of NCC at S-383 and T-58, respectively, in WNK4(+/+) but not WNK4(-/-) mice. Thus, the absence of WNK4 in vivo precludes NCC and SPAK phosphorylation promoted by a low-salt diet or AngII infusion, suggesting that AngII action on the NCC occurs via a WNK4-SPAK-dependent signaling pathway. Additionally, stimulation of aldosterone secretion by AngII, but not by a high-K(+) diet, was impaired in WNK4(-/-) mice.     

Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine

An isoform of the mammalian renal type II Na/P_i-cotransporter is described. Homology of this isoform to described mammalian and nonmammalian type II cotransporters is between 57 and 75%. Based on major diversities at the C terminus, the new isoform is designed as type IIb Na/P_i-cotransporter. Na/P_i-cotransport mediated by the type IIb cotransporter was studied in oocytes of Xenopus laevis. The results indicate that type IIb Na/P_i-cotransport is electrogenic and in contrast to the renal type II isoform of opposite pH dependence. Expression of type IIb mRNA was detected in various tissues, including small intestine. The type IIb protein was detected as a 108-kDa protein by Western blots using isolated small intestinal brush border membranes and by immunohistochemistry was localized at the luminal membrane of mouse enterocytes. Expression of the type IIb protein in the brush borders of enterocytes and transport characteristics suggest that the described type IIb Na/P_i-cotransporter represents a candidate for small intestinal apical Na/P_i-cotransport.     

Difference between human red blood cell Na+-Li+ countertransport and renal Na+-H+ exchange

Several laboratories have reported that the activities of sodium-lithium countertransport are increased in red blood cells from patients with essential hypertension. Based on the many similarities between this transport system and the renal sodium-proton exchanger, a hypothesis has been put forth in the literature that increased red blood cell sodium-lithium countertransport activity may be a marker for increased sodium-proton exchange activity in the renal proximal tubule. The present studies were designed to test the hypothesis that sodium-lithium countertransport in red blood cells from humans or rabbits is mediated by the same transport mechanism that mediates sodium-proton exchange in the renal brush border from those species. Similar to what has been reported for the rabbit, the present studies show that an amiloride-sensitive sodium-proton exchanger is present in human renal brush border vesicles. However, Na+-Li+ countertransport in human and rabbit red blood cells, assayed under several different conditions, was not inhibited by amiloride. In agreement with what has been reported for humans, the present studies show that extracellular proton-stimulated sodium efflux is inhibited by amiloride in rabbit red blood cells. These data demonstrate a difference (amiloride sensitivity) between the red blood cell sodium-lithium countertransporter and the renal brush border sodium-proton exchanger in humans and rabbits. These experiments detract from the hypothesis that increased red blood cell sodium-lithium countertransport activity in patients with essential hypertension is a marker for increased sodium-proton exchange activity in the renal brush border.     

Identification and characterization of the human type II collagen gene (COL2A1).

The gene contained in the human cosmid clone CosHcol1, previously designated an alpha 1(I) collagen-like gene, has now been identified. CosHcol1 hybridizes strongly to a single 5.9-kilobase mRNA species present only in tissue in which type II collagen is expressed. DNA sequence analysis shows that this clone is highly homologous to the chicken alpha 1(II) collagen gene. These data together suggest that CosHcol1 contains the human alpha 1(II) collagen gene COL2A1. The clone appears to contain the whole gene (30 kilobases in length) and will be extremely useful in the study of cartilage development and for identifying those inherited chondrodystrophies in which defects occur in this gene.     

Renal expression of the sodium/phosphate cotransporter gene, Npt2, is not required for regulation of renal 1 alpha-hydroxylase by phosphate

