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(1) add-on therapy with LINA to EMPA increased USE in DKD rats compared with EMPA alone in association with the decrease in p-Nedd4-2 and ENaC expression in the kidneys, (2) EMPA + LINA therapy, but not EMPA treatment alone, significantly reduced serum Cre, proteinuria, urinary NAG excretion levels, mesangial matrix area, and ctgf gene expression in the kidneys of DKD rats, (3) combination therapy of EMPA and LINA increased USE and reduced sBP in DS mice, which were associated with the reduction in podocyte injury, mesangial matrix expansion, albuminuria, and ENaC expression in DS mice, whereas all of the parameters were not affected by EMPA treatment alone, (4) time-lagged acute administration of LINA to EMPA, but not concurrent administration of the two, or either EMPA or LINA alone, increased USE, and its effect was sustained during 3 h after the treatment, (5) HS + HG treatment upregulated ENaC expression in MDCTs, which was inhibited by LINA in association with the decreased p-Nedd4-2, whose effects were not enhanced by co-treatment of GLP-1, and (6) USE was higher and ENaC expression was lower in DKD patients who received combination therapy of DPP4is and SGLT2is than those without DPP4is

Importantly, repeated daily intrathecal injections of morroniside over seven days did not result in the development of tolerance to its anti-allodynic effects [73]

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