Several reports have suggested that the regulation of renal 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] synthesis by extracellular phosphate (Pi) is dependent on normal transepithelial Pi transport by the renal tubule. Mice homozygous for the disrupted Na/Pi cotransporter gene Npt2 (Npt2(-/-)) exhibit renal Pi wasting, an approximately 85% decrease in renal brush border membrane Na/Pi cotransport, hypophosphatemia, and an increase in serum 1,25-(OH)(2)D concentration. We undertook 1) to determine the mechanism for the increased circulating levels of 1,25-(OH)(2)D in Npt2(-/-) mice and 2) to establish whether renal 1alpha-hydroxylase was appropriately regulated by dietary Pi in the absence of Npt2 gene expression. On a control diet, the 2.5-fold increase in the serum 1,25-(OH)(2)D concentration in Npt2(-/-) mice, relative to that in Npt2(+/+) littermates, is associated with a corresponding increase in renal mitochondrial 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity and messenger RNA (mRNA) abundance. A low Pi diet elicits an increase in serum 1,25-(OH)(2)D concentration, renal 1alpha-hydroxylase activity, and mRNA abundance in Npt2(+/+) and Npt2(-/-) mice to similar levels in both mouse strains. A high Pi diet has no effect on serum 1,25-(OH)(2)D concentration, renal 1 alpha-hydroxylase activity, or mRNA abundance in Npt2(+/+) mice, but normalizes these parameters in Npt2(-/-) mice. In addition, renal 24-hydroxylase mRNA abundance is significantly reduced in Npt2(-/-) mice compared with that in Npt2(+/+) mice under all dietary conditions. In summary, we demonstrate that 1) increased renal synthesis of 1,25-(OH)(2)D is responsible for the increased serum 1,25-(OH)(2)D concentration in Npt2(-/-) mice; and 2) renal 1alpha-hydroxylase gene expression is appropriately regulated by dietary manipulation of serum Pi in both Npt2(+/+) and Npt2(-/-) mice. Thus, intact renal Na/Pi cotransport is not required for the regulation of renal 1alpha-hydroxylase by Pi.     

Sodium-glucose cotransporter type 2 inhibitors (SGLT2): from familial renal glucosuria to the treatment of type 2 diabetes mellitus

For centuries, the kidney has been considered primarily an organ of elimination and a regulator of salt and ion balance. Although once thought that the kidney was the structural cause of diabetes, which in recent years has been ignored as a regulator of glucose homeostasis, is now recognized as a major player in the field of metabolic regulation carbohydrate. During fasting, 55% of the glucose comes from gluconeogenesis. Only 2 organs have this capability: the liver and kidney. The latter is responsible for 20% of total glucose production and 40% of that produced by gluconeogenesis. Today we have a better understanding of the physiology of renal glucose transport via specific transporters, such as type 2 sodium-glucose cotransporter  (SGLT2). A natural compound, phlorizin, was isolated in early 1800 and for decades played an important role in diabetes and renal physiology research. Finally, at the nexus of these findings mentioned above, recognized the effect of phlorizin-like compounds in the renal glucose transporter, which has offered a new mechanism to treat hyperglycemia. This has led to the development of several potentially effective treatment modalities for the treatment of diabetes.     

Regulation of Na+ channels in lung alveolar type II epithelial cells

Amiloride-sensitive sodium channels in the lung play an important role in lung fluid balance. Particularly in the alveoli, sodium transport is closely regulated to maintain an appropriate fluid layer on the surface of the alveoli. Alveolar type II cells appear to play an important role in this sodium transport. In alveolar type II cells, there are a variety of different amiloride-sensitive, sodium-permeable channels. This significant diversity appears to play a role in both normal lung physiology and pathologic states. In many epithelial tissues, amiloride-sensitive epithelial sodium channels (ENaC) are formed from three subunit proteins designated alpha-ENaC, beta-ENaC, and gamma-ENaC. At least part of the diversity of sodium-permeable channels in lung arises from assembling different combinations of these subunits to form channels with different biophysical properties and different mechanisms for regulation. This leads to epithelial tissue in the lung that has enormous flexibility to alter the magnitude and regulation of salt and water transport. In this article, we discuss the regulation of ENaCs composed of varying subunits and some of the implications of the regulation for normal pulmonary function.     

Angiotensin II and Na+/H+ exchange in human blood platelets

Human blood platelets have a high potency for Na+/H+ exchange activity; they also bear receptors for angiotensin II (Ang II). To explore the effect of Ang II on the exchange, we have used a fluorimetric analysis capable of detecting cytoplasmic changes of 0.01 pH units in platelets, together with an Ang II preparation which has been proven to be effective as a vasoconstrictor. Thrombin and adenosine diphosphate (ADP) affected Na+/H+ exchange, but Ang II did not affect Na+/H+ exchange for a wide range of concentrations and experimental conditions. It is concluded that in contrast to its function in vascular smooth muscle cells, Ang II apparently does not play a role in the regulation of Na+/H+ exchange in human blood platelets.     

Oxidative stress causes renal angiotensin II type 1 receptor upregulation, Na+/H+ exchanger 3 overstimulation, and hypertension

Oxidative stress modulates angiotensin (Ang) II type 1 receptor (AT(1)R) expression and function. Ang II activates renal Na(+)/H(+) exchanger 3 (NHE3) to increase sodium reabsorption, but the mechanisms are still elusive. In addition, the upregulation of AT(1)R during oxidative stress could promote sodium retention and lead to an increase in blood pressure. Herein, we investigated the mechanism of Ang II-mediated, AT(1)R-dependent renal NHE3 regulation and effect of oxidative stress on AT(1)R signaling and development of hypertension. Male Sprague-Dawley rats received tap water (control) or 30 mmol/L of l-buthionine-sulfoximine, an oxidant, with and without 1 mmol/L of Tempol, an antioxidant, for 3 weeks. l-Buthionine-sulfoximine-treated rats exhibited oxidative stress and high blood pressure. Incubation of renal proximal tubules with Ang II caused significantly higher NHE3 activation in l-buthionine-sulfoximine-treated rats compared with control. The activation of NHE3 was sensitive to AT(1)R blocker and inhibitors of phospholipase C, tyrosine kinase, janus kinase 2 (Jak2), Ca(2+)-dependent calmodulin (CaM), and Ca(2+) chelator. Also, incubation of proximal tubules with Ang II caused Jak2-dependent CaM phosphorylation, which led to Jak2-CaM complex formation and increased Jak2-CaM interaction with NHE3. The activation of these signaling molecules was exaggerated in l-buthionine-sulfoximine-treated rats, whereas Tempol normalized the AT(1)R signaling. In conclusion, Ang II activates renal proximal tubular NHE3 through novel pathways that involve phospholipase C and an increase in intracellular Ca(2+), Jak2, and CaM. In addition, oxidative stress exaggerates Ang II signaling, which leads to overstimulation of renal NHE3 and contributes to an increase in blood pressure.     

Structure of human type II 5 alpha-reductase gene.

The best known activity of steroid 5 alpha-reductase is the transformation of testosterone into dihydrotestosterone, the most potent androgen. Two types of human steroid 5 alpha-reductase cDNAs and the type I gene have previously been isolated and characterized. This report describes the isolation and characterization of the human type II 5 alpha-reductase gene, the gene most likely responsible for male pseudohermaphroditism due to 5 alpha-reductase deficiency as well as the one presumed to be involved in a major androgen-related diseases such as prostate cancer and benign prostatic hyperplasia. The type II 5 alpha-reductase gene contains five exons of 352, 164, 102, 151 and 1695 bp, respectively, which share 43.8% to 64.1% homology with exons of the corresponding type I gene. These exons are separated by four introns of greater than 29, and approximately 2.3, 2.0 and 3.0 kb. Analysis of primer extension products by polyacrylamide gel electrophoresis as well as by subcloning and sequencing reveals a start site located 71 nucleotides upstream the ATG initiating codon.     

Regulation of the Na+/Ca2+ exchanger (NCX) in the murine embryonic heart

OBJECTIVE: The Na+/Ca2+ exchanger (NCX) is involved in embryonic heart development and function demonstrated by the abnormal myofibrillar organization, defects in heartbeat, and early embryonic death of NCX-null embryos. It was therefore the aim of our study to identify key functional regulators of the embryonic NCX. METHODS: NCX current (I(NCX)) density was measured as the Ni2+ (5 mM)-sensitive current applying the whole-cell patch-clamp technique in early (EDS, E10.5V) and late developmental stage (LDS, E16.5V) mouse ventricular cardiomyocytes. RESULTS: Compared to LDS, cardiomyocytes derived from EDS showed a significantly higher basal I(NCX) density for the I(NCX) forward (-120 mV: -4.1+/-1 pA/pF, n=15 versus -1.7+/-0.4, n=11, p<0.05) and reverse modes (+60 mV: 4.0+/-0.9 pA/pF, n=15 versus 1.8+/-0.4, n=11, p<0.05). There was 2-3-fold elevation of forward and reverse current in LDS on application of ATP-gamma-S (2 mM) together with forskolin (1 microM) as well as intracellular application of the catalytic subunit of cAMP-dependent protein kinase (cPKA, 200 U/mL), cAMP (200 microM), phorbol 12-myristate-13-acetate (PMA), a direct activator of protein kinase C (PKC), and 8-Br-cGMP, a membrane permeable analog of cGMP. The specific PKC inhibitor Ro 31-8220 significantly reduced I(NCX) by 70%. Co-application of 20 microM PKA inhibitor Fragment 14-22 (PKI), a specific inhibitor of PKA, and cAMP significantly reduced the exchanger activity by approx 60%. Despite these obvious effects in LDS we could not detect a significant impact of these compounds on I(NCX) in EDS-derived cardiomyocytes. Application of the alkaline phosphatase to test for constitutive phosphorylation of NCX did not affect I(NCX) density in LDS but led to an approx 80% reduction of I(NCX) in EDS. CONCLUSION: In EDS cardiomyocytes I(NCX) density is upregulated, at least in part by the high phosphorylation of the exchanger protein. At LDS, embryonic cardiomyocytes showed a strong increase of I(NCX) density upon stimulation by PKC- and PKA-dependent signalling pathways.     

Endothelin-1 stimulates the Na+/Ca2+ exchanger reverse mode through intracellular Na+ (Na+i)-dependent and Na+i-independent pathways

This study aimed to explore the signaling pathways involved in the positive inotropic effect (PIE) of low doses of endothelin-1 (ET-1). Cat papillary muscles were used for force and intracellular Na(+) concentration (Na(+)(i)) measurements, and isolated cat ventricular myocytes for patch-clamp experiments. ET-1 (5 nmol/L) induced a PIE and an associated increase in Na(+)(i) that were abolished by Na(+)/H(+) exchanger (NHE) inhibition with HOE642. Reverse-mode Na(+)/Ca(2+) exchanger (NCX) blockade with KB-R7943 reversed the ET-1-induced PIE. These results suggest that the ET-1-induced PIE is totally attributable to the NHE-mediated Na(+)(i) increase. However, an additional direct stimulating effect of ET-1 on NCX after the necessary increase in Na(+)(i) could occur. Thus, the ET-1-induced increase in Na(+)(i) and contractility was compared with that induced by partial inhibition of the Na(+)/K(+) ATPase by lowering extracellular K(+) (K(+)(o)). For a given Na(+)(i), ET-1 induced a greater PIE than low K(+)(o). In the presence of HOE642 and after increasing contractility and Na(+)(i) by low K(+)(o), ET-1 induced an additional PIE that was reversed by KB-R7943 or the protein kinase C (PKC) inhibitor chelerythrine. ET-1 increased the NCX current and negatively shifted the NCX reversal potential (E(NCX)). HOE642 attenuated the increase in NCX outward current and abolished the E(NCX) shift. These results indicate that whereas the NHE-mediated ET-1-induced increase in Na(+)(i) seems to be mandatory to drive NCX in reverse and enhance contractility, Na(+)(i)-independent and PKC-dependent NCX stimulation appears to additionally contribute to the PIE. However, it is important to stress that the latter can only occur after the primary participation of the former.     

Structure and expression of genes encoding murine Qa-2 class I antigens.

DNA structural analysis of the Qa region in two BALB/c mouse substrains with different Qa-2 phenotypes reveals that a deletion of DNA has occurred in BALB/cBy (Qa-2-) mice relative to BALB/c (Qa-2+) mice. We propose that this deletion arises from unequal crossing-over and recombination between adjacent BALB/c class I genes and results in the generation of a hybrid class I gene in BALB/cBy mice. Furthermore, we suggest that this is a direct cause of the change in Qa-2 phenotype. Further support for this model was obtained from transfection experiments in which cloned genes from the equivalent part of the Qa region in C57BL/10 mice were introduced into L cells. Four C57BL/10 genes, arranged in two almost identical pairs, encode polypeptides that are precipitated from lysates of transfectants with anti-Qa-2/3 antiserum. Although loss of one pair of these genes in BALB/c mice has no qualitative effect on Qa-2 phenotype, the loss of both pairs of genes via gene fusion leads to the loss of the Qa-2+ phenotype in BALB/cBy mice.     

人高亲和力钠依赖二羧酸转运蛋白3对人成纤维细胞衰老进程的影响

目的 探讨人高亲和力钠依赖二羧酸转运蛋白3(hNaDC3)在人胚肺二倍体成纤维细胞(WI38)衰老中的作用。方法 通过构建逆转录病毒载体．使用含有hNaDC3基因的逆转录病毒液将hNaDC3基因导入WI-38中．并获得表达．观察其对WI-38细胞衰老的影响。结果 与对照细胞相比，hNaDC3基因导入后．WI-38细胞传代数减少10～13代，生长速率降低40％．细胞周期阻滞于G期，细胞形态呈衰老细胞样变化．衰老相关-β-半乳糖苷酶(SA-β-gal)染色阳性率上升-线粒体膜电位下降。结论 hNaDC3可能促进人WI-38衰老。     

Selective induction of brain type II Na+ channels by nerve growth factor.

Cells derived from a rat pheochromocytoma (PC12 cells) can generate an action potential only upon treatment with nerve growth factor. Using electrophysiological methods, we found that the appearance of action potentials in nerve growth factor-treated PC12 cells can be explained by an increase in the density of Na+ channels. The functional properties of Na+ channels in PC12 cells are similar to those described for peripheral nerves but appear to be different from Na+ channels synthesized in Xenopus oocytes injected with brain type II Na+ -channel mRNA. To determine if PC12 cells express the brain type II Na+ -channel gene, we performed RNase-protection analyses using probes that can distinguish between the brain type I and type II Na+ -channel mRNAs. The results from these studies indicate that undifferentiated PC12 cells express the type II but not the type I Na+ -channel gene. Treatment with nerve growth factor increases expression of the type II Na+ -channel gene but has no effect on type I gene expression. Our findings suggest that Na+ -channel excitability in PC12 cells is due to the specific induction of the brain type II gene by nerve growth factor.     

Exon-intron organization and sequence comparison of human and murine T11 (CD2) genes.

Genomic DNA clones containing the human and murine genes coding for the 50-kDa T11 (CD2) T-cell surface glycoprotein were characterized. The human T11 gene is approximately equal to 12 kilobases long and comprised of five exons. A leader exon (L) contains the 5'-untranslated region and most of the nucleotides defining the signal peptide [amino acids (aa) -24 to -5]. Two exons encode the extracellular segment; exon Ex1 is 321 base pairs (bp) long and codes for four residues of the leader peptide and aa 1-103 of the mature protein, and exon Ex2 is 231 bp long and encodes aa 104-180. Exon TM is 123 bp long and codes for the single transmembrane region of the molecule (aa 181-221). Exon C is a large 765-bp exon encoding virtually the entire cytoplasmic domain (aa 222-327) and the 3'-untranslated region. The murine T11 gene has a similar organization with exon-intron boundaries essentially identical to the human gene. Substantial conservation of nucleotide sequences between species in both 5'- and 3'-gene flanking regions equivalent to that among homologous exons suggests that murine and human genes may be regulated in a similar fashion. The probable relationship of the individual T11 exons to functional and structural protein domains is discussed.     

Structure and phosphorylation of microtubule-associated protein 2 (MAP 2).

Chymotryptic fragments of microtubule-associated protein 2 (MAP 2) containing the portion of the molecule responsible for promoting microtubule assembly were identified. These assembly-promoting fragments displaced intact MAP 2, but not MAP 1, from assembled microtubules. This indicates that the association of MAP 2 with the microtubule surface is reversible. Both the assembly-promoting fragments and fragments representing the portion of the MAP 2 molecule observed as a projection on the microtubule surface were found to contain sites for endogenous cyclic AMP-dependent phosphorylation. The projection fragments were capable of endogenous phosphorylation even after their physical separation from microtubules. This suggests an intimate association of a kinase activity with the projections. Detailed analysis of the properties of the chymotryptic fragments of MAP 2 has led to a map of the molecule showing the major sites of proteolytic attack and the sites of phosphorylation.     

Efficacy,renal safety and tolerability of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in elderly patients with type 2 diabetes: A real-world experience

AimsTo evaluate efficacy, renal safety and tolerability of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in a cohort of patients with type 2 diabetes (T2DM) aged ≥65 years.MethodsWe retrospectively evaluated 364 elderly individuals with T2DM starting SGLT2i from June 2015 to June 2018. Patients were divided into 2 subgroups based on median age (70 years). Linear mixed effect models were used to estimate changes in glycated hemoglobin (HbA1c), body mass index (BMI), and glomerular filtration rate (eGFR). SGLT2i discontinuation rate and causes of treatment interruption were also recorded.ResultsA significantly higher percentage of patients achieved HbA1c <7.5% (46.7% vs. 31.6%, p < 0.01) and <8.0% (68.9% vs. 47.2%, p < 0.01) compared to baseline. Each year of therapy was associated with an average HbA1c decrease of 0.34% (p < 0.01) and BMI loss of 0.71 kg/m² (p < 0.01), without significant interaction across age classes. In the younger group eGFR increased by 1.02 ml/min/year, while in the older group it declined by 0.42 ml/min/year (p = 0.08). Overall discontinuation rate during the follow-up period was similar across age groups (34.2% vs. 36.1%, long-rank p = 0.26). Genitourinary infections were the most frequent cause of treatment interruption (15.8% vs. 17.2%, p = 0.69) in both study groups, while persistent eGFR decline (4.4%) and orthostatic hypotension (1.7%) were only present in older age class.ConclusionsEfficacy, renal safety and tolerability of SGLT2i were similar in people >70 compared to 65–70 years of age, suggesting that a wider use should not be worried even in the elderly. However, some caution must be paid to the occurrence of persistent eGFR decline and orthostatic hypotension, especially in patients >70 years old.